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Merkel Cell: Immunotherapy Not Used for Many Patients With Metastatic Disease
PHOENIX — Immunotherapy has revolutionized outcomes for patients are better at high-volume centers.
The study has important implications, said study author Shayan Cheraghlou, MD, an incoming fellow in Mohs surgery at New York University, New York City. “We can see that in a real-world setting, these agents have an impact on survival,” he said. “We also found high-volume centers were significantly more likely to use the agents than low-volume centers.” He presented the findings at the annual meeting of the American College of Mohs Surgery.
MCC is a neuroendocrine skin cancer with a high rate of mortality, and even though it remains relatively rare, its incidence has been rising rapidly since the late 1990s and continues to increase. There were no approved treatments available until 2017, when the US Food and Drug Administration (FDA) approved the immunotherapy drug avelumab (Bavencio) to treat advanced MCC. Two years later, pembrolizumab (Keytruda) also received regulatory approval for MCC, and these two agents have revolutionized outcomes.
“In clinical trial settings, these agents led to significant and durable responses, and they are now the recommended treatments in guidelines for metastatic Merkel cell carcinoma,” said Dr. Cheraghlou. “However, we don’t have data as to how they are being used in the real-world setting and if survival outcomes are similar.”
Real World vs Clinical Trials
Real-world outcomes can differ from clinical trial data, and the adoption of novel therapeutics can be gradual. The goal of this study was to see if clinical trial data matched what was being observed in actual clinical use and if the agents were being used uniformly in centers across the United States.
The authors used data from the National Cancer Database that included patients diagnosed with cancer from 2004 to 2019 and identified 1017 adult cases of metastatic MCC. They then looked at the association of a variety of patient characteristics, tumors, and system factors with the likelihood of receiving systemic treatment for their disease.
“Our first finding was maybe the least surprising,” he said. “Patients who received these therapeutic agents had significantly improved survival compared to those who have not.”
Those who received immunotherapy had a 35% decrease in the risk for death per year compared with those who did not. The 1-, 3-, and 5-year survival rates were 47.2%, 21.8%, and 16.5%, respectively, for patients who did not receive immunotherapy compared with 62.7%, 34.4%, and 23.6%, respectively, for those who were treated with these agents.
Dr. Cheraghlou noted that they started to get some “surprising” findings when they looked at utilization data. “While it has been increasing over time, it is not as high as it should be,” he emphasized.
From 2017 to 2019, 54.2% of patients with metastatic MCC received immunotherapy. The data also showed an increase in use from 45.1% in 2017 to 63.0% in 2019. “This is an effective treatment for aggressive malignancy, so we have to ask why more patients aren’t getting them,” said Dr. Cheraghlou.
Their findings did suggest one possible reason, and that was that high-volume centers were significantly more likely to use the agents than low-volume centers. Centers that were in the top percentile for MCC case volume were three times as likely to use immunotherapy for MCC compared with other institutions. “So, if you have metastatic Merkel cell carcinoma and go to a low volume center, you may be less likely to get potential lifesaving treatment,” he noted.
Implications Going Forward
Dr. Cheraghlou concluded his presentation by pointing out that this study has important implications. The data showed that in a real-world setting, these agents have an impact on survival, but all eligible patients do not have access. “In other countries, there are established referral patterns for all patients with aggressive rare malignancies and really all cancers,” he added. “But in the US, cancer care is more decentralized. Studies like this and others show that high-volume centers have much better outcomes for aggressive rare malignancies, and we should be looking at why this is the case and mitigating these disparities and outcomes.”
Commenting on the study results, Jeffrey M. Farma, MD, co-director of the Melanoma and Skin Cancer Program and professor of surgical oncology at Fox Chase Cancer Center, Philadelphia, referred to the two immunotherapies that have been approved for MCC since 2017, which have demonstrated a survival benefit and improved outcomes in patients with metastatic MCC.
“In their study, immunotherapy was associated with improved outcomes,” said Dr. Farma. “This study highlights the continued lag of implementation of guidelines when new therapies are approved, and that for rare cancers like Merkel cell carcinoma, being treated at high-volume centers and the regionalization of care can lead to improved outcomes for patients.”
Dr. Cheraghlou and Dr. Farma had no disclosures.
A version of this article appeared on Medscape.com.
PHOENIX — Immunotherapy has revolutionized outcomes for patients are better at high-volume centers.
The study has important implications, said study author Shayan Cheraghlou, MD, an incoming fellow in Mohs surgery at New York University, New York City. “We can see that in a real-world setting, these agents have an impact on survival,” he said. “We also found high-volume centers were significantly more likely to use the agents than low-volume centers.” He presented the findings at the annual meeting of the American College of Mohs Surgery.
MCC is a neuroendocrine skin cancer with a high rate of mortality, and even though it remains relatively rare, its incidence has been rising rapidly since the late 1990s and continues to increase. There were no approved treatments available until 2017, when the US Food and Drug Administration (FDA) approved the immunotherapy drug avelumab (Bavencio) to treat advanced MCC. Two years later, pembrolizumab (Keytruda) also received regulatory approval for MCC, and these two agents have revolutionized outcomes.
“In clinical trial settings, these agents led to significant and durable responses, and they are now the recommended treatments in guidelines for metastatic Merkel cell carcinoma,” said Dr. Cheraghlou. “However, we don’t have data as to how they are being used in the real-world setting and if survival outcomes are similar.”
Real World vs Clinical Trials
Real-world outcomes can differ from clinical trial data, and the adoption of novel therapeutics can be gradual. The goal of this study was to see if clinical trial data matched what was being observed in actual clinical use and if the agents were being used uniformly in centers across the United States.
The authors used data from the National Cancer Database that included patients diagnosed with cancer from 2004 to 2019 and identified 1017 adult cases of metastatic MCC. They then looked at the association of a variety of patient characteristics, tumors, and system factors with the likelihood of receiving systemic treatment for their disease.
“Our first finding was maybe the least surprising,” he said. “Patients who received these therapeutic agents had significantly improved survival compared to those who have not.”
Those who received immunotherapy had a 35% decrease in the risk for death per year compared with those who did not. The 1-, 3-, and 5-year survival rates were 47.2%, 21.8%, and 16.5%, respectively, for patients who did not receive immunotherapy compared with 62.7%, 34.4%, and 23.6%, respectively, for those who were treated with these agents.
Dr. Cheraghlou noted that they started to get some “surprising” findings when they looked at utilization data. “While it has been increasing over time, it is not as high as it should be,” he emphasized.
From 2017 to 2019, 54.2% of patients with metastatic MCC received immunotherapy. The data also showed an increase in use from 45.1% in 2017 to 63.0% in 2019. “This is an effective treatment for aggressive malignancy, so we have to ask why more patients aren’t getting them,” said Dr. Cheraghlou.
Their findings did suggest one possible reason, and that was that high-volume centers were significantly more likely to use the agents than low-volume centers. Centers that were in the top percentile for MCC case volume were three times as likely to use immunotherapy for MCC compared with other institutions. “So, if you have metastatic Merkel cell carcinoma and go to a low volume center, you may be less likely to get potential lifesaving treatment,” he noted.
Implications Going Forward
Dr. Cheraghlou concluded his presentation by pointing out that this study has important implications. The data showed that in a real-world setting, these agents have an impact on survival, but all eligible patients do not have access. “In other countries, there are established referral patterns for all patients with aggressive rare malignancies and really all cancers,” he added. “But in the US, cancer care is more decentralized. Studies like this and others show that high-volume centers have much better outcomes for aggressive rare malignancies, and we should be looking at why this is the case and mitigating these disparities and outcomes.”
Commenting on the study results, Jeffrey M. Farma, MD, co-director of the Melanoma and Skin Cancer Program and professor of surgical oncology at Fox Chase Cancer Center, Philadelphia, referred to the two immunotherapies that have been approved for MCC since 2017, which have demonstrated a survival benefit and improved outcomes in patients with metastatic MCC.
“In their study, immunotherapy was associated with improved outcomes,” said Dr. Farma. “This study highlights the continued lag of implementation of guidelines when new therapies are approved, and that for rare cancers like Merkel cell carcinoma, being treated at high-volume centers and the regionalization of care can lead to improved outcomes for patients.”
Dr. Cheraghlou and Dr. Farma had no disclosures.
A version of this article appeared on Medscape.com.
PHOENIX — Immunotherapy has revolutionized outcomes for patients are better at high-volume centers.
The study has important implications, said study author Shayan Cheraghlou, MD, an incoming fellow in Mohs surgery at New York University, New York City. “We can see that in a real-world setting, these agents have an impact on survival,” he said. “We also found high-volume centers were significantly more likely to use the agents than low-volume centers.” He presented the findings at the annual meeting of the American College of Mohs Surgery.
MCC is a neuroendocrine skin cancer with a high rate of mortality, and even though it remains relatively rare, its incidence has been rising rapidly since the late 1990s and continues to increase. There were no approved treatments available until 2017, when the US Food and Drug Administration (FDA) approved the immunotherapy drug avelumab (Bavencio) to treat advanced MCC. Two years later, pembrolizumab (Keytruda) also received regulatory approval for MCC, and these two agents have revolutionized outcomes.
“In clinical trial settings, these agents led to significant and durable responses, and they are now the recommended treatments in guidelines for metastatic Merkel cell carcinoma,” said Dr. Cheraghlou. “However, we don’t have data as to how they are being used in the real-world setting and if survival outcomes are similar.”
Real World vs Clinical Trials
Real-world outcomes can differ from clinical trial data, and the adoption of novel therapeutics can be gradual. The goal of this study was to see if clinical trial data matched what was being observed in actual clinical use and if the agents were being used uniformly in centers across the United States.
The authors used data from the National Cancer Database that included patients diagnosed with cancer from 2004 to 2019 and identified 1017 adult cases of metastatic MCC. They then looked at the association of a variety of patient characteristics, tumors, and system factors with the likelihood of receiving systemic treatment for their disease.
“Our first finding was maybe the least surprising,” he said. “Patients who received these therapeutic agents had significantly improved survival compared to those who have not.”
Those who received immunotherapy had a 35% decrease in the risk for death per year compared with those who did not. The 1-, 3-, and 5-year survival rates were 47.2%, 21.8%, and 16.5%, respectively, for patients who did not receive immunotherapy compared with 62.7%, 34.4%, and 23.6%, respectively, for those who were treated with these agents.
Dr. Cheraghlou noted that they started to get some “surprising” findings when they looked at utilization data. “While it has been increasing over time, it is not as high as it should be,” he emphasized.
From 2017 to 2019, 54.2% of patients with metastatic MCC received immunotherapy. The data also showed an increase in use from 45.1% in 2017 to 63.0% in 2019. “This is an effective treatment for aggressive malignancy, so we have to ask why more patients aren’t getting them,” said Dr. Cheraghlou.
Their findings did suggest one possible reason, and that was that high-volume centers were significantly more likely to use the agents than low-volume centers. Centers that were in the top percentile for MCC case volume were three times as likely to use immunotherapy for MCC compared with other institutions. “So, if you have metastatic Merkel cell carcinoma and go to a low volume center, you may be less likely to get potential lifesaving treatment,” he noted.
Implications Going Forward
Dr. Cheraghlou concluded his presentation by pointing out that this study has important implications. The data showed that in a real-world setting, these agents have an impact on survival, but all eligible patients do not have access. “In other countries, there are established referral patterns for all patients with aggressive rare malignancies and really all cancers,” he added. “But in the US, cancer care is more decentralized. Studies like this and others show that high-volume centers have much better outcomes for aggressive rare malignancies, and we should be looking at why this is the case and mitigating these disparities and outcomes.”
Commenting on the study results, Jeffrey M. Farma, MD, co-director of the Melanoma and Skin Cancer Program and professor of surgical oncology at Fox Chase Cancer Center, Philadelphia, referred to the two immunotherapies that have been approved for MCC since 2017, which have demonstrated a survival benefit and improved outcomes in patients with metastatic MCC.
“In their study, immunotherapy was associated with improved outcomes,” said Dr. Farma. “This study highlights the continued lag of implementation of guidelines when new therapies are approved, and that for rare cancers like Merkel cell carcinoma, being treated at high-volume centers and the regionalization of care can lead to improved outcomes for patients.”
Dr. Cheraghlou and Dr. Farma had no disclosures.
A version of this article appeared on Medscape.com.
FROM ACMS 2024
Use of Radiotherapy for Nonmelanoma Skin Cancer Increasing, Study Finds
PHOENIX — More specifically, the persistent growth in the use of superficial radiotherapy (SRT) devices and electronic brachytherapy (eBT) to treat nonmelanoma skin cancer (NMSC) has exceeded that of traditional procedures among dermatologists using these modalities, according to Christian Gronbeck, MD, a resident in dermatology at the University of Connecticut Health Center, Farmington.
“These services increased substantially over the study period,” Dr. Gronbeck said at the annual meeting of the American College of Mohs Surgery, where he presented the results of the study. “Our findings suggest that those using eBT/SRT were frequently general dermatologists and non-fellowship–trained Mohs surgeons who have less formalized surgical training.”
He also noted that billing for these services also rose substantially, which is being driven by growing utilization and an increased SRT payment rate.
Surgical approaches are standard for most NMSC cases, but some patients are not good surgical candidates because of medical comorbidities and/or other factors, and radiotherapy is emerging as a potential treatment option for those patients. Traditionally, radiotherapy was administered by radiation oncologists, but with the growing availability of SRT devices and the introduction of eBT, dermatologists are now treating patients with these modalities.
“It is a potential treatment option for nonmelanoma skin cancer and keloids, and these lower energy devices can be used in the outpatient setting,” said Dr. Gronbeck. “Treatment typically involves a series of fractions over a period of several weeks. There has been recent growth in the use of radiotherapy despite this being a secondary option in skin cancer, primarily when surgery is contraindicated.”
Steady Expansion of Use
Dr. Gronbeck and colleagues sought to gain a better understanding of the use of SRT and eBT for NMSC among dermatologists, as well as trends in cost. Data were obtained from the 2016-2021 Medicare Public Use Files to evaluate the trend in the volume of Medicare Part B claims for eBT (CPT 0394T) and SRT (CPT 77401) by dermatologists, and they also looked at related billable services for radiotherapy.
Of 12,050 dermatologists, 293 (2.4%) were identified as utilizing eBT or SRT in 2021, representing a 75.4% increase from 2016. The usage of both eBT and SRT increased by 59.6% and 148.4%, respectively, from 2016 to 2021.
There were notable geographic differences in the utilization of radiotherapy. “Florida, California, Texas, and Arizona had the highest utilization,” Dr. Gronbeck said, although during the study period, utilization increased in other states, including North Carolina and Alabama.
When looking at geographic regions as a whole, the highest number of dermatologists using radiotherapy were located in the South (n = 143, 50.9%), followed by the West (n = 69, 23.6%). Utilization was more common in metro areas than in nonmetro/rural areas (86% vs 14%).
Differences were also noted among dermatologists. Those who performed eBT/SRT than those who did not were significantly more likely to have had 15 or more years of independent practice (70.1% vs 48.6%), be in a small private dermatology practice (62.7% vs 47.5%), and be non–fellowship-trained Mohs surgeons (33.5% vs 10.2%). Dermatologists utilizing radiotherapy were also more likely to treat Medicare beneficiaries who were older, with a mean age over 75 years (39.3% vs 31.1%) and a mean hierarchical condition category (HCC) score, above the national average (55.2% vs 44.6%).
Dr. Gronbeck and colleagues also looked at cost. The number of direct payments for eBT/SRT payments increased throughout the study period, from 3,678,224 in 2016 to 11,680,925 in 2021, nearly a 218% increase. The change in payments for services related to eBT/SRT, such as radiotherapy simulation, radiotherapy dosing, and ultrasound guidance, increased by 621.4% during this same timeframe.
Radiotherapy in dermatology has primarily been assessed through retrospective studies. “Our findings suggest that eBT and SRT are more frequently utilized by dermatologists managing older and sicker patients, but further studies are needed to identify whether these interventions are truly addressing poor surgical candidates,” Dr. Gronbeck said.
The Centers for Medicare & Medicaid Services (CMS) has recently proposed changes in Medicare coverage in seven states for Image-Guided Superficial Radiation Therapy (image-guided SRT or IGSRT) for the treatment of NMSC. The proposed local coverage determination, or LCD, if finalized in its current form, would affect residents in North Carolina, South Carolina, Virginia, West Virginia, Alabama, Georgia, and Tennessee.
“These changes would mean more restrictive coverage,” said Dr. Gronbeck, and further support the need for “improved clinical data and development of guidelines to support evidence-based utilization.”
Surgical Management Standard, but SRT Has a Role
Asked to comment on the findings, Seemal R. Desai, MD, president of the American Academy of Dermatology (AAD), who was not involved with the study, reiterated that according to this abstract, efficacy has mainly been assessed through retrospective studies, and results are likely inferior to Mohs surgery, require multiple treatment visits, and are associated with significant costs. More study is needed for the use of radiation therapy in dermatology, he told this news organization.
“The Academy supports continued research and studies for therapies that can help improve patient outcomes and offer treatment options, as well as further studies on long-term outcomes for treatments like superficial radiation therapy,” he said.
“Well-designed studies can certainly be helpful to better assess efficacy and outcomes,” Dr. Desai continued. “This is why the Academy supports the idea of scientific studies that continue to expand the body of literature and data, which can help dermatologists tailor therapeutic options for their patients.”
As for general dermatologists using radiation therapy, he pointed out that SRT was developed within the dermatology specialty with dermatologists being the experts in delivering SRT for patients with NMSCs when indicated. “SRT has been used for over 100 years to treat skin cancer,” said Dr. Desai, of the department of dermatology, UT Southwestern Medical Center, Dallas. “While certain radiation devices have historically been used by dermatologists, dermatologists engaged in providing superficial radiation therapy must have adequate education and training to administer this therapy safely and effectively.”
The AAD Association (AADA) has a position statement that supports the use of SRT as an option for the treatment of basal cell carcinoma and squamous cell carcinoma in certain circumstances. “This could be when surgical intervention is contraindicated or refused and after the benefits and risk of treatment alternatives have been discussed with the patient,” he said. “Based on current evidence, surgical management remains the most effective treatment for NMSC.”
Dr. Desai added that the AADA is also concerned that if the Proposed LCD is finalized by CMS, it “could restrict dermatologists from performing SRT and impede patient access to SRT as a potential treatment when indicated.”
The study was independently supported. Dr. Gronbeck and Dr. Desai reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
PHOENIX — More specifically, the persistent growth in the use of superficial radiotherapy (SRT) devices and electronic brachytherapy (eBT) to treat nonmelanoma skin cancer (NMSC) has exceeded that of traditional procedures among dermatologists using these modalities, according to Christian Gronbeck, MD, a resident in dermatology at the University of Connecticut Health Center, Farmington.
“These services increased substantially over the study period,” Dr. Gronbeck said at the annual meeting of the American College of Mohs Surgery, where he presented the results of the study. “Our findings suggest that those using eBT/SRT were frequently general dermatologists and non-fellowship–trained Mohs surgeons who have less formalized surgical training.”
He also noted that billing for these services also rose substantially, which is being driven by growing utilization and an increased SRT payment rate.
Surgical approaches are standard for most NMSC cases, but some patients are not good surgical candidates because of medical comorbidities and/or other factors, and radiotherapy is emerging as a potential treatment option for those patients. Traditionally, radiotherapy was administered by radiation oncologists, but with the growing availability of SRT devices and the introduction of eBT, dermatologists are now treating patients with these modalities.
“It is a potential treatment option for nonmelanoma skin cancer and keloids, and these lower energy devices can be used in the outpatient setting,” said Dr. Gronbeck. “Treatment typically involves a series of fractions over a period of several weeks. There has been recent growth in the use of radiotherapy despite this being a secondary option in skin cancer, primarily when surgery is contraindicated.”
Steady Expansion of Use
Dr. Gronbeck and colleagues sought to gain a better understanding of the use of SRT and eBT for NMSC among dermatologists, as well as trends in cost. Data were obtained from the 2016-2021 Medicare Public Use Files to evaluate the trend in the volume of Medicare Part B claims for eBT (CPT 0394T) and SRT (CPT 77401) by dermatologists, and they also looked at related billable services for radiotherapy.
Of 12,050 dermatologists, 293 (2.4%) were identified as utilizing eBT or SRT in 2021, representing a 75.4% increase from 2016. The usage of both eBT and SRT increased by 59.6% and 148.4%, respectively, from 2016 to 2021.
There were notable geographic differences in the utilization of radiotherapy. “Florida, California, Texas, and Arizona had the highest utilization,” Dr. Gronbeck said, although during the study period, utilization increased in other states, including North Carolina and Alabama.
When looking at geographic regions as a whole, the highest number of dermatologists using radiotherapy were located in the South (n = 143, 50.9%), followed by the West (n = 69, 23.6%). Utilization was more common in metro areas than in nonmetro/rural areas (86% vs 14%).
Differences were also noted among dermatologists. Those who performed eBT/SRT than those who did not were significantly more likely to have had 15 or more years of independent practice (70.1% vs 48.6%), be in a small private dermatology practice (62.7% vs 47.5%), and be non–fellowship-trained Mohs surgeons (33.5% vs 10.2%). Dermatologists utilizing radiotherapy were also more likely to treat Medicare beneficiaries who were older, with a mean age over 75 years (39.3% vs 31.1%) and a mean hierarchical condition category (HCC) score, above the national average (55.2% vs 44.6%).
Dr. Gronbeck and colleagues also looked at cost. The number of direct payments for eBT/SRT payments increased throughout the study period, from 3,678,224 in 2016 to 11,680,925 in 2021, nearly a 218% increase. The change in payments for services related to eBT/SRT, such as radiotherapy simulation, radiotherapy dosing, and ultrasound guidance, increased by 621.4% during this same timeframe.
Radiotherapy in dermatology has primarily been assessed through retrospective studies. “Our findings suggest that eBT and SRT are more frequently utilized by dermatologists managing older and sicker patients, but further studies are needed to identify whether these interventions are truly addressing poor surgical candidates,” Dr. Gronbeck said.
The Centers for Medicare & Medicaid Services (CMS) has recently proposed changes in Medicare coverage in seven states for Image-Guided Superficial Radiation Therapy (image-guided SRT or IGSRT) for the treatment of NMSC. The proposed local coverage determination, or LCD, if finalized in its current form, would affect residents in North Carolina, South Carolina, Virginia, West Virginia, Alabama, Georgia, and Tennessee.
“These changes would mean more restrictive coverage,” said Dr. Gronbeck, and further support the need for “improved clinical data and development of guidelines to support evidence-based utilization.”
Surgical Management Standard, but SRT Has a Role
Asked to comment on the findings, Seemal R. Desai, MD, president of the American Academy of Dermatology (AAD), who was not involved with the study, reiterated that according to this abstract, efficacy has mainly been assessed through retrospective studies, and results are likely inferior to Mohs surgery, require multiple treatment visits, and are associated with significant costs. More study is needed for the use of radiation therapy in dermatology, he told this news organization.
“The Academy supports continued research and studies for therapies that can help improve patient outcomes and offer treatment options, as well as further studies on long-term outcomes for treatments like superficial radiation therapy,” he said.
“Well-designed studies can certainly be helpful to better assess efficacy and outcomes,” Dr. Desai continued. “This is why the Academy supports the idea of scientific studies that continue to expand the body of literature and data, which can help dermatologists tailor therapeutic options for their patients.”
As for general dermatologists using radiation therapy, he pointed out that SRT was developed within the dermatology specialty with dermatologists being the experts in delivering SRT for patients with NMSCs when indicated. “SRT has been used for over 100 years to treat skin cancer,” said Dr. Desai, of the department of dermatology, UT Southwestern Medical Center, Dallas. “While certain radiation devices have historically been used by dermatologists, dermatologists engaged in providing superficial radiation therapy must have adequate education and training to administer this therapy safely and effectively.”
The AAD Association (AADA) has a position statement that supports the use of SRT as an option for the treatment of basal cell carcinoma and squamous cell carcinoma in certain circumstances. “This could be when surgical intervention is contraindicated or refused and after the benefits and risk of treatment alternatives have been discussed with the patient,” he said. “Based on current evidence, surgical management remains the most effective treatment for NMSC.”
Dr. Desai added that the AADA is also concerned that if the Proposed LCD is finalized by CMS, it “could restrict dermatologists from performing SRT and impede patient access to SRT as a potential treatment when indicated.”
The study was independently supported. Dr. Gronbeck and Dr. Desai reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
PHOENIX — More specifically, the persistent growth in the use of superficial radiotherapy (SRT) devices and electronic brachytherapy (eBT) to treat nonmelanoma skin cancer (NMSC) has exceeded that of traditional procedures among dermatologists using these modalities, according to Christian Gronbeck, MD, a resident in dermatology at the University of Connecticut Health Center, Farmington.
“These services increased substantially over the study period,” Dr. Gronbeck said at the annual meeting of the American College of Mohs Surgery, where he presented the results of the study. “Our findings suggest that those using eBT/SRT were frequently general dermatologists and non-fellowship–trained Mohs surgeons who have less formalized surgical training.”
He also noted that billing for these services also rose substantially, which is being driven by growing utilization and an increased SRT payment rate.
Surgical approaches are standard for most NMSC cases, but some patients are not good surgical candidates because of medical comorbidities and/or other factors, and radiotherapy is emerging as a potential treatment option for those patients. Traditionally, radiotherapy was administered by radiation oncologists, but with the growing availability of SRT devices and the introduction of eBT, dermatologists are now treating patients with these modalities.
“It is a potential treatment option for nonmelanoma skin cancer and keloids, and these lower energy devices can be used in the outpatient setting,” said Dr. Gronbeck. “Treatment typically involves a series of fractions over a period of several weeks. There has been recent growth in the use of radiotherapy despite this being a secondary option in skin cancer, primarily when surgery is contraindicated.”
Steady Expansion of Use
Dr. Gronbeck and colleagues sought to gain a better understanding of the use of SRT and eBT for NMSC among dermatologists, as well as trends in cost. Data were obtained from the 2016-2021 Medicare Public Use Files to evaluate the trend in the volume of Medicare Part B claims for eBT (CPT 0394T) and SRT (CPT 77401) by dermatologists, and they also looked at related billable services for radiotherapy.
Of 12,050 dermatologists, 293 (2.4%) were identified as utilizing eBT or SRT in 2021, representing a 75.4% increase from 2016. The usage of both eBT and SRT increased by 59.6% and 148.4%, respectively, from 2016 to 2021.
There were notable geographic differences in the utilization of radiotherapy. “Florida, California, Texas, and Arizona had the highest utilization,” Dr. Gronbeck said, although during the study period, utilization increased in other states, including North Carolina and Alabama.
When looking at geographic regions as a whole, the highest number of dermatologists using radiotherapy were located in the South (n = 143, 50.9%), followed by the West (n = 69, 23.6%). Utilization was more common in metro areas than in nonmetro/rural areas (86% vs 14%).
Differences were also noted among dermatologists. Those who performed eBT/SRT than those who did not were significantly more likely to have had 15 or more years of independent practice (70.1% vs 48.6%), be in a small private dermatology practice (62.7% vs 47.5%), and be non–fellowship-trained Mohs surgeons (33.5% vs 10.2%). Dermatologists utilizing radiotherapy were also more likely to treat Medicare beneficiaries who were older, with a mean age over 75 years (39.3% vs 31.1%) and a mean hierarchical condition category (HCC) score, above the national average (55.2% vs 44.6%).
Dr. Gronbeck and colleagues also looked at cost. The number of direct payments for eBT/SRT payments increased throughout the study period, from 3,678,224 in 2016 to 11,680,925 in 2021, nearly a 218% increase. The change in payments for services related to eBT/SRT, such as radiotherapy simulation, radiotherapy dosing, and ultrasound guidance, increased by 621.4% during this same timeframe.
Radiotherapy in dermatology has primarily been assessed through retrospective studies. “Our findings suggest that eBT and SRT are more frequently utilized by dermatologists managing older and sicker patients, but further studies are needed to identify whether these interventions are truly addressing poor surgical candidates,” Dr. Gronbeck said.
The Centers for Medicare & Medicaid Services (CMS) has recently proposed changes in Medicare coverage in seven states for Image-Guided Superficial Radiation Therapy (image-guided SRT or IGSRT) for the treatment of NMSC. The proposed local coverage determination, or LCD, if finalized in its current form, would affect residents in North Carolina, South Carolina, Virginia, West Virginia, Alabama, Georgia, and Tennessee.
“These changes would mean more restrictive coverage,” said Dr. Gronbeck, and further support the need for “improved clinical data and development of guidelines to support evidence-based utilization.”
Surgical Management Standard, but SRT Has a Role
Asked to comment on the findings, Seemal R. Desai, MD, president of the American Academy of Dermatology (AAD), who was not involved with the study, reiterated that according to this abstract, efficacy has mainly been assessed through retrospective studies, and results are likely inferior to Mohs surgery, require multiple treatment visits, and are associated with significant costs. More study is needed for the use of radiation therapy in dermatology, he told this news organization.
“The Academy supports continued research and studies for therapies that can help improve patient outcomes and offer treatment options, as well as further studies on long-term outcomes for treatments like superficial radiation therapy,” he said.
“Well-designed studies can certainly be helpful to better assess efficacy and outcomes,” Dr. Desai continued. “This is why the Academy supports the idea of scientific studies that continue to expand the body of literature and data, which can help dermatologists tailor therapeutic options for their patients.”
As for general dermatologists using radiation therapy, he pointed out that SRT was developed within the dermatology specialty with dermatologists being the experts in delivering SRT for patients with NMSCs when indicated. “SRT has been used for over 100 years to treat skin cancer,” said Dr. Desai, of the department of dermatology, UT Southwestern Medical Center, Dallas. “While certain radiation devices have historically been used by dermatologists, dermatologists engaged in providing superficial radiation therapy must have adequate education and training to administer this therapy safely and effectively.”
The AAD Association (AADA) has a position statement that supports the use of SRT as an option for the treatment of basal cell carcinoma and squamous cell carcinoma in certain circumstances. “This could be when surgical intervention is contraindicated or refused and after the benefits and risk of treatment alternatives have been discussed with the patient,” he said. “Based on current evidence, surgical management remains the most effective treatment for NMSC.”
Dr. Desai added that the AADA is also concerned that if the Proposed LCD is finalized by CMS, it “could restrict dermatologists from performing SRT and impede patient access to SRT as a potential treatment when indicated.”
The study was independently supported. Dr. Gronbeck and Dr. Desai reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM ACMS 2024
Post–Mohs Surgery Opioid Prescribing More Common in Some Patient Groups
PHOENIX — The study also found that patients who do receive opioids postoperatively are at an increased risk for chronic opioid use and complications.
This report represents the largest analysis to date of opioid prescribing after dermatologic surgery, said lead author Kyle C. Lauck, MD, a dermatology resident at Baylor University Medical Center, Dallas, Texas. “Females, African Americans, and Latino patients may be at a higher risk of opioid prescription after dermatologic surgery. Surgeons should be aware of these populations and the risks they face when determining candidacy for postsurgical opioid analgesia.”
He presented the results at the annual meeting of the American College of Mohs Surgery.
The opioid epidemic is a concern across all areas of medicine, and the majority of opioid prescriptions in dermatology are given following surgery. Dr. Lauck noted that even though guidelines delegate opioids as second line for pain control, the existing data on opioid prescribing in dermatologic surgery is mixed. For example, some reports have shown that up to 58% of patients receive opioids postoperatively. “No consensus exists when we should routinely give opioids to these patients,” he said.
Even though most surgeons prescribe short courses of opioids, even brief regimens are associated with increased risks for overuse and substance abuse. Population-level data are limited concerning opioid prescriptions in dermatologic surgery, and in particular, there is an absence of data on the risk for long-term complications associated with use.
Certain Populations at Risk
To evaluate opioid prescription rates in dermatologic surgery, focusing on disparities between demographic populations, as well as the risk for long-term complications of postoperative opioid prescriptions, Dr. Lauck and colleagues conducted a retrospective study that included 914,721 dermatologic surgery patients, with billing codes for Mohs micrographic surgery. Patient data were obtained from TriNetX, a federated health research network.
The mean age of patients in this cohort was 54 years, and 124,494 (13.6%) were prescribed postsurgical oral opioids. The most common was oxycodone, prescribed to 43% of patients. Dr. Lauck noted that, according to their data, certain groups appeared more likely to receive a prescription for opioids following surgery. These included Black or African American patients (23.75% vs 12.86% for White patients), females (13.73% vs 13.16% for males), and Latino or Hispanic patients (17.02% vs 13.61% non-Latino/Hispanic patients).
Patients with a history of prior oral opioid prescription, prior opioid abuse or dependence, and any type of substance abuse had a significant increase in absolute risk of being prescribed postsurgical opioids (P < .0001).
The type of surgery also was associated with prescribed postop opioids. For a malignant excision, 18.29% of patients were prescribed postop opioids compared with 14.9% for a benign excision. About a third of patients (34.9%) undergoing a graft repair received opioids.
There was an elevated rate of postop opioid prescribing that was specific to the site of surgery, with the highest rates observed with eyelids, scalp and neck, trunk, and genital sites. The highest overall rates of opioid prescriptions were for patients who underwent excisions in the genital area (54.5%).
Long-Term Consequences
The authors also looked at the longer-term consequences of postop opioid use. “Nearly one in three patients who were prescribed opioids needed subsequent prescriptions down the line,” said Dr. Lauck.
From 3 months to 5 years after surgery, patients who received postsurgical opioids were at significantly higher risk for not only subsequent oral opioid prescription but also opiate abuse, any substance abuse, overdose by opioid narcotics, constipation, and chronic pain. “An opioid prescription may confer further risks of longitudinal complications of chronic opioid use,” he concluded.
Commenting on the study, Jesse M. Lewin, MD, chief of Mohs micrographic and dermatologic surgery at Icahn School of Medicine at Mount Sinai, New York City, noted an important finding of this study was the long-term sequelae of patients who did receive postop opioids.
“This is striking given that postsurgical opiate prescriptions are for short durations and limited number of pills,” he told this news organization. “This study highlights the potential danger of even short course of opiates and should serve as a reminder to dermatologic surgeons to be judicious about opiate prescribing.”
Dr. Lauck and Dr. Lewin had no disclosures.
A version of this article appeared on Medscape.com.
PHOENIX — The study also found that patients who do receive opioids postoperatively are at an increased risk for chronic opioid use and complications.
This report represents the largest analysis to date of opioid prescribing after dermatologic surgery, said lead author Kyle C. Lauck, MD, a dermatology resident at Baylor University Medical Center, Dallas, Texas. “Females, African Americans, and Latino patients may be at a higher risk of opioid prescription after dermatologic surgery. Surgeons should be aware of these populations and the risks they face when determining candidacy for postsurgical opioid analgesia.”
He presented the results at the annual meeting of the American College of Mohs Surgery.
The opioid epidemic is a concern across all areas of medicine, and the majority of opioid prescriptions in dermatology are given following surgery. Dr. Lauck noted that even though guidelines delegate opioids as second line for pain control, the existing data on opioid prescribing in dermatologic surgery is mixed. For example, some reports have shown that up to 58% of patients receive opioids postoperatively. “No consensus exists when we should routinely give opioids to these patients,” he said.
Even though most surgeons prescribe short courses of opioids, even brief regimens are associated with increased risks for overuse and substance abuse. Population-level data are limited concerning opioid prescriptions in dermatologic surgery, and in particular, there is an absence of data on the risk for long-term complications associated with use.
Certain Populations at Risk
To evaluate opioid prescription rates in dermatologic surgery, focusing on disparities between demographic populations, as well as the risk for long-term complications of postoperative opioid prescriptions, Dr. Lauck and colleagues conducted a retrospective study that included 914,721 dermatologic surgery patients, with billing codes for Mohs micrographic surgery. Patient data were obtained from TriNetX, a federated health research network.
The mean age of patients in this cohort was 54 years, and 124,494 (13.6%) were prescribed postsurgical oral opioids. The most common was oxycodone, prescribed to 43% of patients. Dr. Lauck noted that, according to their data, certain groups appeared more likely to receive a prescription for opioids following surgery. These included Black or African American patients (23.75% vs 12.86% for White patients), females (13.73% vs 13.16% for males), and Latino or Hispanic patients (17.02% vs 13.61% non-Latino/Hispanic patients).
Patients with a history of prior oral opioid prescription, prior opioid abuse or dependence, and any type of substance abuse had a significant increase in absolute risk of being prescribed postsurgical opioids (P < .0001).
The type of surgery also was associated with prescribed postop opioids. For a malignant excision, 18.29% of patients were prescribed postop opioids compared with 14.9% for a benign excision. About a third of patients (34.9%) undergoing a graft repair received opioids.
There was an elevated rate of postop opioid prescribing that was specific to the site of surgery, with the highest rates observed with eyelids, scalp and neck, trunk, and genital sites. The highest overall rates of opioid prescriptions were for patients who underwent excisions in the genital area (54.5%).
Long-Term Consequences
The authors also looked at the longer-term consequences of postop opioid use. “Nearly one in three patients who were prescribed opioids needed subsequent prescriptions down the line,” said Dr. Lauck.
From 3 months to 5 years after surgery, patients who received postsurgical opioids were at significantly higher risk for not only subsequent oral opioid prescription but also opiate abuse, any substance abuse, overdose by opioid narcotics, constipation, and chronic pain. “An opioid prescription may confer further risks of longitudinal complications of chronic opioid use,” he concluded.
Commenting on the study, Jesse M. Lewin, MD, chief of Mohs micrographic and dermatologic surgery at Icahn School of Medicine at Mount Sinai, New York City, noted an important finding of this study was the long-term sequelae of patients who did receive postop opioids.
“This is striking given that postsurgical opiate prescriptions are for short durations and limited number of pills,” he told this news organization. “This study highlights the potential danger of even short course of opiates and should serve as a reminder to dermatologic surgeons to be judicious about opiate prescribing.”
Dr. Lauck and Dr. Lewin had no disclosures.
A version of this article appeared on Medscape.com.
PHOENIX — The study also found that patients who do receive opioids postoperatively are at an increased risk for chronic opioid use and complications.
This report represents the largest analysis to date of opioid prescribing after dermatologic surgery, said lead author Kyle C. Lauck, MD, a dermatology resident at Baylor University Medical Center, Dallas, Texas. “Females, African Americans, and Latino patients may be at a higher risk of opioid prescription after dermatologic surgery. Surgeons should be aware of these populations and the risks they face when determining candidacy for postsurgical opioid analgesia.”
He presented the results at the annual meeting of the American College of Mohs Surgery.
The opioid epidemic is a concern across all areas of medicine, and the majority of opioid prescriptions in dermatology are given following surgery. Dr. Lauck noted that even though guidelines delegate opioids as second line for pain control, the existing data on opioid prescribing in dermatologic surgery is mixed. For example, some reports have shown that up to 58% of patients receive opioids postoperatively. “No consensus exists when we should routinely give opioids to these patients,” he said.
Even though most surgeons prescribe short courses of opioids, even brief regimens are associated with increased risks for overuse and substance abuse. Population-level data are limited concerning opioid prescriptions in dermatologic surgery, and in particular, there is an absence of data on the risk for long-term complications associated with use.
Certain Populations at Risk
To evaluate opioid prescription rates in dermatologic surgery, focusing on disparities between demographic populations, as well as the risk for long-term complications of postoperative opioid prescriptions, Dr. Lauck and colleagues conducted a retrospective study that included 914,721 dermatologic surgery patients, with billing codes for Mohs micrographic surgery. Patient data were obtained from TriNetX, a federated health research network.
The mean age of patients in this cohort was 54 years, and 124,494 (13.6%) were prescribed postsurgical oral opioids. The most common was oxycodone, prescribed to 43% of patients. Dr. Lauck noted that, according to their data, certain groups appeared more likely to receive a prescription for opioids following surgery. These included Black or African American patients (23.75% vs 12.86% for White patients), females (13.73% vs 13.16% for males), and Latino or Hispanic patients (17.02% vs 13.61% non-Latino/Hispanic patients).
Patients with a history of prior oral opioid prescription, prior opioid abuse or dependence, and any type of substance abuse had a significant increase in absolute risk of being prescribed postsurgical opioids (P < .0001).
The type of surgery also was associated with prescribed postop opioids. For a malignant excision, 18.29% of patients were prescribed postop opioids compared with 14.9% for a benign excision. About a third of patients (34.9%) undergoing a graft repair received opioids.
There was an elevated rate of postop opioid prescribing that was specific to the site of surgery, with the highest rates observed with eyelids, scalp and neck, trunk, and genital sites. The highest overall rates of opioid prescriptions were for patients who underwent excisions in the genital area (54.5%).
Long-Term Consequences
The authors also looked at the longer-term consequences of postop opioid use. “Nearly one in three patients who were prescribed opioids needed subsequent prescriptions down the line,” said Dr. Lauck.
From 3 months to 5 years after surgery, patients who received postsurgical opioids were at significantly higher risk for not only subsequent oral opioid prescription but also opiate abuse, any substance abuse, overdose by opioid narcotics, constipation, and chronic pain. “An opioid prescription may confer further risks of longitudinal complications of chronic opioid use,” he concluded.
Commenting on the study, Jesse M. Lewin, MD, chief of Mohs micrographic and dermatologic surgery at Icahn School of Medicine at Mount Sinai, New York City, noted an important finding of this study was the long-term sequelae of patients who did receive postop opioids.
“This is striking given that postsurgical opiate prescriptions are for short durations and limited number of pills,” he told this news organization. “This study highlights the potential danger of even short course of opiates and should serve as a reminder to dermatologic surgeons to be judicious about opiate prescribing.”
Dr. Lauck and Dr. Lewin had no disclosures.
A version of this article appeared on Medscape.com.
FROM ACMS 2024
Mirikizumab Shows Promise for Moderate to Severe Crohn’s Disease
WASHINGTON — , according to results of the phase 3 randomized, double blind, treat-through VIVID-1 study.
Bruce E. Sands, MD, AGAF, chief of gastroenterology at the Icahn School of Medicine at Mount Sinai in New York, reported the findings in a poster (Abstract Su1801) at the annual Digestive Disease Week® (DDW).
The FDA approved mirikizumab (Omvoh, Eli Lilly) to treat moderate to severe ulcerative colitis in October 2023.
Dr. Sands and a team of US and international collaborators studied 1065 adults with Crohn’s disease or fistulizing Crohn’s disease for 3 months or more, with a mean duration of more than 7 years. At baseline, participants had a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of 7 or more and reported an inadequate response, lost response, or intolerance to other therapy.
A total of 579 people were randomly assigned to mirikizumab and another 199 to placebo. Another 287 patients received ustekinumab; though they were not included in this current analysis, the findings were presented separately at DDW 2024.
Mean age of study participants was 30 years, and men comprised 57%-59% of the groups. Nearly half (49%) of each group previously failed biologic therapy.
A primary composite endpoint was clinical response at 12 weeks according to patient reported outcome and endoscopic response at 52 weeks measured with the SES-CD. A second primary endpoint was clinical response at 12 weeks by patient reported outcome combined with clinical remission on Crohn’s Disease Activity Index (CDAI) at 52 weeks.
Researchers also tracked 12 major secondary endpoints for mirikizumab vs placebo, including clinical response, endoscopic response, and clinical remission at week 12 and week 52.
Efficacy Findings
A higher percentage of participants in the mirikizumab group achieved 12-week secondary endpoints compared with placebo. In the treatment group, 32.5% reached endoscopic response vs 12.6% in the placebo group, a statistically significant difference (P < .000001). In addition, 17.6% achieved endoscopic remission in the treatment group vs 7.0% in the placebo group at 12 weeks (P < .000213).
The “treat-through” results at 52 weeks revealed that a higher proportion of the group taking mirikizumab met the co-primary endpoints compared with placebo. A total of 48.4% in the mirikizumab group vs 9.0% in the placebo group achieved endoscopic response (P < .000001). Similarly, a higher proportion met clinical remission on the CDAI, 54.1% in the treatment group vs 19.6% in the placebo group (P < .000001).
Overall, 38% of mirikizumab-treated patients vs 9% of the placebo group reached a composite endpoint of patient reported clinical response at week 12 and endoscopic response by SES-CD at week 52 (P < .000001).
Dr. Sands and colleagues also combined clinical response reported by patients at 12 weeks with CDAI findings for clinical remission at week 52. A total of 45.4% in the treatment group met the combined endpoint compared with 19.6% of the placebo group (P < .000001).
In an additional analysis, the researchers looked at this composite endpoint in patients in both groups who had failed or not failed a prior biologic for a total of 43.4% vs 12.4%, and 47.3% vs 26.5%, respectively.
“Mirikizumab demonstrated statistically significant and clinically meaningful improvements” in the study co-primary endpoints and secondary endpoints compared with placebo, the researchers concluded.
Safety Findings
Safety outcomes during the 52-week study were “consistent with the known safety profile” of mirikizumab, the researchers noted.
Treatment-emergent adverse events occurred in 78.6% of mirikizumab participants vs 73.0% of the placebo group. The most common were COVID-19, anemia, and arthralgia. Serious adverse events were reported in 10.3% of the mirikizumab group vs 17.1% of the placebo group. There were seven opportunistic infections in the treatment group, including herpes zoster and Candida, compared with none in the placebo group.
One person in the placebo cohort died of a pulmonary embolism; there were no deaths in the mirikizumab group.
People randomly assigned to placebo without a response at 12 weeks were switched over to mirikizumab. However, the findings from this group between 12 and 52 weeks were excluded from the 1-year data presented at DDW 2024, including one death from worsening Crohn’s disease during that time.
Mirikizumab looked particularly robust in this study, and it may turn out to be a critically important option for our patients, said Jordan Axelrad, MD, MPH, co-director of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City. Dr. Axelrad was not involved in this study.
Of importance, effect sizes were similar for “bio-naive and previously biologic-exposed patients,” he added.
These data “really underscore that therapies targeting IL-23 may be clinically useful for Crohn’s disease patients with prior biologic failure, representing a significant departure from our previous experience with other biologic classes,” Dr. Axelrad said.
The study was funded by Eli Lilly and Company. Dr. Sands is a consultant and receives grant funding from Lilly. Dr. Axelrad had no relevant disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON — , according to results of the phase 3 randomized, double blind, treat-through VIVID-1 study.
Bruce E. Sands, MD, AGAF, chief of gastroenterology at the Icahn School of Medicine at Mount Sinai in New York, reported the findings in a poster (Abstract Su1801) at the annual Digestive Disease Week® (DDW).
The FDA approved mirikizumab (Omvoh, Eli Lilly) to treat moderate to severe ulcerative colitis in October 2023.
Dr. Sands and a team of US and international collaborators studied 1065 adults with Crohn’s disease or fistulizing Crohn’s disease for 3 months or more, with a mean duration of more than 7 years. At baseline, participants had a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of 7 or more and reported an inadequate response, lost response, or intolerance to other therapy.
A total of 579 people were randomly assigned to mirikizumab and another 199 to placebo. Another 287 patients received ustekinumab; though they were not included in this current analysis, the findings were presented separately at DDW 2024.
Mean age of study participants was 30 years, and men comprised 57%-59% of the groups. Nearly half (49%) of each group previously failed biologic therapy.
A primary composite endpoint was clinical response at 12 weeks according to patient reported outcome and endoscopic response at 52 weeks measured with the SES-CD. A second primary endpoint was clinical response at 12 weeks by patient reported outcome combined with clinical remission on Crohn’s Disease Activity Index (CDAI) at 52 weeks.
Researchers also tracked 12 major secondary endpoints for mirikizumab vs placebo, including clinical response, endoscopic response, and clinical remission at week 12 and week 52.
Efficacy Findings
A higher percentage of participants in the mirikizumab group achieved 12-week secondary endpoints compared with placebo. In the treatment group, 32.5% reached endoscopic response vs 12.6% in the placebo group, a statistically significant difference (P < .000001). In addition, 17.6% achieved endoscopic remission in the treatment group vs 7.0% in the placebo group at 12 weeks (P < .000213).
The “treat-through” results at 52 weeks revealed that a higher proportion of the group taking mirikizumab met the co-primary endpoints compared with placebo. A total of 48.4% in the mirikizumab group vs 9.0% in the placebo group achieved endoscopic response (P < .000001). Similarly, a higher proportion met clinical remission on the CDAI, 54.1% in the treatment group vs 19.6% in the placebo group (P < .000001).
Overall, 38% of mirikizumab-treated patients vs 9% of the placebo group reached a composite endpoint of patient reported clinical response at week 12 and endoscopic response by SES-CD at week 52 (P < .000001).
Dr. Sands and colleagues also combined clinical response reported by patients at 12 weeks with CDAI findings for clinical remission at week 52. A total of 45.4% in the treatment group met the combined endpoint compared with 19.6% of the placebo group (P < .000001).
In an additional analysis, the researchers looked at this composite endpoint in patients in both groups who had failed or not failed a prior biologic for a total of 43.4% vs 12.4%, and 47.3% vs 26.5%, respectively.
“Mirikizumab demonstrated statistically significant and clinically meaningful improvements” in the study co-primary endpoints and secondary endpoints compared with placebo, the researchers concluded.
Safety Findings
Safety outcomes during the 52-week study were “consistent with the known safety profile” of mirikizumab, the researchers noted.
Treatment-emergent adverse events occurred in 78.6% of mirikizumab participants vs 73.0% of the placebo group. The most common were COVID-19, anemia, and arthralgia. Serious adverse events were reported in 10.3% of the mirikizumab group vs 17.1% of the placebo group. There were seven opportunistic infections in the treatment group, including herpes zoster and Candida, compared with none in the placebo group.
One person in the placebo cohort died of a pulmonary embolism; there were no deaths in the mirikizumab group.
People randomly assigned to placebo without a response at 12 weeks were switched over to mirikizumab. However, the findings from this group between 12 and 52 weeks were excluded from the 1-year data presented at DDW 2024, including one death from worsening Crohn’s disease during that time.
Mirikizumab looked particularly robust in this study, and it may turn out to be a critically important option for our patients, said Jordan Axelrad, MD, MPH, co-director of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City. Dr. Axelrad was not involved in this study.
Of importance, effect sizes were similar for “bio-naive and previously biologic-exposed patients,” he added.
These data “really underscore that therapies targeting IL-23 may be clinically useful for Crohn’s disease patients with prior biologic failure, representing a significant departure from our previous experience with other biologic classes,” Dr. Axelrad said.
The study was funded by Eli Lilly and Company. Dr. Sands is a consultant and receives grant funding from Lilly. Dr. Axelrad had no relevant disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON — , according to results of the phase 3 randomized, double blind, treat-through VIVID-1 study.
Bruce E. Sands, MD, AGAF, chief of gastroenterology at the Icahn School of Medicine at Mount Sinai in New York, reported the findings in a poster (Abstract Su1801) at the annual Digestive Disease Week® (DDW).
The FDA approved mirikizumab (Omvoh, Eli Lilly) to treat moderate to severe ulcerative colitis in October 2023.
Dr. Sands and a team of US and international collaborators studied 1065 adults with Crohn’s disease or fistulizing Crohn’s disease for 3 months or more, with a mean duration of more than 7 years. At baseline, participants had a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of 7 or more and reported an inadequate response, lost response, or intolerance to other therapy.
A total of 579 people were randomly assigned to mirikizumab and another 199 to placebo. Another 287 patients received ustekinumab; though they were not included in this current analysis, the findings were presented separately at DDW 2024.
Mean age of study participants was 30 years, and men comprised 57%-59% of the groups. Nearly half (49%) of each group previously failed biologic therapy.
A primary composite endpoint was clinical response at 12 weeks according to patient reported outcome and endoscopic response at 52 weeks measured with the SES-CD. A second primary endpoint was clinical response at 12 weeks by patient reported outcome combined with clinical remission on Crohn’s Disease Activity Index (CDAI) at 52 weeks.
Researchers also tracked 12 major secondary endpoints for mirikizumab vs placebo, including clinical response, endoscopic response, and clinical remission at week 12 and week 52.
Efficacy Findings
A higher percentage of participants in the mirikizumab group achieved 12-week secondary endpoints compared with placebo. In the treatment group, 32.5% reached endoscopic response vs 12.6% in the placebo group, a statistically significant difference (P < .000001). In addition, 17.6% achieved endoscopic remission in the treatment group vs 7.0% in the placebo group at 12 weeks (P < .000213).
The “treat-through” results at 52 weeks revealed that a higher proportion of the group taking mirikizumab met the co-primary endpoints compared with placebo. A total of 48.4% in the mirikizumab group vs 9.0% in the placebo group achieved endoscopic response (P < .000001). Similarly, a higher proportion met clinical remission on the CDAI, 54.1% in the treatment group vs 19.6% in the placebo group (P < .000001).
Overall, 38% of mirikizumab-treated patients vs 9% of the placebo group reached a composite endpoint of patient reported clinical response at week 12 and endoscopic response by SES-CD at week 52 (P < .000001).
Dr. Sands and colleagues also combined clinical response reported by patients at 12 weeks with CDAI findings for clinical remission at week 52. A total of 45.4% in the treatment group met the combined endpoint compared with 19.6% of the placebo group (P < .000001).
In an additional analysis, the researchers looked at this composite endpoint in patients in both groups who had failed or not failed a prior biologic for a total of 43.4% vs 12.4%, and 47.3% vs 26.5%, respectively.
“Mirikizumab demonstrated statistically significant and clinically meaningful improvements” in the study co-primary endpoints and secondary endpoints compared with placebo, the researchers concluded.
Safety Findings
Safety outcomes during the 52-week study were “consistent with the known safety profile” of mirikizumab, the researchers noted.
Treatment-emergent adverse events occurred in 78.6% of mirikizumab participants vs 73.0% of the placebo group. The most common were COVID-19, anemia, and arthralgia. Serious adverse events were reported in 10.3% of the mirikizumab group vs 17.1% of the placebo group. There were seven opportunistic infections in the treatment group, including herpes zoster and Candida, compared with none in the placebo group.
One person in the placebo cohort died of a pulmonary embolism; there were no deaths in the mirikizumab group.
People randomly assigned to placebo without a response at 12 weeks were switched over to mirikizumab. However, the findings from this group between 12 and 52 weeks were excluded from the 1-year data presented at DDW 2024, including one death from worsening Crohn’s disease during that time.
Mirikizumab looked particularly robust in this study, and it may turn out to be a critically important option for our patients, said Jordan Axelrad, MD, MPH, co-director of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City. Dr. Axelrad was not involved in this study.
Of importance, effect sizes were similar for “bio-naive and previously biologic-exposed patients,” he added.
These data “really underscore that therapies targeting IL-23 may be clinically useful for Crohn’s disease patients with prior biologic failure, representing a significant departure from our previous experience with other biologic classes,” Dr. Axelrad said.
The study was funded by Eli Lilly and Company. Dr. Sands is a consultant and receives grant funding from Lilly. Dr. Axelrad had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM DDW 2024
Maternal Complication Risk Higher For Cesarean Deliveries With Low-Lying Placenta
SAN FRANCISCO — Patients with a low-lying placenta who underwent cesarean deliveries were at higher risk for multiple complications even if they did not have placenta previa, according to data presented at the annual meeting of the American College of Obstetricians and Gynecologists.
Rates of preterm delivery, postpartum hemorrhage, placenta accreta, and need for hysterectomy and transfusion were all significantly higher in patients with low-lying placenta than in patients without, Jacob Thomas, MD, of Advocate Aurora Health in Chicago, Illinois, and Ascension Illinois St. Alexius Medical Center in Hoffman Estates, reported at the meeting.
A low-lying placenta is defined as a placental edge less than 20 mm from the internal os but not covering it. Most studies looking at low-lying placentas, however, group them with placenta previa, making it difficult to know if there are differences in risk of adverse outcomes for those who don’t have placenta previa.
“These are not necessarily shocking findings, but it shows that even low-lying placentas have significant morbidity in and of themselves, not just when they’re lumped with placenta previas,” Dr. Thomas said in an interview. “This means, if you’re doing a C-section for a low-lying placenta, you probably want to treat it a lot like you would treat a placenta previa. You may have blood ready, whether or not you’re going to give it, and you’re going to be more prepared for those complications.”
Noting that approximately 30% of patients with low-lying placenta had preterm deliveries, Dr. Thomas added that these patients might need to be counseled differently as well. The researchers did not have data on how preterm the deliveries were — many could have been 35-37 weeks, for example — but “how you prepare those patients is different,” he said.
Breanna Bolivar, MD, MPH, an obgyn hospitalist at MAHEC Ob/Gyn Specialists in Asheville, North Carolina, said the findings confirm her experience in practice.
“Low-lying placentas are treated very similarly to placenta previas and the results seem similar to patients that have placenta previas,” Dr. Bolivar said in an interview. “In my practice, I treat patients with low-lying placenta the same as I do with placenta previa. I have the same risk factors in mind, and I prepare in the same way.”
The researchers conducted a retrospective analysis of all patients who underwent a cesarean delivery in the National Inpatient Sample from 2017 to 2019 through the Healthcare Cost and Utilization Project from the Agency for Healthcare Research and Quality. After excluding patients with placenta previa, the researchers compared outcomes among patients with ICD-10 codes for low-lying placenta to those of patients without low-lying placenta. The researchers specifically looked at preterm delivery, hemorrhage, hysterectomy, placenta accreta spectrum (PAS), sepsis, shock, disseminated intravascular coagulation, and blood transfusion.
Among 700,635 patients with cesarean deliveries in the database, 0.4% had low-lying placenta. These patients were more likely to be older, to be anemic, and to deliver at a large or urban teaching hospital. They were less likely to have public insurance or a previous cesarean.
After controlling for confounders that differed between the two populations, the researchers found a higher likelihood of all adverse maternal outcomes studied in patients with low-lying placenta (P < .05). These patients had three times greater risk for preterm delivery (adjusted odds ratio [aOR], 3.07; 95% CI, 2.81-3.35) and nearly three times greater risk for shock (aOR 2.55; 95% CI, 1.44-4.52), and transfusion (aOR, 2.56; 95% CI, 2.14-3.06).
Compared to those without low-lying placenta, risk for patients with low-lying placenta was even higher for hemorrhage (aOR, 8.87; 95% CI, 8.10-9.73), hysterectomy (aOR, 9.42; 95% CI, 7.11-12.47), and PAS (aOR, 13.41; 95% CI, 10.34-17.39).
Within the group with low-lying placenta, older patients were modestly, but significantly, more likely to have hemorrhage, hysterectomy, and PAS (aOR, 1.06 for all). The risk was more elevated and significant in patients with tobacco use for hemorrhage (aOR, 1.43), hysterectomy (aOR, 1.40), and PAS (aOR, 1.40). Patients with anemia were also significantly more likely to experience PAS (aOR, 1.34).
“Interestingly, in this population, prior cesarean was not associated with increased rates of hemorrhage or hysterectomy,” the researchers reported. The findings can also “help guide research in terms of questions for the future,” Dr. Thomas said, such as looking at complication rates for vaginal deliveries in people with low-lying placenta.
No external funding was noted, and the authors all had no disclosures. Dr. Bolivar had no disclosures.
SAN FRANCISCO — Patients with a low-lying placenta who underwent cesarean deliveries were at higher risk for multiple complications even if they did not have placenta previa, according to data presented at the annual meeting of the American College of Obstetricians and Gynecologists.
Rates of preterm delivery, postpartum hemorrhage, placenta accreta, and need for hysterectomy and transfusion were all significantly higher in patients with low-lying placenta than in patients without, Jacob Thomas, MD, of Advocate Aurora Health in Chicago, Illinois, and Ascension Illinois St. Alexius Medical Center in Hoffman Estates, reported at the meeting.
A low-lying placenta is defined as a placental edge less than 20 mm from the internal os but not covering it. Most studies looking at low-lying placentas, however, group them with placenta previa, making it difficult to know if there are differences in risk of adverse outcomes for those who don’t have placenta previa.
“These are not necessarily shocking findings, but it shows that even low-lying placentas have significant morbidity in and of themselves, not just when they’re lumped with placenta previas,” Dr. Thomas said in an interview. “This means, if you’re doing a C-section for a low-lying placenta, you probably want to treat it a lot like you would treat a placenta previa. You may have blood ready, whether or not you’re going to give it, and you’re going to be more prepared for those complications.”
Noting that approximately 30% of patients with low-lying placenta had preterm deliveries, Dr. Thomas added that these patients might need to be counseled differently as well. The researchers did not have data on how preterm the deliveries were — many could have been 35-37 weeks, for example — but “how you prepare those patients is different,” he said.
Breanna Bolivar, MD, MPH, an obgyn hospitalist at MAHEC Ob/Gyn Specialists in Asheville, North Carolina, said the findings confirm her experience in practice.
“Low-lying placentas are treated very similarly to placenta previas and the results seem similar to patients that have placenta previas,” Dr. Bolivar said in an interview. “In my practice, I treat patients with low-lying placenta the same as I do with placenta previa. I have the same risk factors in mind, and I prepare in the same way.”
The researchers conducted a retrospective analysis of all patients who underwent a cesarean delivery in the National Inpatient Sample from 2017 to 2019 through the Healthcare Cost and Utilization Project from the Agency for Healthcare Research and Quality. After excluding patients with placenta previa, the researchers compared outcomes among patients with ICD-10 codes for low-lying placenta to those of patients without low-lying placenta. The researchers specifically looked at preterm delivery, hemorrhage, hysterectomy, placenta accreta spectrum (PAS), sepsis, shock, disseminated intravascular coagulation, and blood transfusion.
Among 700,635 patients with cesarean deliveries in the database, 0.4% had low-lying placenta. These patients were more likely to be older, to be anemic, and to deliver at a large or urban teaching hospital. They were less likely to have public insurance or a previous cesarean.
After controlling for confounders that differed between the two populations, the researchers found a higher likelihood of all adverse maternal outcomes studied in patients with low-lying placenta (P < .05). These patients had three times greater risk for preterm delivery (adjusted odds ratio [aOR], 3.07; 95% CI, 2.81-3.35) and nearly three times greater risk for shock (aOR 2.55; 95% CI, 1.44-4.52), and transfusion (aOR, 2.56; 95% CI, 2.14-3.06).
Compared to those without low-lying placenta, risk for patients with low-lying placenta was even higher for hemorrhage (aOR, 8.87; 95% CI, 8.10-9.73), hysterectomy (aOR, 9.42; 95% CI, 7.11-12.47), and PAS (aOR, 13.41; 95% CI, 10.34-17.39).
Within the group with low-lying placenta, older patients were modestly, but significantly, more likely to have hemorrhage, hysterectomy, and PAS (aOR, 1.06 for all). The risk was more elevated and significant in patients with tobacco use for hemorrhage (aOR, 1.43), hysterectomy (aOR, 1.40), and PAS (aOR, 1.40). Patients with anemia were also significantly more likely to experience PAS (aOR, 1.34).
“Interestingly, in this population, prior cesarean was not associated with increased rates of hemorrhage or hysterectomy,” the researchers reported. The findings can also “help guide research in terms of questions for the future,” Dr. Thomas said, such as looking at complication rates for vaginal deliveries in people with low-lying placenta.
No external funding was noted, and the authors all had no disclosures. Dr. Bolivar had no disclosures.
SAN FRANCISCO — Patients with a low-lying placenta who underwent cesarean deliveries were at higher risk for multiple complications even if they did not have placenta previa, according to data presented at the annual meeting of the American College of Obstetricians and Gynecologists.
Rates of preterm delivery, postpartum hemorrhage, placenta accreta, and need for hysterectomy and transfusion were all significantly higher in patients with low-lying placenta than in patients without, Jacob Thomas, MD, of Advocate Aurora Health in Chicago, Illinois, and Ascension Illinois St. Alexius Medical Center in Hoffman Estates, reported at the meeting.
A low-lying placenta is defined as a placental edge less than 20 mm from the internal os but not covering it. Most studies looking at low-lying placentas, however, group them with placenta previa, making it difficult to know if there are differences in risk of adverse outcomes for those who don’t have placenta previa.
“These are not necessarily shocking findings, but it shows that even low-lying placentas have significant morbidity in and of themselves, not just when they’re lumped with placenta previas,” Dr. Thomas said in an interview. “This means, if you’re doing a C-section for a low-lying placenta, you probably want to treat it a lot like you would treat a placenta previa. You may have blood ready, whether or not you’re going to give it, and you’re going to be more prepared for those complications.”
Noting that approximately 30% of patients with low-lying placenta had preterm deliveries, Dr. Thomas added that these patients might need to be counseled differently as well. The researchers did not have data on how preterm the deliveries were — many could have been 35-37 weeks, for example — but “how you prepare those patients is different,” he said.
Breanna Bolivar, MD, MPH, an obgyn hospitalist at MAHEC Ob/Gyn Specialists in Asheville, North Carolina, said the findings confirm her experience in practice.
“Low-lying placentas are treated very similarly to placenta previas and the results seem similar to patients that have placenta previas,” Dr. Bolivar said in an interview. “In my practice, I treat patients with low-lying placenta the same as I do with placenta previa. I have the same risk factors in mind, and I prepare in the same way.”
The researchers conducted a retrospective analysis of all patients who underwent a cesarean delivery in the National Inpatient Sample from 2017 to 2019 through the Healthcare Cost and Utilization Project from the Agency for Healthcare Research and Quality. After excluding patients with placenta previa, the researchers compared outcomes among patients with ICD-10 codes for low-lying placenta to those of patients without low-lying placenta. The researchers specifically looked at preterm delivery, hemorrhage, hysterectomy, placenta accreta spectrum (PAS), sepsis, shock, disseminated intravascular coagulation, and blood transfusion.
Among 700,635 patients with cesarean deliveries in the database, 0.4% had low-lying placenta. These patients were more likely to be older, to be anemic, and to deliver at a large or urban teaching hospital. They were less likely to have public insurance or a previous cesarean.
After controlling for confounders that differed between the two populations, the researchers found a higher likelihood of all adverse maternal outcomes studied in patients with low-lying placenta (P < .05). These patients had three times greater risk for preterm delivery (adjusted odds ratio [aOR], 3.07; 95% CI, 2.81-3.35) and nearly three times greater risk for shock (aOR 2.55; 95% CI, 1.44-4.52), and transfusion (aOR, 2.56; 95% CI, 2.14-3.06).
Compared to those without low-lying placenta, risk for patients with low-lying placenta was even higher for hemorrhage (aOR, 8.87; 95% CI, 8.10-9.73), hysterectomy (aOR, 9.42; 95% CI, 7.11-12.47), and PAS (aOR, 13.41; 95% CI, 10.34-17.39).
Within the group with low-lying placenta, older patients were modestly, but significantly, more likely to have hemorrhage, hysterectomy, and PAS (aOR, 1.06 for all). The risk was more elevated and significant in patients with tobacco use for hemorrhage (aOR, 1.43), hysterectomy (aOR, 1.40), and PAS (aOR, 1.40). Patients with anemia were also significantly more likely to experience PAS (aOR, 1.34).
“Interestingly, in this population, prior cesarean was not associated with increased rates of hemorrhage or hysterectomy,” the researchers reported. The findings can also “help guide research in terms of questions for the future,” Dr. Thomas said, such as looking at complication rates for vaginal deliveries in people with low-lying placenta.
No external funding was noted, and the authors all had no disclosures. Dr. Bolivar had no disclosures.
FROM ACOG 2024
Statin Use May Extend Life for Early Breast Cancer Patients
Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
What Is Known About Statins and Breast Cancer?
Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.
Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.
The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
How Was the Current Study Designed?
To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.
As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.
The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.
The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
What Did the Results Show?
The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).
The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).
The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.
“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.
The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
What Is the Takeaway Message for Clinical Practice?
“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.
What Are the Next Steps for Research?
The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.
However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.
Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
What Do Clinicians Think of the Study?
The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.
Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.
“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.
Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.
“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.
The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.
The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.
The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.
Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
What Is Known About Statins and Breast Cancer?
Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.
Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.
The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
How Was the Current Study Designed?
To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.
As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.
The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.
The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
What Did the Results Show?
The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).
The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).
The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.
“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.
The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
What Is the Takeaway Message for Clinical Practice?
“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.
What Are the Next Steps for Research?
The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.
However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.
Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
What Do Clinicians Think of the Study?
The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.
Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.
“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.
Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.
“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.
The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.
The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.
The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.
Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
What Is Known About Statins and Breast Cancer?
Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.
Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.
The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
How Was the Current Study Designed?
To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.
As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.
The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.
The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
What Did the Results Show?
The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).
The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).
The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.
“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.
The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
What Is the Takeaway Message for Clinical Practice?
“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.
What Are the Next Steps for Research?
The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.
However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.
Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
What Do Clinicians Think of the Study?
The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.
Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.
“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.
Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.
“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.
The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.
The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.
The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.
FROM ESMO BREAST CANCER 2024
Novel ENV-101 associated with improved lung function in IPF
SAN DIEGO —
Early efficacy data from a phase 2a safety trial suggest that the novel oral agent, dubbed ENV-101, is associated with improvements in forced vital capacity (FVC) and other measures of lung function, and may be a disease-modifying therapy for IPF, according to Toby M. Maher, MD, PhD, director of the interstitial lung disease program at Keck School of Medicine, University of Southern California, Los Angeles. Dr. Maher presented the results at the American Thoracic Society’s international conference.
“Historically we’ve not been seeing improvements in FVC, which is what we’ve been seeing [with ENV-101], and I think it’s conceivable that you can get remodeling of early areas of fibrosis in the lung,” Dr. Maher said in an interview with Chest Physician.
“We know from histology studies that if you look at IPF lungs you’ll see areas of end-stage fibrosis, but even in advanced disease you’ll see areas where the lung is relatively well preserved and there’s early fibrosis, so I think it’s conceivable that there is remodeling of some of those early areas of fibrosis,” he said.
Vital pathway
The Hedgehog pathway is highly conserved in evolution. The cell-signaling pathway is active embryogenesis, tissue proliferation, and organ development. There is also evidence to suggest that in adult the pathway becomes reactivated following tissue injury, as can occur in lung epithelia, Dr. Maher explained.
Although as the word “idiopathic” in IPF indicates the etiology of the disease is unknown, investigators have found that in IPF repetitive epithelial injury to lung tissue leads to activation of the Hedgehog pathway. Hedgehog signaling in turn induces formation and activation of myofibroblasts that lay down fibrotic matrix and contract lung tissue, leading to significant impairments in gas exchange, Dr. Maher said.
ENV-101 blocks Hedgehog from binding to the PTCH1 receptor, preventing release of the zinc-finger protein GLI1 from the kinase complex into the cell cytoplasm. With signaling blocked, myofibroblasts undergo apoptosis instead of initiating wound repair as they normally would, thereby eliminating an evident mechanism of IPF pathology, he explained.
Study details
In the phase 2a trial, investigators enrolled patients with IPF who were not taking antifibrotic agents and who had a percent predicted FVC greater than 50%, percent predicted diffusing capacity for carbon monoxide (DLCO) of at least 35%, and life expectancy of more than 1 year.
The patients were randomized to receive 200 mg oral ENV-101 daily (18 patients) or placebo (15 patients) for 12 weeks.
The primary endpoint of the trial was safety of the experimental agent. A previous phase 1b study of a different Hedgehog inhibitor — vismodegib (Erivedge), in combination with the antifibrotic agent pirfenidone (Pirespa) — in patients with IPF was discontinued because of poor tolerability.
In the current study, the most common treatment-related adverse events were dysgeusia in 57% of patients who received the drug, alopecia in 52%, and muscle spasms in 43%. The spasms were generally less severe than those seen in the vismodegib/pirfenidone trial mentioned above.
Seven patients (33%) had treatment-emergent events leading to dose interruption. Five patients discontinued treatment: one who withdrew because of taste alterations, one who was lost to follow-up after an IPF exacerbation, and three who withdrew consent.
There were no treatment-related deaths, and no clinically significant findings on labs, vital signs, electrocardiograms, or physical exam.
Efficacy endpoints
An analysis of the secondary efficacy endpoints showed a 1.9% mean improvement in FVC from baseline among patients assigned to ENV-101, compared with a mean decline of 1.3% of patients assigned to placebo (P = .035).
Patients on the active drug also had a 200-mL mean increase in total lung capacity, compared with a mean decline of 56 mL for patients on placebo (P = .005).
In addition, high-resolution CR studies showed a 9.4% absolute decrease from baseline in quantitative interstitial lung disease with ENV-101, vs. a 1.1% increase among controls, a 2% absolute decline from baseline in quantitative lung fibrosis compared with a 0.87% increase with placebo, and a 4.6% absolute decrease from baseline in quantitative ground glass, compared with an increase of 0.29% with placebo.
Bad taste a good sign?
Reinoud Gosens PhD, University of Groningen, the Netherlands, who co-moderated the session but was not involved in the study, questioned whether the dysgeusia seen in patients who received ENV-101 might be related to the dysgeusia seen in clinical trials of P2X3 receptor antagonists for cough.
“I was wondering if there would be a mechanistic overlap between Hedgehog inhibition and cough, which would be quite relevant for IPF,” he said in an interview.
The increase in FVC seen with ENV-101 and with the investigational agent buloxibutid, a novel angiotensin II type 2 receptor agonist described in a separate presentation by Dr. Maher, suggests that these drugs may have the ability to help remodel damaged lungs, Dr. Gosens said.
Investigators are currently planning a phase 2 dose-ranging trial (WHISTLE-PF) in patients with IPF or progressive pulmonary fibrosis.
The phase 2a trial was supported by Endeavor BioMedicines. Dr. Maher disclosed consultancy or speaker fees from Endeavor and others. Dr. Gosens had no relevant disclosures.
SAN DIEGO —
Early efficacy data from a phase 2a safety trial suggest that the novel oral agent, dubbed ENV-101, is associated with improvements in forced vital capacity (FVC) and other measures of lung function, and may be a disease-modifying therapy for IPF, according to Toby M. Maher, MD, PhD, director of the interstitial lung disease program at Keck School of Medicine, University of Southern California, Los Angeles. Dr. Maher presented the results at the American Thoracic Society’s international conference.
“Historically we’ve not been seeing improvements in FVC, which is what we’ve been seeing [with ENV-101], and I think it’s conceivable that you can get remodeling of early areas of fibrosis in the lung,” Dr. Maher said in an interview with Chest Physician.
“We know from histology studies that if you look at IPF lungs you’ll see areas of end-stage fibrosis, but even in advanced disease you’ll see areas where the lung is relatively well preserved and there’s early fibrosis, so I think it’s conceivable that there is remodeling of some of those early areas of fibrosis,” he said.
Vital pathway
The Hedgehog pathway is highly conserved in evolution. The cell-signaling pathway is active embryogenesis, tissue proliferation, and organ development. There is also evidence to suggest that in adult the pathway becomes reactivated following tissue injury, as can occur in lung epithelia, Dr. Maher explained.
Although as the word “idiopathic” in IPF indicates the etiology of the disease is unknown, investigators have found that in IPF repetitive epithelial injury to lung tissue leads to activation of the Hedgehog pathway. Hedgehog signaling in turn induces formation and activation of myofibroblasts that lay down fibrotic matrix and contract lung tissue, leading to significant impairments in gas exchange, Dr. Maher said.
ENV-101 blocks Hedgehog from binding to the PTCH1 receptor, preventing release of the zinc-finger protein GLI1 from the kinase complex into the cell cytoplasm. With signaling blocked, myofibroblasts undergo apoptosis instead of initiating wound repair as they normally would, thereby eliminating an evident mechanism of IPF pathology, he explained.
Study details
In the phase 2a trial, investigators enrolled patients with IPF who were not taking antifibrotic agents and who had a percent predicted FVC greater than 50%, percent predicted diffusing capacity for carbon monoxide (DLCO) of at least 35%, and life expectancy of more than 1 year.
The patients were randomized to receive 200 mg oral ENV-101 daily (18 patients) or placebo (15 patients) for 12 weeks.
The primary endpoint of the trial was safety of the experimental agent. A previous phase 1b study of a different Hedgehog inhibitor — vismodegib (Erivedge), in combination with the antifibrotic agent pirfenidone (Pirespa) — in patients with IPF was discontinued because of poor tolerability.
In the current study, the most common treatment-related adverse events were dysgeusia in 57% of patients who received the drug, alopecia in 52%, and muscle spasms in 43%. The spasms were generally less severe than those seen in the vismodegib/pirfenidone trial mentioned above.
Seven patients (33%) had treatment-emergent events leading to dose interruption. Five patients discontinued treatment: one who withdrew because of taste alterations, one who was lost to follow-up after an IPF exacerbation, and three who withdrew consent.
There were no treatment-related deaths, and no clinically significant findings on labs, vital signs, electrocardiograms, or physical exam.
Efficacy endpoints
An analysis of the secondary efficacy endpoints showed a 1.9% mean improvement in FVC from baseline among patients assigned to ENV-101, compared with a mean decline of 1.3% of patients assigned to placebo (P = .035).
Patients on the active drug also had a 200-mL mean increase in total lung capacity, compared with a mean decline of 56 mL for patients on placebo (P = .005).
In addition, high-resolution CR studies showed a 9.4% absolute decrease from baseline in quantitative interstitial lung disease with ENV-101, vs. a 1.1% increase among controls, a 2% absolute decline from baseline in quantitative lung fibrosis compared with a 0.87% increase with placebo, and a 4.6% absolute decrease from baseline in quantitative ground glass, compared with an increase of 0.29% with placebo.
Bad taste a good sign?
Reinoud Gosens PhD, University of Groningen, the Netherlands, who co-moderated the session but was not involved in the study, questioned whether the dysgeusia seen in patients who received ENV-101 might be related to the dysgeusia seen in clinical trials of P2X3 receptor antagonists for cough.
“I was wondering if there would be a mechanistic overlap between Hedgehog inhibition and cough, which would be quite relevant for IPF,” he said in an interview.
The increase in FVC seen with ENV-101 and with the investigational agent buloxibutid, a novel angiotensin II type 2 receptor agonist described in a separate presentation by Dr. Maher, suggests that these drugs may have the ability to help remodel damaged lungs, Dr. Gosens said.
Investigators are currently planning a phase 2 dose-ranging trial (WHISTLE-PF) in patients with IPF or progressive pulmonary fibrosis.
The phase 2a trial was supported by Endeavor BioMedicines. Dr. Maher disclosed consultancy or speaker fees from Endeavor and others. Dr. Gosens had no relevant disclosures.
SAN DIEGO —
Early efficacy data from a phase 2a safety trial suggest that the novel oral agent, dubbed ENV-101, is associated with improvements in forced vital capacity (FVC) and other measures of lung function, and may be a disease-modifying therapy for IPF, according to Toby M. Maher, MD, PhD, director of the interstitial lung disease program at Keck School of Medicine, University of Southern California, Los Angeles. Dr. Maher presented the results at the American Thoracic Society’s international conference.
“Historically we’ve not been seeing improvements in FVC, which is what we’ve been seeing [with ENV-101], and I think it’s conceivable that you can get remodeling of early areas of fibrosis in the lung,” Dr. Maher said in an interview with Chest Physician.
“We know from histology studies that if you look at IPF lungs you’ll see areas of end-stage fibrosis, but even in advanced disease you’ll see areas where the lung is relatively well preserved and there’s early fibrosis, so I think it’s conceivable that there is remodeling of some of those early areas of fibrosis,” he said.
Vital pathway
The Hedgehog pathway is highly conserved in evolution. The cell-signaling pathway is active embryogenesis, tissue proliferation, and organ development. There is also evidence to suggest that in adult the pathway becomes reactivated following tissue injury, as can occur in lung epithelia, Dr. Maher explained.
Although as the word “idiopathic” in IPF indicates the etiology of the disease is unknown, investigators have found that in IPF repetitive epithelial injury to lung tissue leads to activation of the Hedgehog pathway. Hedgehog signaling in turn induces formation and activation of myofibroblasts that lay down fibrotic matrix and contract lung tissue, leading to significant impairments in gas exchange, Dr. Maher said.
ENV-101 blocks Hedgehog from binding to the PTCH1 receptor, preventing release of the zinc-finger protein GLI1 from the kinase complex into the cell cytoplasm. With signaling blocked, myofibroblasts undergo apoptosis instead of initiating wound repair as they normally would, thereby eliminating an evident mechanism of IPF pathology, he explained.
Study details
In the phase 2a trial, investigators enrolled patients with IPF who were not taking antifibrotic agents and who had a percent predicted FVC greater than 50%, percent predicted diffusing capacity for carbon monoxide (DLCO) of at least 35%, and life expectancy of more than 1 year.
The patients were randomized to receive 200 mg oral ENV-101 daily (18 patients) or placebo (15 patients) for 12 weeks.
The primary endpoint of the trial was safety of the experimental agent. A previous phase 1b study of a different Hedgehog inhibitor — vismodegib (Erivedge), in combination with the antifibrotic agent pirfenidone (Pirespa) — in patients with IPF was discontinued because of poor tolerability.
In the current study, the most common treatment-related adverse events were dysgeusia in 57% of patients who received the drug, alopecia in 52%, and muscle spasms in 43%. The spasms were generally less severe than those seen in the vismodegib/pirfenidone trial mentioned above.
Seven patients (33%) had treatment-emergent events leading to dose interruption. Five patients discontinued treatment: one who withdrew because of taste alterations, one who was lost to follow-up after an IPF exacerbation, and three who withdrew consent.
There were no treatment-related deaths, and no clinically significant findings on labs, vital signs, electrocardiograms, or physical exam.
Efficacy endpoints
An analysis of the secondary efficacy endpoints showed a 1.9% mean improvement in FVC from baseline among patients assigned to ENV-101, compared with a mean decline of 1.3% of patients assigned to placebo (P = .035).
Patients on the active drug also had a 200-mL mean increase in total lung capacity, compared with a mean decline of 56 mL for patients on placebo (P = .005).
In addition, high-resolution CR studies showed a 9.4% absolute decrease from baseline in quantitative interstitial lung disease with ENV-101, vs. a 1.1% increase among controls, a 2% absolute decline from baseline in quantitative lung fibrosis compared with a 0.87% increase with placebo, and a 4.6% absolute decrease from baseline in quantitative ground glass, compared with an increase of 0.29% with placebo.
Bad taste a good sign?
Reinoud Gosens PhD, University of Groningen, the Netherlands, who co-moderated the session but was not involved in the study, questioned whether the dysgeusia seen in patients who received ENV-101 might be related to the dysgeusia seen in clinical trials of P2X3 receptor antagonists for cough.
“I was wondering if there would be a mechanistic overlap between Hedgehog inhibition and cough, which would be quite relevant for IPF,” he said in an interview.
The increase in FVC seen with ENV-101 and with the investigational agent buloxibutid, a novel angiotensin II type 2 receptor agonist described in a separate presentation by Dr. Maher, suggests that these drugs may have the ability to help remodel damaged lungs, Dr. Gosens said.
Investigators are currently planning a phase 2 dose-ranging trial (WHISTLE-PF) in patients with IPF or progressive pulmonary fibrosis.
The phase 2a trial was supported by Endeavor BioMedicines. Dr. Maher disclosed consultancy or speaker fees from Endeavor and others. Dr. Gosens had no relevant disclosures.
FROM ATS 2024
Demand for Permanent Contraception Up Nationwide Since Dobbs Ruling
The number of Americans seeking permanent forms of contraception has surged in the nearly 2 years since the Dobbs v. Jackson Women’s Health Organization Supreme Court decision that overturned a federal right to abortion, according to a study presented on May 5 at the annual meeting of the American Urological Association (AUA) (abstract PD40-03). Several other studies at the conference reported similar findings.
Rates of vasectomy and tubal ligation have increased in states where abortion became illegal after the court’s June 2022 ruling, researchers found. Rates of tubal sterilization had already been higher in states where abortion was illegal compared with those where access to the procedure remained available and was expected to remain so, but the difference widened after the decision.
“Our study showed trends of increasing utilization of permanent contraception post-Dobbs, with a significant increase in patients less than 30 years old pursuing any type of permanent contraception post-Dobbs,” Jessica N. Schardein, MD, MS, of University of Utah Health in Salt Lake City, told attendees. “Reproductive autonomy is important for people of all genders and may be influenced by legal climate. Understanding the relationship between state-level abortion laws and trends in permanent contraception is crucial for us to determine how to best allocate resources for education and services to ensure reproductive rights for all patients.”
Dr. Schardein told this news organization the increase in vasectomies post-Dobbs was consistent across most states regardless of legal climate, showing that “reproductive health matters to all people,” both women and men.
“We should continue to offer permanent contraception to patients who are not interested in future fertility, regardless of their age or marital status, to ensure reproductive autonomy for those patients,” Dr. Schardein said. “Patients may need increased access to these procedures if the increased rates continue over time.”
Dr. Schardein’s study investigated national trends in the use of permanent contraception before and after the Dobbs ruling. She and her colleagues analyzed data from the Epic Cosmos database of more than 217 million patients from an estimated 27,000 clinics and 1260 hospitals nationwide. The researchers identified all adults who underwent a vasectomy or tubal ligation from July to December 2021 and then from July to December 2022, in the 5 months following the decision.
Among adults aged 18-30 years, rates of vasectomy were 1.59 times higher and rates of tubal ligation were 1.29 times higher after the Dobbs ruling than before it (P < .001). Although overall rates of tubal ligation among single women did not change after Dobbs, rates of vasectomy in single men were 1.13 times higher (P < .001).
States were categorized as not hostile to abortion access (abortion access remained available), hostile (access was restricted or might become illegal), or illegal on the basis of information from the Center for Reproductive Rights. Vasectomies increased in most states, with the biggest gain in Tennessee, where abortions are illegal.
The increase in vasectomy rates was similar across nonhostile (incidence rate ratio [IRR], 1.43), hostile (IRR, 1.46), and illegal (IRR, 1.41) states (P < .001). Although the rate of increase was similar regardless of legal climate, the rate of vasectomies was higher in hostile and illegal states than in nonhostile states both before and after the Dobbs ruling, according to the researchers.
Rates of tubal ligation did not change as substantially across the United States after Dobbs, remaining unchanged in states hostile to abortion access and rising slightly in nonhostile states (IRR, 1.06) and in states where abortion is now illegal (IRR, 1.12; P < .001 for both).
However, when the researchers looked at tubal ligation in nonhostile states and hostile or illegal states, they found that rates of the procedure were nearly double in the hostile or illegal states both before and after Dobbs, with a bigger increase after Dobbs in illegal states. Tubal ligation rates were 1.85 times higher in illegal states than in nonhostile states after Dobbs, compared with being 1.76 times higher than in nonhostile states before Dobbs.
Other Studies Support the Findings
Another study assessed the change in the volume of vasectomy consultations at six US academic medical centers in the 17 months before and 5 months after Dobbs (abstract PD40-02). The researchers reported that the rate was roughly 7% higher after the ruling than before (143 vs 134 cases per month, respectively). Again, the men seeking vasectomies after Dobbs were younger than those who sought the procedure before Dobbs (median age, 38 vs 39 years; P < .001). Post-Dobbs patients were also significantly more likely to be non-Hispanic White, English-speaking, and privately insured.
“Younger, childless people are choosing vasectomies as permanent method of birth control,” lead author Kara L. Watts, MD, associate professor of urology at Montefiore Medical Center in Bronx, New York, told attendees. “The impact of this decision is likely to be long-lasting, requiring urologists and medical centers to adjust practice patterns to account for the increased demand.”
Twice as many childless married men underwent vasectomies after Dobbs than before the ruling (11% vs 5%, respectively; P = .001), but substantially more childless single men had the procedure after Dobbs than before it (36% vs 21%; P = .003). Those seeking vasectomies after Dobbs had to wait a median of 8 days longer between consult and procedure (59 vs 51 days pre-Dobbs; P < .001). Several of the same researchers had identified an increase in online searches about vasectomies in the months just after the Dobbs decision.
“We’ve been trying to get men to take more responsibility” for their role in unplanned pregnancies, Ajay K. Nangia, MD, MBBS, professor and vice chair of urology at University of Kansas Medical Center in Overland Park, told this news organization. Dr. Nangia, who helped conduct the study of vasectomy consultations and has spent years on research related to pharmaceutical contraception options for men, said the sudden increase in interest in vasectomies can be ethically fraught. Only 25% of vasectomies can be reversed, and some patients who seek the surgery may not have permanently ruled out having children.
“They’re going into this with their eyes wide open, knowing that it’s not 100% going to be reversible with a vasectomy,” he said. But fear of not having abortion access for their partners is part of their motivation, which creates tension for providers in balancing ethical counseling with the potential paternalism of advising against a vasectomy if they’re not certain that they don’t want children.
“What happens in that situation, when it’s a political decision making you change your medical decision?” Dr. Nangia said. “I worry about that ethically.”
Dr. Nangia noted that the findings of his study cannot show that the Dobbs decision was the cause of the increase in vasectomies. However, in another abstract from the same session (PD40-01), researchers at The Ohio State University College of Medicine in Columbus presented findings from a survey of 57 men who underwent vasectomies in the preceding 2 years. Those results revealed that abortion access had been a factor among some of the 47% of patients whose procedures were performed after Dobbs. Post-Dobbs patients were significantly more likely to say they sought a vasectomy because of concerns about not being able to get abortion (P = .026) and because they didn’t want “to bring children into the current political climate” (P = .002).
A study presented on May 6 (abstract MP76-06) involved a retrospective review of all 631 patients who underwent a vasectomy consult at UC San Diego Medical Center from June 2021 to June 2023. More vasectomy consults occurred after the Dobbs decision than before it (56% vs 44%). The gap for vasectomy consults was slightly wider for partnerless patients after vs before Dobbs (58% vs 42%) and substantially larger for childless patients post-Dobbs compared with pre-Dobbs (63% vs 37%). The childless men undergoing vasectomies after Dobbs also were significantly younger than those who had had this procedure before the ruling (mean, 36.4 vs 39.8 years; P <.001).
“Patients should be counseled on the permanent nature of this procedure, underscoring need for effective and reversible male contraception,” the authors concluded.
Dr. Schardein and Dr. Watts reported no relevant financial conflicts of interest. Dr. Nangia is conducting an idiopathic infertility study with funding from Ferring Pharmaceuticals. None of the studies reported external funding.
A version of this article first appeared on Medscape.com.
The number of Americans seeking permanent forms of contraception has surged in the nearly 2 years since the Dobbs v. Jackson Women’s Health Organization Supreme Court decision that overturned a federal right to abortion, according to a study presented on May 5 at the annual meeting of the American Urological Association (AUA) (abstract PD40-03). Several other studies at the conference reported similar findings.
Rates of vasectomy and tubal ligation have increased in states where abortion became illegal after the court’s June 2022 ruling, researchers found. Rates of tubal sterilization had already been higher in states where abortion was illegal compared with those where access to the procedure remained available and was expected to remain so, but the difference widened after the decision.
“Our study showed trends of increasing utilization of permanent contraception post-Dobbs, with a significant increase in patients less than 30 years old pursuing any type of permanent contraception post-Dobbs,” Jessica N. Schardein, MD, MS, of University of Utah Health in Salt Lake City, told attendees. “Reproductive autonomy is important for people of all genders and may be influenced by legal climate. Understanding the relationship between state-level abortion laws and trends in permanent contraception is crucial for us to determine how to best allocate resources for education and services to ensure reproductive rights for all patients.”
Dr. Schardein told this news organization the increase in vasectomies post-Dobbs was consistent across most states regardless of legal climate, showing that “reproductive health matters to all people,” both women and men.
“We should continue to offer permanent contraception to patients who are not interested in future fertility, regardless of their age or marital status, to ensure reproductive autonomy for those patients,” Dr. Schardein said. “Patients may need increased access to these procedures if the increased rates continue over time.”
Dr. Schardein’s study investigated national trends in the use of permanent contraception before and after the Dobbs ruling. She and her colleagues analyzed data from the Epic Cosmos database of more than 217 million patients from an estimated 27,000 clinics and 1260 hospitals nationwide. The researchers identified all adults who underwent a vasectomy or tubal ligation from July to December 2021 and then from July to December 2022, in the 5 months following the decision.
Among adults aged 18-30 years, rates of vasectomy were 1.59 times higher and rates of tubal ligation were 1.29 times higher after the Dobbs ruling than before it (P < .001). Although overall rates of tubal ligation among single women did not change after Dobbs, rates of vasectomy in single men were 1.13 times higher (P < .001).
States were categorized as not hostile to abortion access (abortion access remained available), hostile (access was restricted or might become illegal), or illegal on the basis of information from the Center for Reproductive Rights. Vasectomies increased in most states, with the biggest gain in Tennessee, where abortions are illegal.
The increase in vasectomy rates was similar across nonhostile (incidence rate ratio [IRR], 1.43), hostile (IRR, 1.46), and illegal (IRR, 1.41) states (P < .001). Although the rate of increase was similar regardless of legal climate, the rate of vasectomies was higher in hostile and illegal states than in nonhostile states both before and after the Dobbs ruling, according to the researchers.
Rates of tubal ligation did not change as substantially across the United States after Dobbs, remaining unchanged in states hostile to abortion access and rising slightly in nonhostile states (IRR, 1.06) and in states where abortion is now illegal (IRR, 1.12; P < .001 for both).
However, when the researchers looked at tubal ligation in nonhostile states and hostile or illegal states, they found that rates of the procedure were nearly double in the hostile or illegal states both before and after Dobbs, with a bigger increase after Dobbs in illegal states. Tubal ligation rates were 1.85 times higher in illegal states than in nonhostile states after Dobbs, compared with being 1.76 times higher than in nonhostile states before Dobbs.
Other Studies Support the Findings
Another study assessed the change in the volume of vasectomy consultations at six US academic medical centers in the 17 months before and 5 months after Dobbs (abstract PD40-02). The researchers reported that the rate was roughly 7% higher after the ruling than before (143 vs 134 cases per month, respectively). Again, the men seeking vasectomies after Dobbs were younger than those who sought the procedure before Dobbs (median age, 38 vs 39 years; P < .001). Post-Dobbs patients were also significantly more likely to be non-Hispanic White, English-speaking, and privately insured.
“Younger, childless people are choosing vasectomies as permanent method of birth control,” lead author Kara L. Watts, MD, associate professor of urology at Montefiore Medical Center in Bronx, New York, told attendees. “The impact of this decision is likely to be long-lasting, requiring urologists and medical centers to adjust practice patterns to account for the increased demand.”
Twice as many childless married men underwent vasectomies after Dobbs than before the ruling (11% vs 5%, respectively; P = .001), but substantially more childless single men had the procedure after Dobbs than before it (36% vs 21%; P = .003). Those seeking vasectomies after Dobbs had to wait a median of 8 days longer between consult and procedure (59 vs 51 days pre-Dobbs; P < .001). Several of the same researchers had identified an increase in online searches about vasectomies in the months just after the Dobbs decision.
“We’ve been trying to get men to take more responsibility” for their role in unplanned pregnancies, Ajay K. Nangia, MD, MBBS, professor and vice chair of urology at University of Kansas Medical Center in Overland Park, told this news organization. Dr. Nangia, who helped conduct the study of vasectomy consultations and has spent years on research related to pharmaceutical contraception options for men, said the sudden increase in interest in vasectomies can be ethically fraught. Only 25% of vasectomies can be reversed, and some patients who seek the surgery may not have permanently ruled out having children.
“They’re going into this with their eyes wide open, knowing that it’s not 100% going to be reversible with a vasectomy,” he said. But fear of not having abortion access for their partners is part of their motivation, which creates tension for providers in balancing ethical counseling with the potential paternalism of advising against a vasectomy if they’re not certain that they don’t want children.
“What happens in that situation, when it’s a political decision making you change your medical decision?” Dr. Nangia said. “I worry about that ethically.”
Dr. Nangia noted that the findings of his study cannot show that the Dobbs decision was the cause of the increase in vasectomies. However, in another abstract from the same session (PD40-01), researchers at The Ohio State University College of Medicine in Columbus presented findings from a survey of 57 men who underwent vasectomies in the preceding 2 years. Those results revealed that abortion access had been a factor among some of the 47% of patients whose procedures were performed after Dobbs. Post-Dobbs patients were significantly more likely to say they sought a vasectomy because of concerns about not being able to get abortion (P = .026) and because they didn’t want “to bring children into the current political climate” (P = .002).
A study presented on May 6 (abstract MP76-06) involved a retrospective review of all 631 patients who underwent a vasectomy consult at UC San Diego Medical Center from June 2021 to June 2023. More vasectomy consults occurred after the Dobbs decision than before it (56% vs 44%). The gap for vasectomy consults was slightly wider for partnerless patients after vs before Dobbs (58% vs 42%) and substantially larger for childless patients post-Dobbs compared with pre-Dobbs (63% vs 37%). The childless men undergoing vasectomies after Dobbs also were significantly younger than those who had had this procedure before the ruling (mean, 36.4 vs 39.8 years; P <.001).
“Patients should be counseled on the permanent nature of this procedure, underscoring need for effective and reversible male contraception,” the authors concluded.
Dr. Schardein and Dr. Watts reported no relevant financial conflicts of interest. Dr. Nangia is conducting an idiopathic infertility study with funding from Ferring Pharmaceuticals. None of the studies reported external funding.
A version of this article first appeared on Medscape.com.
The number of Americans seeking permanent forms of contraception has surged in the nearly 2 years since the Dobbs v. Jackson Women’s Health Organization Supreme Court decision that overturned a federal right to abortion, according to a study presented on May 5 at the annual meeting of the American Urological Association (AUA) (abstract PD40-03). Several other studies at the conference reported similar findings.
Rates of vasectomy and tubal ligation have increased in states where abortion became illegal after the court’s June 2022 ruling, researchers found. Rates of tubal sterilization had already been higher in states where abortion was illegal compared with those where access to the procedure remained available and was expected to remain so, but the difference widened after the decision.
“Our study showed trends of increasing utilization of permanent contraception post-Dobbs, with a significant increase in patients less than 30 years old pursuing any type of permanent contraception post-Dobbs,” Jessica N. Schardein, MD, MS, of University of Utah Health in Salt Lake City, told attendees. “Reproductive autonomy is important for people of all genders and may be influenced by legal climate. Understanding the relationship between state-level abortion laws and trends in permanent contraception is crucial for us to determine how to best allocate resources for education and services to ensure reproductive rights for all patients.”
Dr. Schardein told this news organization the increase in vasectomies post-Dobbs was consistent across most states regardless of legal climate, showing that “reproductive health matters to all people,” both women and men.
“We should continue to offer permanent contraception to patients who are not interested in future fertility, regardless of their age or marital status, to ensure reproductive autonomy for those patients,” Dr. Schardein said. “Patients may need increased access to these procedures if the increased rates continue over time.”
Dr. Schardein’s study investigated national trends in the use of permanent contraception before and after the Dobbs ruling. She and her colleagues analyzed data from the Epic Cosmos database of more than 217 million patients from an estimated 27,000 clinics and 1260 hospitals nationwide. The researchers identified all adults who underwent a vasectomy or tubal ligation from July to December 2021 and then from July to December 2022, in the 5 months following the decision.
Among adults aged 18-30 years, rates of vasectomy were 1.59 times higher and rates of tubal ligation were 1.29 times higher after the Dobbs ruling than before it (P < .001). Although overall rates of tubal ligation among single women did not change after Dobbs, rates of vasectomy in single men were 1.13 times higher (P < .001).
States were categorized as not hostile to abortion access (abortion access remained available), hostile (access was restricted or might become illegal), or illegal on the basis of information from the Center for Reproductive Rights. Vasectomies increased in most states, with the biggest gain in Tennessee, where abortions are illegal.
The increase in vasectomy rates was similar across nonhostile (incidence rate ratio [IRR], 1.43), hostile (IRR, 1.46), and illegal (IRR, 1.41) states (P < .001). Although the rate of increase was similar regardless of legal climate, the rate of vasectomies was higher in hostile and illegal states than in nonhostile states both before and after the Dobbs ruling, according to the researchers.
Rates of tubal ligation did not change as substantially across the United States after Dobbs, remaining unchanged in states hostile to abortion access and rising slightly in nonhostile states (IRR, 1.06) and in states where abortion is now illegal (IRR, 1.12; P < .001 for both).
However, when the researchers looked at tubal ligation in nonhostile states and hostile or illegal states, they found that rates of the procedure were nearly double in the hostile or illegal states both before and after Dobbs, with a bigger increase after Dobbs in illegal states. Tubal ligation rates were 1.85 times higher in illegal states than in nonhostile states after Dobbs, compared with being 1.76 times higher than in nonhostile states before Dobbs.
Other Studies Support the Findings
Another study assessed the change in the volume of vasectomy consultations at six US academic medical centers in the 17 months before and 5 months after Dobbs (abstract PD40-02). The researchers reported that the rate was roughly 7% higher after the ruling than before (143 vs 134 cases per month, respectively). Again, the men seeking vasectomies after Dobbs were younger than those who sought the procedure before Dobbs (median age, 38 vs 39 years; P < .001). Post-Dobbs patients were also significantly more likely to be non-Hispanic White, English-speaking, and privately insured.
“Younger, childless people are choosing vasectomies as permanent method of birth control,” lead author Kara L. Watts, MD, associate professor of urology at Montefiore Medical Center in Bronx, New York, told attendees. “The impact of this decision is likely to be long-lasting, requiring urologists and medical centers to adjust practice patterns to account for the increased demand.”
Twice as many childless married men underwent vasectomies after Dobbs than before the ruling (11% vs 5%, respectively; P = .001), but substantially more childless single men had the procedure after Dobbs than before it (36% vs 21%; P = .003). Those seeking vasectomies after Dobbs had to wait a median of 8 days longer between consult and procedure (59 vs 51 days pre-Dobbs; P < .001). Several of the same researchers had identified an increase in online searches about vasectomies in the months just after the Dobbs decision.
“We’ve been trying to get men to take more responsibility” for their role in unplanned pregnancies, Ajay K. Nangia, MD, MBBS, professor and vice chair of urology at University of Kansas Medical Center in Overland Park, told this news organization. Dr. Nangia, who helped conduct the study of vasectomy consultations and has spent years on research related to pharmaceutical contraception options for men, said the sudden increase in interest in vasectomies can be ethically fraught. Only 25% of vasectomies can be reversed, and some patients who seek the surgery may not have permanently ruled out having children.
“They’re going into this with their eyes wide open, knowing that it’s not 100% going to be reversible with a vasectomy,” he said. But fear of not having abortion access for their partners is part of their motivation, which creates tension for providers in balancing ethical counseling with the potential paternalism of advising against a vasectomy if they’re not certain that they don’t want children.
“What happens in that situation, when it’s a political decision making you change your medical decision?” Dr. Nangia said. “I worry about that ethically.”
Dr. Nangia noted that the findings of his study cannot show that the Dobbs decision was the cause of the increase in vasectomies. However, in another abstract from the same session (PD40-01), researchers at The Ohio State University College of Medicine in Columbus presented findings from a survey of 57 men who underwent vasectomies in the preceding 2 years. Those results revealed that abortion access had been a factor among some of the 47% of patients whose procedures were performed after Dobbs. Post-Dobbs patients were significantly more likely to say they sought a vasectomy because of concerns about not being able to get abortion (P = .026) and because they didn’t want “to bring children into the current political climate” (P = .002).
A study presented on May 6 (abstract MP76-06) involved a retrospective review of all 631 patients who underwent a vasectomy consult at UC San Diego Medical Center from June 2021 to June 2023. More vasectomy consults occurred after the Dobbs decision than before it (56% vs 44%). The gap for vasectomy consults was slightly wider for partnerless patients after vs before Dobbs (58% vs 42%) and substantially larger for childless patients post-Dobbs compared with pre-Dobbs (63% vs 37%). The childless men undergoing vasectomies after Dobbs also were significantly younger than those who had had this procedure before the ruling (mean, 36.4 vs 39.8 years; P <.001).
“Patients should be counseled on the permanent nature of this procedure, underscoring need for effective and reversible male contraception,” the authors concluded.
Dr. Schardein and Dr. Watts reported no relevant financial conflicts of interest. Dr. Nangia is conducting an idiopathic infertility study with funding from Ferring Pharmaceuticals. None of the studies reported external funding.
A version of this article first appeared on Medscape.com.
FROM AUA 2024
Green Initiative Reduces Endoscopic Waste During Colonoscopies
WASHINGTON — As part of a quality improvement initiative, , according to a study presented at Digestive Disease Week® (DDW).
After discussing environmentally conscious practices during regular meetings, the odds of gastroenterologists using a single tool — either biopsy forceps or a snare — compared with multiple disposable tools was three times higher.
“The burden of waste is massive, with GI being the third-largest waste generator in healthcare. The number of procedures is increasing, which just means more waste, and we have to look at ways to reduce it,” said lead author Prateek Harne, MD, a gastroenterology fellow at the University of Texas Health Science Center.
Overall, the healthcare industry generates 8.5% of U.S. greenhouse emissions, with more than 70% coming from used instruments and supplies, he said. GI endoscopy generates 85,000 metric tons of carbon dioxide waste annually. That waste stems from high case volumes, patient travel, the decontamination process, and single-use devices.
After seeing the waste at his institution, Dr. Harne wondered how to reduce single-use device and nonrenewable waste, particularly the tools used during polypectomies. He and colleagues decided to focus on single-tool use and collected data about the tools used during screening colonoscopies for 8 weeks before an intervention.
As part of the intervention, Dr. Harne and colleagues discussed green endoscopy initiatives supported by North American gastrointestinal societies during a journal club meeting with gastroenterology faculty. They also discussed potential strategies to reduce waste in day-to-day practice during a monthly business meeting, particularly focused on being mindful of using tools during polypectomies. The meetings occurred 3 days apart.
Then Dr. Harne and colleagues collected data regarding tool use during screening colonoscopies, looking at the number and type of instruments used. Before the meetings, 210 patients underwent colonoscopies, including 34% that required no intervention, 32% that required one tool, and 33% that required multiple tools.
After the meetings, 112 patients underwent colonoscopies, including 34% that required no tools, 49% that used one tool, and 17% that used multiple tools. This represented a 17% increase in the use of one tool (P < .01) and a 16% decrease in the use of multiple tools (P < .01). The odds of using a single tool compared with multiple tools was 2.98, and there was a statistically significant increase in uptake of snare for polypectomy.
The study was limited by being at a single center, having a small sample size, and using a short-term assessment. At the same time, the findings show potential for a low-cost solution through open discussion with gastroenterologists.
“Sir Isaac Newton had two holes for two different sized cats in his home, but all of his cats ended up using the bigger hole,” Dr. Harne said in his conclusion. “Maybe we can do the same for polypectomies and use only the tools that we need.”
In an interview, Dr. Harne noted he spoke with the janitorial staff at his institution to learn more about endoscopy unit waste, including how much is recycled, how much is incinerated, and who handles the waste. He recognized the work being done in Europe to understand and reduce endoscopic waste and hopes U.S. groups begin to implement more measures.
“Gastroenterologists and their teams need to be more cognizant of the impact we have on the environment,” Dr. Harne said. “As our study shows, if providers are aware that they can and should use fewer tools to get the same results, it can lead to a statistically significant impact, just with a friendly reminder to reduce use.”
After the presentation, Dr. Harne discussed other shifts with conference attendees, such as not opening or unwrapping tools until needed during a procedure.
“Small changes could have big impacts. Everything that we do in QI [quality improvement] is meant to help patients and the environment,” said Amanda Krouse, MD, a research fellow at the University of California, San Diego, who was a moderator of the DDW session on GI fellow–directed QI projects.
In an interview, Alana Persaud, MD, an endoscopy fellow at Geisinger Medical Center in Danville, Pennsylvania, also a moderator of the session, said: “Ultimately, the medical services we’re providing are for the longevity of our patients, but at the same time, we don’t want it to be to the detriment of the environment, so paying attention to green endoscopy when we can preserve and use more discretion with our devices is worth it so we can all thrive together.”
Dr. Harne did not have any disclosures.
WASHINGTON — As part of a quality improvement initiative, , according to a study presented at Digestive Disease Week® (DDW).
After discussing environmentally conscious practices during regular meetings, the odds of gastroenterologists using a single tool — either biopsy forceps or a snare — compared with multiple disposable tools was three times higher.
“The burden of waste is massive, with GI being the third-largest waste generator in healthcare. The number of procedures is increasing, which just means more waste, and we have to look at ways to reduce it,” said lead author Prateek Harne, MD, a gastroenterology fellow at the University of Texas Health Science Center.
Overall, the healthcare industry generates 8.5% of U.S. greenhouse emissions, with more than 70% coming from used instruments and supplies, he said. GI endoscopy generates 85,000 metric tons of carbon dioxide waste annually. That waste stems from high case volumes, patient travel, the decontamination process, and single-use devices.
After seeing the waste at his institution, Dr. Harne wondered how to reduce single-use device and nonrenewable waste, particularly the tools used during polypectomies. He and colleagues decided to focus on single-tool use and collected data about the tools used during screening colonoscopies for 8 weeks before an intervention.
As part of the intervention, Dr. Harne and colleagues discussed green endoscopy initiatives supported by North American gastrointestinal societies during a journal club meeting with gastroenterology faculty. They also discussed potential strategies to reduce waste in day-to-day practice during a monthly business meeting, particularly focused on being mindful of using tools during polypectomies. The meetings occurred 3 days apart.
Then Dr. Harne and colleagues collected data regarding tool use during screening colonoscopies, looking at the number and type of instruments used. Before the meetings, 210 patients underwent colonoscopies, including 34% that required no intervention, 32% that required one tool, and 33% that required multiple tools.
After the meetings, 112 patients underwent colonoscopies, including 34% that required no tools, 49% that used one tool, and 17% that used multiple tools. This represented a 17% increase in the use of one tool (P < .01) and a 16% decrease in the use of multiple tools (P < .01). The odds of using a single tool compared with multiple tools was 2.98, and there was a statistically significant increase in uptake of snare for polypectomy.
The study was limited by being at a single center, having a small sample size, and using a short-term assessment. At the same time, the findings show potential for a low-cost solution through open discussion with gastroenterologists.
“Sir Isaac Newton had two holes for two different sized cats in his home, but all of his cats ended up using the bigger hole,” Dr. Harne said in his conclusion. “Maybe we can do the same for polypectomies and use only the tools that we need.”
In an interview, Dr. Harne noted he spoke with the janitorial staff at his institution to learn more about endoscopy unit waste, including how much is recycled, how much is incinerated, and who handles the waste. He recognized the work being done in Europe to understand and reduce endoscopic waste and hopes U.S. groups begin to implement more measures.
“Gastroenterologists and their teams need to be more cognizant of the impact we have on the environment,” Dr. Harne said. “As our study shows, if providers are aware that they can and should use fewer tools to get the same results, it can lead to a statistically significant impact, just with a friendly reminder to reduce use.”
After the presentation, Dr. Harne discussed other shifts with conference attendees, such as not opening or unwrapping tools until needed during a procedure.
“Small changes could have big impacts. Everything that we do in QI [quality improvement] is meant to help patients and the environment,” said Amanda Krouse, MD, a research fellow at the University of California, San Diego, who was a moderator of the DDW session on GI fellow–directed QI projects.
In an interview, Alana Persaud, MD, an endoscopy fellow at Geisinger Medical Center in Danville, Pennsylvania, also a moderator of the session, said: “Ultimately, the medical services we’re providing are for the longevity of our patients, but at the same time, we don’t want it to be to the detriment of the environment, so paying attention to green endoscopy when we can preserve and use more discretion with our devices is worth it so we can all thrive together.”
Dr. Harne did not have any disclosures.
WASHINGTON — As part of a quality improvement initiative, , according to a study presented at Digestive Disease Week® (DDW).
After discussing environmentally conscious practices during regular meetings, the odds of gastroenterologists using a single tool — either biopsy forceps or a snare — compared with multiple disposable tools was three times higher.
“The burden of waste is massive, with GI being the third-largest waste generator in healthcare. The number of procedures is increasing, which just means more waste, and we have to look at ways to reduce it,” said lead author Prateek Harne, MD, a gastroenterology fellow at the University of Texas Health Science Center.
Overall, the healthcare industry generates 8.5% of U.S. greenhouse emissions, with more than 70% coming from used instruments and supplies, he said. GI endoscopy generates 85,000 metric tons of carbon dioxide waste annually. That waste stems from high case volumes, patient travel, the decontamination process, and single-use devices.
After seeing the waste at his institution, Dr. Harne wondered how to reduce single-use device and nonrenewable waste, particularly the tools used during polypectomies. He and colleagues decided to focus on single-tool use and collected data about the tools used during screening colonoscopies for 8 weeks before an intervention.
As part of the intervention, Dr. Harne and colleagues discussed green endoscopy initiatives supported by North American gastrointestinal societies during a journal club meeting with gastroenterology faculty. They also discussed potential strategies to reduce waste in day-to-day practice during a monthly business meeting, particularly focused on being mindful of using tools during polypectomies. The meetings occurred 3 days apart.
Then Dr. Harne and colleagues collected data regarding tool use during screening colonoscopies, looking at the number and type of instruments used. Before the meetings, 210 patients underwent colonoscopies, including 34% that required no intervention, 32% that required one tool, and 33% that required multiple tools.
After the meetings, 112 patients underwent colonoscopies, including 34% that required no tools, 49% that used one tool, and 17% that used multiple tools. This represented a 17% increase in the use of one tool (P < .01) and a 16% decrease in the use of multiple tools (P < .01). The odds of using a single tool compared with multiple tools was 2.98, and there was a statistically significant increase in uptake of snare for polypectomy.
The study was limited by being at a single center, having a small sample size, and using a short-term assessment. At the same time, the findings show potential for a low-cost solution through open discussion with gastroenterologists.
“Sir Isaac Newton had two holes for two different sized cats in his home, but all of his cats ended up using the bigger hole,” Dr. Harne said in his conclusion. “Maybe we can do the same for polypectomies and use only the tools that we need.”
In an interview, Dr. Harne noted he spoke with the janitorial staff at his institution to learn more about endoscopy unit waste, including how much is recycled, how much is incinerated, and who handles the waste. He recognized the work being done in Europe to understand and reduce endoscopic waste and hopes U.S. groups begin to implement more measures.
“Gastroenterologists and their teams need to be more cognizant of the impact we have on the environment,” Dr. Harne said. “As our study shows, if providers are aware that they can and should use fewer tools to get the same results, it can lead to a statistically significant impact, just with a friendly reminder to reduce use.”
After the presentation, Dr. Harne discussed other shifts with conference attendees, such as not opening or unwrapping tools until needed during a procedure.
“Small changes could have big impacts. Everything that we do in QI [quality improvement] is meant to help patients and the environment,” said Amanda Krouse, MD, a research fellow at the University of California, San Diego, who was a moderator of the DDW session on GI fellow–directed QI projects.
In an interview, Alana Persaud, MD, an endoscopy fellow at Geisinger Medical Center in Danville, Pennsylvania, also a moderator of the session, said: “Ultimately, the medical services we’re providing are for the longevity of our patients, but at the same time, we don’t want it to be to the detriment of the environment, so paying attention to green endoscopy when we can preserve and use more discretion with our devices is worth it so we can all thrive together.”
Dr. Harne did not have any disclosures.
FROM DDW 2024
New Immunotherapy Combo Shows Promise for Triple-Negative Breast Cancer
MORPHEUS-pan BC (NCT03424005) is evaluating multiple treatment combinations in patients with locally advanced or metastatic TNBC.
The trial’s interim clinical data was presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
Rationale for Combining Antibody-Drug Conjugates with Immunotherapy
Peter Schmid, MD, PhD, professor at the Centre for Experimental Cancer Medicine in London, England, presented interim findings from one study arm of MORPHEUS-pan BC at the meeting. The arm consisted of patients with TNBC who were treated with a combination of atezolizumab, a PD-L1 inhibitor, and sacituzumab govitecan, an antibody-drug conjugate targeting the Trop-2 protein commonly expressed in TNBC.
TNBC is one of the most challenging subtypes of breast cancer to treat because of its aggressive characteristics and innate resistance to hormonal therapy and HER2-targeted treatments. However, the recent approval of immunotherapy for TNBC has provided renewed hope for patients, according to Dr. Schmid.
Atezolizumab, in combination with nab-paclitaxel, has already been approved as a first-line treatment for PD-L1–positive, unresectable locally advanced or metastatic TNBC; however, not all patients respond to this combination treatment. Sacituzumab govitecan is approved for second-line and subsequent-line treatment of metastatic TNBC.
“Cancer immunotherapy in combination with chemotherapy has transformed the TNBC treatment landscape, but new combinations are needed to further improve survival outcomes,” Dr. Schmid said during his presentation. “We hoped that combining immunotherapy with an antibody-drug conjugate would not only improve safety but also increase efficacy through enhanced immune activation.”
Study Design
The MORPHEUS-pan BC trial enrolled patients with previously untreated, PD-L1–positive, inoperable, locally advanced or metastatic TNBC. Patients were randomized to receive experimental treatment consisting of atezolizumab plus the antibody-drug conjugate sacituzumab govitecan. Patients in the second arm received a control regimen of atezolizumab plus nab-paclitaxel chemotherapy.
“The control regimen is part of the current standard of care for patients with PD-L1–positive TNBC,” Dr. Schmid explained in his presentation. As of the data cut-off, 11 patients were enrolled in the control arm and 31 in the atezolizumab plus sacituzumab govitecan arm.
During the discussion session after his talk, Dr. Schmid commented on the use of PD-L1 expression to select patients for enrollment, acknowledging that PD-L1 is not the best biomarker.
“Its expression is very dynamic and can change rapidly,” he said. He added, however, that it is currently the most suitable biomarker for patient selection for treatment with anti–PD-1/PD-L1 agents.
Sara M. Tolaney, MD, MPH, added that, because patients were selected based on PD-L1 expression, it is unclear whether this combination therapy would show anti-tumor activity in patients with PD-L1–negative tumors. Dr. Tolaney, a medical oncologist at the Dana-Farber Cancer Institute who was not involved in the study, served as a discussant, providing her expert opinion on the findings presented by Dr. Schmid.
Promising Anti-tumor Activity
The combination of atezolizumab and sacituzumab govitecan demonstrated promising anti-tumor activity as initial treatment for this patient population. The interim analysis at 18 weeks showed an objective response rate of 76.7% (95% CI, 57.7-90.1; n = 23, including five complete responses) in the atezolizumab plus sacituzumab govitecan arm, versus 66.7% (95% CI, 29.9-92.5; n = 6, all of which were partial responses) in the control arm.
“The 66% response rate in the control arm aligns with what we see in historical data from patients treated with immunotherapy plus chemotherapy,” noted Dr. Schmid during his talk.
The clinical benefit rate, which includes complete and partial responses as well as stable disease, was also encouraging at 83.3% (95% CI, 65.3-94.4) with the dual immunotherapy regimen versus 66.7% (95% CI, 29.9-92.5) with standard therapy.
Commenting on the potential mechanisms of the synergistic effect of this combination therapy, Dr. Tolaney said, “In addition to delivering chemotherapy payloads to cancer cells, antibody-drug conjugates can lead to dendritic cell activation, T-cell activation, and immune cell infiltration.”
She added that antibody-drug conjugates can cause Fc activation in NK cells, thereby enhancing antibody-dependent cytotoxicity.
Encouraging survival trends
Interim survival data showed trends favoring atezolizumab plus sacituzumab govitecan over the control arm of atezolizumab plus nab-paclitaxel chemotherapy. The median progression-free survival (PFS) was 12.2 months (95% CI, 7.4-not estimable) in the immunotherapy combination group versus 5.9 months (95% CI, 4.1-8.7) in the control group, yielding a hazard ratio of 0.29 (95% CI, 0.11-0.70). The overall survival data are still immature.
During the discussion session, Dr. Schmid cautioned that, although the benefit of this combination therapy in terms of PFS seems promising, the validity of the hazard ratio is limited because of the small cohort size. He added, “The survival data is still immature, and longer follow-up is needed.”
These encouraging response and PFS rates need to be confirmed in larger studies of this immunotherapy combination as a potential new first-line standard for PD-L1–positive TNBC, according to Dr. Schmid.
Relationship between biomarker expression and response
The MORPHEUS-pan BC trial enrolled only patients with PD-L1–positive tumors at baseline, defined as PD-L1 expression in at least 1% of immune cells infiltrating the tumor. Tumors at baseline were also tested for Trop-2 expression, CD8 immune phenotype, and stromal tumor-infiltrating lymphocytes (TILs).
“We wanted to get an idea of whether these biomarkers are associated with treatment response,” Dr. Schmid explained during his talk.
Although the benefit of sacituzumab govitecan treatment was observed across all Trop-2 expression levels, preliminary analyses suggest that high Trop-2 expression, CD8 immune phenotype, and stromal TILs may be associated with response to atezolizumab plus sacituzumab govitecan. However, Dr. Schmid noted that validation of these associations in larger cohorts is required.
Safety of combination treatment
The side effect profile of atezolizumab plus sacituzumab govitecan appeared consistent with that expected from the two individual drugs, with no new toxicity signals.
All patients in both treatment arms experienced at least one adverse event; however, there were no fatal adverse events. Grade 3-4 adverse events were more common in the experimental arm (70.0%) than in the control arm (44.4%), while serious adverse events were more common in the control group (44.4% versus 23.3%). Immune-related adverse events were considerably more common in the atezolizumab plus sacituzumab govitecan group than in the control group (80.0% versus 55.6%).
The most common adverse events in patients treated with atezolizumab plus sacituzumab govitecan were nausea, alopecia, diarrhea, and neutropenia. Dr. Schmid emphasized in his presentation that this toxicity profile was dominated by adverse events that are common in patients treated with chemotherapy.
“These safety data are significant as they suggest that the combination therapy does not introduce additional risks beyond those already associated with each drug,” he added.
Looking Ahead
Dr. Tolaney highlighted that the cohort size of this study was small and the follow-up time was insufficient to draw conclusions about survival outcomes. Larger studies with long-term follow-up are needed to confirm the efficacy of first-line atezolizumab plus sacituzumab govitecan, she said.
“While this was a small study, the response data is very intriguing, with 17% of patients experiencing complete responses. The PFS data are also impressive, and there seems to be an interesting trend towards better response in patients with high Trop-2 expression and those with high levels of stromal TILs,” she added.
Dr. Tolaney also noted that the response rates and PFS data presented are similar to those of one of the treatment arms in the BEGONIA trial (NCT03742102), which investigated different combinations of immunotherapy in patients with metastatic TNBC. Like MORPHEUS-pan BC (NCT03424005), this study evaluated the efficacy of a different antibody-drug conjugate with chemotherapy. Patients in the study arm of the BEGONIA trial she was referring to received durvalumab (an anti-PD-L1 agent) and datopotamab deruxtecan (an antibody-drug conjugate).
Dr. Schmid said that biomarker analyses are ongoing to assess whether there is a correlation between Trop-2 expression levels and the benefits of sacituzumab govitecan. Studies are also needed to determine whether this combination can improve pathologic complete response rates in early-stage TNBC.
Dr. Tolaney echoed the importance of evaluating the efficacy of antibody-drug conjugates plus immune checkpoint inhibitors in different settings, including patients with PD-L1–negative or immunologically cold tumors and those with early-stage disease. “Ultimately, we want this combination treatment to move forward to early-stage TNBC to see if we could cure more patients,” she said, during the discussion.
Dr. Schmid reported financial relationships with Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (consulting or advisory roles); Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (honoraria); and AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas, and Medivation (research funding). Dr. Tolaney reported financial relationships with Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., Beyond Spring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, and Jazz Pharmaceuticals (consulting or advisory roles); Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Nanostring, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, Cyclacel, Sanofi, and Seattle Genetics (research funding).
MORPHEUS-pan BC (NCT03424005) is evaluating multiple treatment combinations in patients with locally advanced or metastatic TNBC.
The trial’s interim clinical data was presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
Rationale for Combining Antibody-Drug Conjugates with Immunotherapy
Peter Schmid, MD, PhD, professor at the Centre for Experimental Cancer Medicine in London, England, presented interim findings from one study arm of MORPHEUS-pan BC at the meeting. The arm consisted of patients with TNBC who were treated with a combination of atezolizumab, a PD-L1 inhibitor, and sacituzumab govitecan, an antibody-drug conjugate targeting the Trop-2 protein commonly expressed in TNBC.
TNBC is one of the most challenging subtypes of breast cancer to treat because of its aggressive characteristics and innate resistance to hormonal therapy and HER2-targeted treatments. However, the recent approval of immunotherapy for TNBC has provided renewed hope for patients, according to Dr. Schmid.
Atezolizumab, in combination with nab-paclitaxel, has already been approved as a first-line treatment for PD-L1–positive, unresectable locally advanced or metastatic TNBC; however, not all patients respond to this combination treatment. Sacituzumab govitecan is approved for second-line and subsequent-line treatment of metastatic TNBC.
“Cancer immunotherapy in combination with chemotherapy has transformed the TNBC treatment landscape, but new combinations are needed to further improve survival outcomes,” Dr. Schmid said during his presentation. “We hoped that combining immunotherapy with an antibody-drug conjugate would not only improve safety but also increase efficacy through enhanced immune activation.”
Study Design
The MORPHEUS-pan BC trial enrolled patients with previously untreated, PD-L1–positive, inoperable, locally advanced or metastatic TNBC. Patients were randomized to receive experimental treatment consisting of atezolizumab plus the antibody-drug conjugate sacituzumab govitecan. Patients in the second arm received a control regimen of atezolizumab plus nab-paclitaxel chemotherapy.
“The control regimen is part of the current standard of care for patients with PD-L1–positive TNBC,” Dr. Schmid explained in his presentation. As of the data cut-off, 11 patients were enrolled in the control arm and 31 in the atezolizumab plus sacituzumab govitecan arm.
During the discussion session after his talk, Dr. Schmid commented on the use of PD-L1 expression to select patients for enrollment, acknowledging that PD-L1 is not the best biomarker.
“Its expression is very dynamic and can change rapidly,” he said. He added, however, that it is currently the most suitable biomarker for patient selection for treatment with anti–PD-1/PD-L1 agents.
Sara M. Tolaney, MD, MPH, added that, because patients were selected based on PD-L1 expression, it is unclear whether this combination therapy would show anti-tumor activity in patients with PD-L1–negative tumors. Dr. Tolaney, a medical oncologist at the Dana-Farber Cancer Institute who was not involved in the study, served as a discussant, providing her expert opinion on the findings presented by Dr. Schmid.
Promising Anti-tumor Activity
The combination of atezolizumab and sacituzumab govitecan demonstrated promising anti-tumor activity as initial treatment for this patient population. The interim analysis at 18 weeks showed an objective response rate of 76.7% (95% CI, 57.7-90.1; n = 23, including five complete responses) in the atezolizumab plus sacituzumab govitecan arm, versus 66.7% (95% CI, 29.9-92.5; n = 6, all of which were partial responses) in the control arm.
“The 66% response rate in the control arm aligns with what we see in historical data from patients treated with immunotherapy plus chemotherapy,” noted Dr. Schmid during his talk.
The clinical benefit rate, which includes complete and partial responses as well as stable disease, was also encouraging at 83.3% (95% CI, 65.3-94.4) with the dual immunotherapy regimen versus 66.7% (95% CI, 29.9-92.5) with standard therapy.
Commenting on the potential mechanisms of the synergistic effect of this combination therapy, Dr. Tolaney said, “In addition to delivering chemotherapy payloads to cancer cells, antibody-drug conjugates can lead to dendritic cell activation, T-cell activation, and immune cell infiltration.”
She added that antibody-drug conjugates can cause Fc activation in NK cells, thereby enhancing antibody-dependent cytotoxicity.
Encouraging survival trends
Interim survival data showed trends favoring atezolizumab plus sacituzumab govitecan over the control arm of atezolizumab plus nab-paclitaxel chemotherapy. The median progression-free survival (PFS) was 12.2 months (95% CI, 7.4-not estimable) in the immunotherapy combination group versus 5.9 months (95% CI, 4.1-8.7) in the control group, yielding a hazard ratio of 0.29 (95% CI, 0.11-0.70). The overall survival data are still immature.
During the discussion session, Dr. Schmid cautioned that, although the benefit of this combination therapy in terms of PFS seems promising, the validity of the hazard ratio is limited because of the small cohort size. He added, “The survival data is still immature, and longer follow-up is needed.”
These encouraging response and PFS rates need to be confirmed in larger studies of this immunotherapy combination as a potential new first-line standard for PD-L1–positive TNBC, according to Dr. Schmid.
Relationship between biomarker expression and response
The MORPHEUS-pan BC trial enrolled only patients with PD-L1–positive tumors at baseline, defined as PD-L1 expression in at least 1% of immune cells infiltrating the tumor. Tumors at baseline were also tested for Trop-2 expression, CD8 immune phenotype, and stromal tumor-infiltrating lymphocytes (TILs).
“We wanted to get an idea of whether these biomarkers are associated with treatment response,” Dr. Schmid explained during his talk.
Although the benefit of sacituzumab govitecan treatment was observed across all Trop-2 expression levels, preliminary analyses suggest that high Trop-2 expression, CD8 immune phenotype, and stromal TILs may be associated with response to atezolizumab plus sacituzumab govitecan. However, Dr. Schmid noted that validation of these associations in larger cohorts is required.
Safety of combination treatment
The side effect profile of atezolizumab plus sacituzumab govitecan appeared consistent with that expected from the two individual drugs, with no new toxicity signals.
All patients in both treatment arms experienced at least one adverse event; however, there were no fatal adverse events. Grade 3-4 adverse events were more common in the experimental arm (70.0%) than in the control arm (44.4%), while serious adverse events were more common in the control group (44.4% versus 23.3%). Immune-related adverse events were considerably more common in the atezolizumab plus sacituzumab govitecan group than in the control group (80.0% versus 55.6%).
The most common adverse events in patients treated with atezolizumab plus sacituzumab govitecan were nausea, alopecia, diarrhea, and neutropenia. Dr. Schmid emphasized in his presentation that this toxicity profile was dominated by adverse events that are common in patients treated with chemotherapy.
“These safety data are significant as they suggest that the combination therapy does not introduce additional risks beyond those already associated with each drug,” he added.
Looking Ahead
Dr. Tolaney highlighted that the cohort size of this study was small and the follow-up time was insufficient to draw conclusions about survival outcomes. Larger studies with long-term follow-up are needed to confirm the efficacy of first-line atezolizumab plus sacituzumab govitecan, she said.
“While this was a small study, the response data is very intriguing, with 17% of patients experiencing complete responses. The PFS data are also impressive, and there seems to be an interesting trend towards better response in patients with high Trop-2 expression and those with high levels of stromal TILs,” she added.
Dr. Tolaney also noted that the response rates and PFS data presented are similar to those of one of the treatment arms in the BEGONIA trial (NCT03742102), which investigated different combinations of immunotherapy in patients with metastatic TNBC. Like MORPHEUS-pan BC (NCT03424005), this study evaluated the efficacy of a different antibody-drug conjugate with chemotherapy. Patients in the study arm of the BEGONIA trial she was referring to received durvalumab (an anti-PD-L1 agent) and datopotamab deruxtecan (an antibody-drug conjugate).
Dr. Schmid said that biomarker analyses are ongoing to assess whether there is a correlation between Trop-2 expression levels and the benefits of sacituzumab govitecan. Studies are also needed to determine whether this combination can improve pathologic complete response rates in early-stage TNBC.
Dr. Tolaney echoed the importance of evaluating the efficacy of antibody-drug conjugates plus immune checkpoint inhibitors in different settings, including patients with PD-L1–negative or immunologically cold tumors and those with early-stage disease. “Ultimately, we want this combination treatment to move forward to early-stage TNBC to see if we could cure more patients,” she said, during the discussion.
Dr. Schmid reported financial relationships with Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (consulting or advisory roles); Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (honoraria); and AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas, and Medivation (research funding). Dr. Tolaney reported financial relationships with Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., Beyond Spring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, and Jazz Pharmaceuticals (consulting or advisory roles); Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Nanostring, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, Cyclacel, Sanofi, and Seattle Genetics (research funding).
MORPHEUS-pan BC (NCT03424005) is evaluating multiple treatment combinations in patients with locally advanced or metastatic TNBC.
The trial’s interim clinical data was presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
Rationale for Combining Antibody-Drug Conjugates with Immunotherapy
Peter Schmid, MD, PhD, professor at the Centre for Experimental Cancer Medicine in London, England, presented interim findings from one study arm of MORPHEUS-pan BC at the meeting. The arm consisted of patients with TNBC who were treated with a combination of atezolizumab, a PD-L1 inhibitor, and sacituzumab govitecan, an antibody-drug conjugate targeting the Trop-2 protein commonly expressed in TNBC.
TNBC is one of the most challenging subtypes of breast cancer to treat because of its aggressive characteristics and innate resistance to hormonal therapy and HER2-targeted treatments. However, the recent approval of immunotherapy for TNBC has provided renewed hope for patients, according to Dr. Schmid.
Atezolizumab, in combination with nab-paclitaxel, has already been approved as a first-line treatment for PD-L1–positive, unresectable locally advanced or metastatic TNBC; however, not all patients respond to this combination treatment. Sacituzumab govitecan is approved for second-line and subsequent-line treatment of metastatic TNBC.
“Cancer immunotherapy in combination with chemotherapy has transformed the TNBC treatment landscape, but new combinations are needed to further improve survival outcomes,” Dr. Schmid said during his presentation. “We hoped that combining immunotherapy with an antibody-drug conjugate would not only improve safety but also increase efficacy through enhanced immune activation.”
Study Design
The MORPHEUS-pan BC trial enrolled patients with previously untreated, PD-L1–positive, inoperable, locally advanced or metastatic TNBC. Patients were randomized to receive experimental treatment consisting of atezolizumab plus the antibody-drug conjugate sacituzumab govitecan. Patients in the second arm received a control regimen of atezolizumab plus nab-paclitaxel chemotherapy.
“The control regimen is part of the current standard of care for patients with PD-L1–positive TNBC,” Dr. Schmid explained in his presentation. As of the data cut-off, 11 patients were enrolled in the control arm and 31 in the atezolizumab plus sacituzumab govitecan arm.
During the discussion session after his talk, Dr. Schmid commented on the use of PD-L1 expression to select patients for enrollment, acknowledging that PD-L1 is not the best biomarker.
“Its expression is very dynamic and can change rapidly,” he said. He added, however, that it is currently the most suitable biomarker for patient selection for treatment with anti–PD-1/PD-L1 agents.
Sara M. Tolaney, MD, MPH, added that, because patients were selected based on PD-L1 expression, it is unclear whether this combination therapy would show anti-tumor activity in patients with PD-L1–negative tumors. Dr. Tolaney, a medical oncologist at the Dana-Farber Cancer Institute who was not involved in the study, served as a discussant, providing her expert opinion on the findings presented by Dr. Schmid.
Promising Anti-tumor Activity
The combination of atezolizumab and sacituzumab govitecan demonstrated promising anti-tumor activity as initial treatment for this patient population. The interim analysis at 18 weeks showed an objective response rate of 76.7% (95% CI, 57.7-90.1; n = 23, including five complete responses) in the atezolizumab plus sacituzumab govitecan arm, versus 66.7% (95% CI, 29.9-92.5; n = 6, all of which were partial responses) in the control arm.
“The 66% response rate in the control arm aligns with what we see in historical data from patients treated with immunotherapy plus chemotherapy,” noted Dr. Schmid during his talk.
The clinical benefit rate, which includes complete and partial responses as well as stable disease, was also encouraging at 83.3% (95% CI, 65.3-94.4) with the dual immunotherapy regimen versus 66.7% (95% CI, 29.9-92.5) with standard therapy.
Commenting on the potential mechanisms of the synergistic effect of this combination therapy, Dr. Tolaney said, “In addition to delivering chemotherapy payloads to cancer cells, antibody-drug conjugates can lead to dendritic cell activation, T-cell activation, and immune cell infiltration.”
She added that antibody-drug conjugates can cause Fc activation in NK cells, thereby enhancing antibody-dependent cytotoxicity.
Encouraging survival trends
Interim survival data showed trends favoring atezolizumab plus sacituzumab govitecan over the control arm of atezolizumab plus nab-paclitaxel chemotherapy. The median progression-free survival (PFS) was 12.2 months (95% CI, 7.4-not estimable) in the immunotherapy combination group versus 5.9 months (95% CI, 4.1-8.7) in the control group, yielding a hazard ratio of 0.29 (95% CI, 0.11-0.70). The overall survival data are still immature.
During the discussion session, Dr. Schmid cautioned that, although the benefit of this combination therapy in terms of PFS seems promising, the validity of the hazard ratio is limited because of the small cohort size. He added, “The survival data is still immature, and longer follow-up is needed.”
These encouraging response and PFS rates need to be confirmed in larger studies of this immunotherapy combination as a potential new first-line standard for PD-L1–positive TNBC, according to Dr. Schmid.
Relationship between biomarker expression and response
The MORPHEUS-pan BC trial enrolled only patients with PD-L1–positive tumors at baseline, defined as PD-L1 expression in at least 1% of immune cells infiltrating the tumor. Tumors at baseline were also tested for Trop-2 expression, CD8 immune phenotype, and stromal tumor-infiltrating lymphocytes (TILs).
“We wanted to get an idea of whether these biomarkers are associated with treatment response,” Dr. Schmid explained during his talk.
Although the benefit of sacituzumab govitecan treatment was observed across all Trop-2 expression levels, preliminary analyses suggest that high Trop-2 expression, CD8 immune phenotype, and stromal TILs may be associated with response to atezolizumab plus sacituzumab govitecan. However, Dr. Schmid noted that validation of these associations in larger cohorts is required.
Safety of combination treatment
The side effect profile of atezolizumab plus sacituzumab govitecan appeared consistent with that expected from the two individual drugs, with no new toxicity signals.
All patients in both treatment arms experienced at least one adverse event; however, there were no fatal adverse events. Grade 3-4 adverse events were more common in the experimental arm (70.0%) than in the control arm (44.4%), while serious adverse events were more common in the control group (44.4% versus 23.3%). Immune-related adverse events were considerably more common in the atezolizumab plus sacituzumab govitecan group than in the control group (80.0% versus 55.6%).
The most common adverse events in patients treated with atezolizumab plus sacituzumab govitecan were nausea, alopecia, diarrhea, and neutropenia. Dr. Schmid emphasized in his presentation that this toxicity profile was dominated by adverse events that are common in patients treated with chemotherapy.
“These safety data are significant as they suggest that the combination therapy does not introduce additional risks beyond those already associated with each drug,” he added.
Looking Ahead
Dr. Tolaney highlighted that the cohort size of this study was small and the follow-up time was insufficient to draw conclusions about survival outcomes. Larger studies with long-term follow-up are needed to confirm the efficacy of first-line atezolizumab plus sacituzumab govitecan, she said.
“While this was a small study, the response data is very intriguing, with 17% of patients experiencing complete responses. The PFS data are also impressive, and there seems to be an interesting trend towards better response in patients with high Trop-2 expression and those with high levels of stromal TILs,” she added.
Dr. Tolaney also noted that the response rates and PFS data presented are similar to those of one of the treatment arms in the BEGONIA trial (NCT03742102), which investigated different combinations of immunotherapy in patients with metastatic TNBC. Like MORPHEUS-pan BC (NCT03424005), this study evaluated the efficacy of a different antibody-drug conjugate with chemotherapy. Patients in the study arm of the BEGONIA trial she was referring to received durvalumab (an anti-PD-L1 agent) and datopotamab deruxtecan (an antibody-drug conjugate).
Dr. Schmid said that biomarker analyses are ongoing to assess whether there is a correlation between Trop-2 expression levels and the benefits of sacituzumab govitecan. Studies are also needed to determine whether this combination can improve pathologic complete response rates in early-stage TNBC.
Dr. Tolaney echoed the importance of evaluating the efficacy of antibody-drug conjugates plus immune checkpoint inhibitors in different settings, including patients with PD-L1–negative or immunologically cold tumors and those with early-stage disease. “Ultimately, we want this combination treatment to move forward to early-stage TNBC to see if we could cure more patients,” she said, during the discussion.
Dr. Schmid reported financial relationships with Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (consulting or advisory roles); Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (honoraria); and AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas, and Medivation (research funding). Dr. Tolaney reported financial relationships with Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., Beyond Spring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, and Jazz Pharmaceuticals (consulting or advisory roles); Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Nanostring, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, Cyclacel, Sanofi, and Seattle Genetics (research funding).
FROM ESMO BREAST CANCER 2024