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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
Survey Spotlights Identification of Dermatologic Adverse Events From Cancer Therapies
“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.
The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”
To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.
Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).
“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”
Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”
Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”
Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.
“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”
Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
A version of this article first appeared on Medscape.com.
“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.
The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”
To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.
Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).
“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”
Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”
Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”
Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.
“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”
Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
A version of this article first appeared on Medscape.com.
“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.
The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”
To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.
Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).
“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”
Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”
Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”
Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.
“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”
Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
A version of this article first appeared on Medscape.com.
FROM AAD 2024
Do Patients Benefit from Cancer Trial Participation?
TOPLINE:
METHODOLOGY:
- The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
- To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
- The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
- The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.
TAKEAWAY:
- Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
- Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
- Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).
IN PRACTICE:
“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote.
“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”
SOURCE:
Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.
LIMITATIONS:
There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported.
DISCLOSURES:
Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
- To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
- The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
- The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.
TAKEAWAY:
- Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
- Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
- Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).
IN PRACTICE:
“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote.
“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”
SOURCE:
Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.
LIMITATIONS:
There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported.
DISCLOSURES:
Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
- To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
- The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
- The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.
TAKEAWAY:
- Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
- Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
- Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).
IN PRACTICE:
“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote.
“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”
SOURCE:
Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.
LIMITATIONS:
There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported.
DISCLOSURES:
Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.
A version of this article appeared on Medscape.com.
FDA Approves New Bladder Cancer Drug
Specifically, the agent is approved to treat patients with BCG-unresponsive non–muscle-invasive bladder cancer carcinoma in situ with or without Ta or T1 papillary disease.
The FDA declined an initial approval for the combination in May 2023 because of deficiencies the agency observed during its prelicense inspection of third-party manufacturing organizations. In October 2023, ImmunityBio resubmitted the Biologics License Application, which was accepted.
The new therapy represents addresses “an unmet need” in this high-risk bladder cancer population, the company stated in a press release announcing the initial study findings. Typically, patients with intermediate or high-risk disease undergo bladder tumor resection followed by treatment with BCG, but the cancer recurs in up to 50% of patients, including those who experience a complete response, explained ImmunityBio, which acquired Altor BioScience.
Approval was based on findings from the single arm, phase 2/3 open-label QUILT-3.032 study, which included 77 patients with BCG-unresponsive, high-risk disease following transurethral resection. All had Eastern Cooperative Oncology Group performance status of 0-2.
Patients received nogapendekin alfa inbakicept-pmln induction via intravesical instillation with BCG followed by maintenance therapy for up to 37 months.
According to the FDA’s press release, 62% of patients had a complete response, defined as a negative cystoscopy and urine cytology; 58% of those with a complete response had a duration of response lasting at least 12 months and 40% had a duration of response lasting 24 months or longer.
The safety of the combination was evaluated in a cohort of 88 patients. Serious adverse reactions occurred in 16% of patients. The most common treatment-emergent adverse effects included dysuria, pollakiuria, and hematuria, which are associated with intravesical BCG; 86% of these events were grade 1 or 2. Overall, 7% of patients discontinued the combination owing to adverse reactions.
The recommended dose is 400 mcg administered intravesically with BCG once a week for 6 weeks as induction therapy, with an option for a second induction course if patients don’t achieve a complete response at 3 months. The recommended maintenance therapy dose is 400 mcg with BCG once a week for 3 weeks at months 4, 7, 10, 13, and 19. Patients who achieve a complete response at 25 months and beyond may receive maintenance instillations with BCG once a week for 3 weeks at months 25, 31, and 37. The maximum treatment duration is 37 months.
The FDA recommends discontinuing treatment if disease persists after second induction or owing to disease recurrence, progression, or unacceptable toxicity.
A version of this article appeared on Medscape.com.
Specifically, the agent is approved to treat patients with BCG-unresponsive non–muscle-invasive bladder cancer carcinoma in situ with or without Ta or T1 papillary disease.
The FDA declined an initial approval for the combination in May 2023 because of deficiencies the agency observed during its prelicense inspection of third-party manufacturing organizations. In October 2023, ImmunityBio resubmitted the Biologics License Application, which was accepted.
The new therapy represents addresses “an unmet need” in this high-risk bladder cancer population, the company stated in a press release announcing the initial study findings. Typically, patients with intermediate or high-risk disease undergo bladder tumor resection followed by treatment with BCG, but the cancer recurs in up to 50% of patients, including those who experience a complete response, explained ImmunityBio, which acquired Altor BioScience.
Approval was based on findings from the single arm, phase 2/3 open-label QUILT-3.032 study, which included 77 patients with BCG-unresponsive, high-risk disease following transurethral resection. All had Eastern Cooperative Oncology Group performance status of 0-2.
Patients received nogapendekin alfa inbakicept-pmln induction via intravesical instillation with BCG followed by maintenance therapy for up to 37 months.
According to the FDA’s press release, 62% of patients had a complete response, defined as a negative cystoscopy and urine cytology; 58% of those with a complete response had a duration of response lasting at least 12 months and 40% had a duration of response lasting 24 months or longer.
The safety of the combination was evaluated in a cohort of 88 patients. Serious adverse reactions occurred in 16% of patients. The most common treatment-emergent adverse effects included dysuria, pollakiuria, and hematuria, which are associated with intravesical BCG; 86% of these events were grade 1 or 2. Overall, 7% of patients discontinued the combination owing to adverse reactions.
The recommended dose is 400 mcg administered intravesically with BCG once a week for 6 weeks as induction therapy, with an option for a second induction course if patients don’t achieve a complete response at 3 months. The recommended maintenance therapy dose is 400 mcg with BCG once a week for 3 weeks at months 4, 7, 10, 13, and 19. Patients who achieve a complete response at 25 months and beyond may receive maintenance instillations with BCG once a week for 3 weeks at months 25, 31, and 37. The maximum treatment duration is 37 months.
The FDA recommends discontinuing treatment if disease persists after second induction or owing to disease recurrence, progression, or unacceptable toxicity.
A version of this article appeared on Medscape.com.
Specifically, the agent is approved to treat patients with BCG-unresponsive non–muscle-invasive bladder cancer carcinoma in situ with or without Ta or T1 papillary disease.
The FDA declined an initial approval for the combination in May 2023 because of deficiencies the agency observed during its prelicense inspection of third-party manufacturing organizations. In October 2023, ImmunityBio resubmitted the Biologics License Application, which was accepted.
The new therapy represents addresses “an unmet need” in this high-risk bladder cancer population, the company stated in a press release announcing the initial study findings. Typically, patients with intermediate or high-risk disease undergo bladder tumor resection followed by treatment with BCG, but the cancer recurs in up to 50% of patients, including those who experience a complete response, explained ImmunityBio, which acquired Altor BioScience.
Approval was based on findings from the single arm, phase 2/3 open-label QUILT-3.032 study, which included 77 patients with BCG-unresponsive, high-risk disease following transurethral resection. All had Eastern Cooperative Oncology Group performance status of 0-2.
Patients received nogapendekin alfa inbakicept-pmln induction via intravesical instillation with BCG followed by maintenance therapy for up to 37 months.
According to the FDA’s press release, 62% of patients had a complete response, defined as a negative cystoscopy and urine cytology; 58% of those with a complete response had a duration of response lasting at least 12 months and 40% had a duration of response lasting 24 months or longer.
The safety of the combination was evaluated in a cohort of 88 patients. Serious adverse reactions occurred in 16% of patients. The most common treatment-emergent adverse effects included dysuria, pollakiuria, and hematuria, which are associated with intravesical BCG; 86% of these events were grade 1 or 2. Overall, 7% of patients discontinued the combination owing to adverse reactions.
The recommended dose is 400 mcg administered intravesically with BCG once a week for 6 weeks as induction therapy, with an option for a second induction course if patients don’t achieve a complete response at 3 months. The recommended maintenance therapy dose is 400 mcg with BCG once a week for 3 weeks at months 4, 7, 10, 13, and 19. Patients who achieve a complete response at 25 months and beyond may receive maintenance instillations with BCG once a week for 3 weeks at months 25, 31, and 37. The maximum treatment duration is 37 months.
The FDA recommends discontinuing treatment if disease persists after second induction or owing to disease recurrence, progression, or unacceptable toxicity.
A version of this article appeared on Medscape.com.
Has Immunotherapy Found Its Place in Pancreatic Cancer?
The trials, however, have focused on adding immune checkpoint inhibitors to chemotherapy in metastatic disease, leaving open the question of whether immunotherapy might have a role in the neoadjuvant setting before surgery.
In the first study to test the hypothesis, Zev A. Wainberg, MD, a gastrointestinal medical oncologist at the University of California Los Angeles, reported promising results at the American Association for Cancer Research annual meeting.
The small, single arm pilot study included 28 patients with borderline resectable pancreatic cancer, meaning that tumors had some degree of vascular involvement. About 20% of pancreatic tumors are borderline resectable, Dr. Wainberg said.
Patients received 480 mg of nivolumab intravenously every 4 weeks plus mFOLFIRINOX chemotherapy (oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil) on days 1 and 15 of the 28-day cycle.
Patients who downstaged to resectable disease after three cycles went on to surgery; if not, treatment continued for another 3 months. The median number of cycles was 5.5, and almost all patients completed at least 3.
Overall, 19 of the 22 patients who proceeded to surgery (86%) had a pathologic response to neoadjuvant treatment with nivolumab: 2 complete responses, 2 near-complete responses, and 15 partial responses.
Among patients receiving surgery, 21 had R0 resections, meaning negative surgical margins with no tumor left behind. This is key because R0 resections predict longer survival, and “every effort should be made to achieve” this outcome, Dr. Wainberg said. The remaining patient had an R1 resection.
Median progression-free survival was 21.9 months among all patients and 27.3 months among the 22 patients who had resections.
Median overall survival was 34.6 months across the entire group and 44 months among those who had surgery. Overall, 82% of patients were alive at 12 months, and 77% were alive at 18 months.
The study outcomes, especially among the surgery cohort, stand in contrast to those observed in patients who receive the current standard neoadjuvant regimen for borderline resectable pancreatic cancer, mFOLFIRINOX alone, with studies finding a median overall survival of 29.8 months.
Adding nivolumab to neoadjuvant treatment also did not increase side effects. More than half of patients had grade 3 or worse adverse events, but they were all related to mFOLFIRINOX. There were no significant surgical complications, including no grade 2 or higher fistulas.
“We are very pleased” with the outcomes, Dr. Wainberg said. “We need to be studying [immune checkpoint inhibitors] earlier on in both borderline and locally advanced disease. Pancreatic cancer needs all the help it can get to engage immunity.”
Moderator Alice Ho, MD, a radiation oncologist at Duke University in Durham, North Carolina, called the R0 resection rate “stunning” in a “field that very much needs improvements and advancements.”
Dr. Ho also noted that the trial raises “a lot of interesting questions.”
For instance, why exactly is the addition of nivolumab seemingly improving outcomes?
The combination neoadjuvant therapy appeared to increase tertiary lymphoid structures, plasma cells, and CD4+ T cells — all indications that immunotherapy is having a positive impact — but the treatment also seemed to upregulate pathways for adenosine, an immunosuppressant associated with worse responses to checkpoint blockade.
A larger study is already in the works. In addition to a PD-1 blocker and mFOLFIRINOX, patients will receive a CD73 inhibitor to block adenosine production, Dr. Wainberg said.
Bristol Myers Squibb (BMS) provided the nivolumab used in the study. Dr. Wainberg is a consultant for and reported research funding from BMS and other companies. Dr. Ho had no relevant disclosures.
A version of this article appeared on Medscape.com.
The trials, however, have focused on adding immune checkpoint inhibitors to chemotherapy in metastatic disease, leaving open the question of whether immunotherapy might have a role in the neoadjuvant setting before surgery.
In the first study to test the hypothesis, Zev A. Wainberg, MD, a gastrointestinal medical oncologist at the University of California Los Angeles, reported promising results at the American Association for Cancer Research annual meeting.
The small, single arm pilot study included 28 patients with borderline resectable pancreatic cancer, meaning that tumors had some degree of vascular involvement. About 20% of pancreatic tumors are borderline resectable, Dr. Wainberg said.
Patients received 480 mg of nivolumab intravenously every 4 weeks plus mFOLFIRINOX chemotherapy (oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil) on days 1 and 15 of the 28-day cycle.
Patients who downstaged to resectable disease after three cycles went on to surgery; if not, treatment continued for another 3 months. The median number of cycles was 5.5, and almost all patients completed at least 3.
Overall, 19 of the 22 patients who proceeded to surgery (86%) had a pathologic response to neoadjuvant treatment with nivolumab: 2 complete responses, 2 near-complete responses, and 15 partial responses.
Among patients receiving surgery, 21 had R0 resections, meaning negative surgical margins with no tumor left behind. This is key because R0 resections predict longer survival, and “every effort should be made to achieve” this outcome, Dr. Wainberg said. The remaining patient had an R1 resection.
Median progression-free survival was 21.9 months among all patients and 27.3 months among the 22 patients who had resections.
Median overall survival was 34.6 months across the entire group and 44 months among those who had surgery. Overall, 82% of patients were alive at 12 months, and 77% were alive at 18 months.
The study outcomes, especially among the surgery cohort, stand in contrast to those observed in patients who receive the current standard neoadjuvant regimen for borderline resectable pancreatic cancer, mFOLFIRINOX alone, with studies finding a median overall survival of 29.8 months.
Adding nivolumab to neoadjuvant treatment also did not increase side effects. More than half of patients had grade 3 or worse adverse events, but they were all related to mFOLFIRINOX. There were no significant surgical complications, including no grade 2 or higher fistulas.
“We are very pleased” with the outcomes, Dr. Wainberg said. “We need to be studying [immune checkpoint inhibitors] earlier on in both borderline and locally advanced disease. Pancreatic cancer needs all the help it can get to engage immunity.”
Moderator Alice Ho, MD, a radiation oncologist at Duke University in Durham, North Carolina, called the R0 resection rate “stunning” in a “field that very much needs improvements and advancements.”
Dr. Ho also noted that the trial raises “a lot of interesting questions.”
For instance, why exactly is the addition of nivolumab seemingly improving outcomes?
The combination neoadjuvant therapy appeared to increase tertiary lymphoid structures, plasma cells, and CD4+ T cells — all indications that immunotherapy is having a positive impact — but the treatment also seemed to upregulate pathways for adenosine, an immunosuppressant associated with worse responses to checkpoint blockade.
A larger study is already in the works. In addition to a PD-1 blocker and mFOLFIRINOX, patients will receive a CD73 inhibitor to block adenosine production, Dr. Wainberg said.
Bristol Myers Squibb (BMS) provided the nivolumab used in the study. Dr. Wainberg is a consultant for and reported research funding from BMS and other companies. Dr. Ho had no relevant disclosures.
A version of this article appeared on Medscape.com.
The trials, however, have focused on adding immune checkpoint inhibitors to chemotherapy in metastatic disease, leaving open the question of whether immunotherapy might have a role in the neoadjuvant setting before surgery.
In the first study to test the hypothesis, Zev A. Wainberg, MD, a gastrointestinal medical oncologist at the University of California Los Angeles, reported promising results at the American Association for Cancer Research annual meeting.
The small, single arm pilot study included 28 patients with borderline resectable pancreatic cancer, meaning that tumors had some degree of vascular involvement. About 20% of pancreatic tumors are borderline resectable, Dr. Wainberg said.
Patients received 480 mg of nivolumab intravenously every 4 weeks plus mFOLFIRINOX chemotherapy (oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil) on days 1 and 15 of the 28-day cycle.
Patients who downstaged to resectable disease after three cycles went on to surgery; if not, treatment continued for another 3 months. The median number of cycles was 5.5, and almost all patients completed at least 3.
Overall, 19 of the 22 patients who proceeded to surgery (86%) had a pathologic response to neoadjuvant treatment with nivolumab: 2 complete responses, 2 near-complete responses, and 15 partial responses.
Among patients receiving surgery, 21 had R0 resections, meaning negative surgical margins with no tumor left behind. This is key because R0 resections predict longer survival, and “every effort should be made to achieve” this outcome, Dr. Wainberg said. The remaining patient had an R1 resection.
Median progression-free survival was 21.9 months among all patients and 27.3 months among the 22 patients who had resections.
Median overall survival was 34.6 months across the entire group and 44 months among those who had surgery. Overall, 82% of patients were alive at 12 months, and 77% were alive at 18 months.
The study outcomes, especially among the surgery cohort, stand in contrast to those observed in patients who receive the current standard neoadjuvant regimen for borderline resectable pancreatic cancer, mFOLFIRINOX alone, with studies finding a median overall survival of 29.8 months.
Adding nivolumab to neoadjuvant treatment also did not increase side effects. More than half of patients had grade 3 or worse adverse events, but they were all related to mFOLFIRINOX. There were no significant surgical complications, including no grade 2 or higher fistulas.
“We are very pleased” with the outcomes, Dr. Wainberg said. “We need to be studying [immune checkpoint inhibitors] earlier on in both borderline and locally advanced disease. Pancreatic cancer needs all the help it can get to engage immunity.”
Moderator Alice Ho, MD, a radiation oncologist at Duke University in Durham, North Carolina, called the R0 resection rate “stunning” in a “field that very much needs improvements and advancements.”
Dr. Ho also noted that the trial raises “a lot of interesting questions.”
For instance, why exactly is the addition of nivolumab seemingly improving outcomes?
The combination neoadjuvant therapy appeared to increase tertiary lymphoid structures, plasma cells, and CD4+ T cells — all indications that immunotherapy is having a positive impact — but the treatment also seemed to upregulate pathways for adenosine, an immunosuppressant associated with worse responses to checkpoint blockade.
A larger study is already in the works. In addition to a PD-1 blocker and mFOLFIRINOX, patients will receive a CD73 inhibitor to block adenosine production, Dr. Wainberg said.
Bristol Myers Squibb (BMS) provided the nivolumab used in the study. Dr. Wainberg is a consultant for and reported research funding from BMS and other companies. Dr. Ho had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM AACR 2024
Most Targeted Cancer Drugs Lack Substantial Clinical Benefit
TOPLINE:
METHODOLOGY:
- The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
- Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
- In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
- The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
- The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).
TAKEAWAY:
- The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
- Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
- Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
- Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.
IN PRACTICE:
“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”
SOURCE:
The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.
LIMITATIONS:
The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.
DISCLOSURES:
The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
- Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
- In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
- The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
- The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).
TAKEAWAY:
- The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
- Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
- Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
- Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.
IN PRACTICE:
“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”
SOURCE:
The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.
LIMITATIONS:
The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.
DISCLOSURES:
The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
- Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
- In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
- The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
- The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).
TAKEAWAY:
- The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
- Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
- Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
- Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.
IN PRACTICE:
“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”
SOURCE:
The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.
LIMITATIONS:
The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.
DISCLOSURES:
The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.
A version of this article appeared on Medscape.com.
How New ICI Combos Change Bladder Cancer Management
according to Thomas W. Flaig, MD, vice chancellor for research at the University of Colorado Anschutz Medical Campus, Aurora.
Combination therapies involving enfortumab and nivolumab are demonstrating success in recent studies and have been incorporated into the latest guidelines, Dr. Flaig said in a presentation at the National Comprehensive Cancer Network (NCCN) annual conference.
What's New in The Updated Guidelines?
Advances in the treatment options for metastatic urothelial carcinoma in the last decade have been dramatic, with ongoing developments and new emerging treatment options, Dr. Flaig told the audience of his session.
This has led to the identification of new and effective immune checkpoint inhibitor combinations. Consequently, immune checkpoint inhibitors are currently included in all preferred/other recommended first-line treatment regimens, he said.
“Enfortumab vedotin plus pembrolizumab is now the sole preferred first-line regimen for locally advanced or metastatic disease.” Based on the recent research, the mindset regarding cisplatin-eligible patient selection may be changing, he added.
“We have used cisplatin eligibility as a key factor in determining first-line therapy for years, and that paradigm is now shifting with the emergence of enfortumab plus pembrolizumab, a new non–cisplatin containing regimen” Dr. Flaig noted.
Although the optimal choice for second- or third-line therapy after immune checkpoint inhibitors is not well-defined, options include platinum regimens, antibody-drug conjugate, and erdafitinib in eligible patients, he said.
Other Current Strategies for Localized Bladder Cancer Management
The incidence of bladder cancer has been stable for decades, with minimal therapeutic developments until the approval of immune checkpoint inhibitors in the last decade, Dr. Flaig said.
Bladder cancer is more common in older adults, with an average onset age of 73 years, and most patients (75%) are male, he said. Comorbid disease is common in these patients, and many have a history of smoking, Dr. Flaig added.
The traditional medical approach to treating bladder cancer has been based on combination therapies including cisplatin. This has also reflected the approach used in the treatment of lung cancer, historically, Dr. Flaig said.
Cisplatin, while effective, is a challenging therapy to administer and is not an option for all bladder cancer patients because of potential adverse effects, he noted. Antibody drug conjugates and immune checkpoint inhibitors are new alternatives for some who are not able to receive cisplatin.
What are the New Options for Treating Metastatic Urothelial Bladder Cancer?
The approval of antibody drug conjugates offers new treatment with a “specific target and therapeutic payload,” said Dr. Flaig in his presentation. Two antibody drug conjugates, enfortumab vedotin and sacituzumab govitecan, have been approved by the US Food and Drug Administration (FDA), he said. Enforumab vedotin was approved by the FDA in 2021 for adults with locally advanced or metastatic urothelial cancer for subsequent line therapy in select patients. In a 2021 study published in The New England Journal of Medicine, the primary outcome of overall response rate was significantly greater in patients with advanced urothelial carcinoma who were treated with enfortumab vedotin than in those treated with standard chemotherapy (overall response rate [ORR] 40.6% vs 17.9%, respectively).
Side effects associated with enfortumab vedotin “are intrinsic to the payload toxicity and the target distribution. Ideally, the target would be present on all of the cancer cells and none of the normal tissue,” said Dr. Flaig. With enfortumab, specific toxicities included neuropathy, skin reactions, and blood glucose elevation/diabetic ketoacidosis, he said.
A second agent, sacituzumab govitecan, was approved by the FDA for metastatic urothelial cancer patients in 2021, based on data from the TROPHY-U-O1 phase 2 open-label study of 113 individuals. In that study, the ORR was 27% at a median follow-up of 9.1 months. Adverse events included neutropenia, leukopenia, and diarrhea.
What Do the Latest Studies of Combination Therapy Show?
Immune checkpoint inhibitor combinations are significantly changing the landscape of bladder cancer treatment, Dr. Flaig explained.
A recent phase 3 study published in 2024 in The New England Journal of Medicine comparing enfortumab vedotin plus pembrolizumab to platinum-based combination chemotherapy showed an overall response rate of 67.7% vs 44.4% in favor of enfortumab/pembrolizumab, said Dr. Flaig. In addition, the risk of disease progression or death was approximately 55% lower in the enfortumab vedotin-pembrolizumab group vs the chemotherapy group (hazard ratio [HR], 0.45; P less than .001) and the median progression-free survival was approximately doubled (12.5 months vs 6.3 months).
Dr. Flaig described this study as “very notable”because “the enfortumab plus pembrolizumab arm was clearly more effective than the long-standing chemotherapy arm, now becoming the preferred, first-line treatment in the NCCN guidelines. Based on preliminary results of the study, this combination was approved by the FDA in 2023 for locally advanced or metastatic urothelial cancer patients regardless of their eligibility for cisplatin.
Another promising combination, nivolumab plus gemcitabine-cisplatin, was associated with significantly longer overall and progression-free survival in patients with previously untreated unresectable or metastatic urothelial carcinoma, Dr. Flaig said. The therapy was approved by the FDA in March 2024 for first-line therapy.
In a study of 608 patients published in The New England Journal of Medicine, median overall survival was 21.7 months for the nivolumab group vs 18.9 months for the gemcitabine-cisplatin alone group. The overall response rates were 57.6% in the nivolumab group vs 43.1% in the gemcitabine-cisplatin–alone group, and complete response rates were 21.7% and 11.8%, respectively. Serious adverse events (grade 3 or higher) were similar between the groups (61.8% and 51.7%, respectively).
What About Targeted Therapy?
Erdafitinib, a tyrosine kinase inhibitor of FGFR1–4, was approved by the FDA in January 2024 for adults with locally advanced or metastatic urothelial carcinoma who had susceptible FGFR3 genetic alterations, said Dr. Flaig, during his presentation. The limitation of this treatment to only those patients with an FGFR3 mutation is a recent update in its use, he noted.
“Up to 20% of patients with advanced urothelial carcinoma have FGFR alterations,” he said. In an open-label phase 2 study of 99 individuals with unresectable or metastatic urothelial carcinoma, past chemotherapy, and FGFR alterations, confirmed response to erdafitinib was 40% with a median overall survival of 13.8 months.
Dr. Flaig disclosed grant/research support from Agensys; Astellas Pharma US; AstraZeneca Pharmaceuticals LP; Bristol Myers Squibb; Genentech, Inc.; Janssen Pharmaceutica Products, LP; Merck & Co.; Sanofi-Aventis U.S.; and SeaGen. He also disclosed equity interest/stock options and intellectual property rights in Aurora Oncology, and serving as a consultant or scientific advisor for Janssen Pharmaceutica Product, LP, and Criterium, Inc.
according to Thomas W. Flaig, MD, vice chancellor for research at the University of Colorado Anschutz Medical Campus, Aurora.
Combination therapies involving enfortumab and nivolumab are demonstrating success in recent studies and have been incorporated into the latest guidelines, Dr. Flaig said in a presentation at the National Comprehensive Cancer Network (NCCN) annual conference.
What's New in The Updated Guidelines?
Advances in the treatment options for metastatic urothelial carcinoma in the last decade have been dramatic, with ongoing developments and new emerging treatment options, Dr. Flaig told the audience of his session.
This has led to the identification of new and effective immune checkpoint inhibitor combinations. Consequently, immune checkpoint inhibitors are currently included in all preferred/other recommended first-line treatment regimens, he said.
“Enfortumab vedotin plus pembrolizumab is now the sole preferred first-line regimen for locally advanced or metastatic disease.” Based on the recent research, the mindset regarding cisplatin-eligible patient selection may be changing, he added.
“We have used cisplatin eligibility as a key factor in determining first-line therapy for years, and that paradigm is now shifting with the emergence of enfortumab plus pembrolizumab, a new non–cisplatin containing regimen” Dr. Flaig noted.
Although the optimal choice for second- or third-line therapy after immune checkpoint inhibitors is not well-defined, options include platinum regimens, antibody-drug conjugate, and erdafitinib in eligible patients, he said.
Other Current Strategies for Localized Bladder Cancer Management
The incidence of bladder cancer has been stable for decades, with minimal therapeutic developments until the approval of immune checkpoint inhibitors in the last decade, Dr. Flaig said.
Bladder cancer is more common in older adults, with an average onset age of 73 years, and most patients (75%) are male, he said. Comorbid disease is common in these patients, and many have a history of smoking, Dr. Flaig added.
The traditional medical approach to treating bladder cancer has been based on combination therapies including cisplatin. This has also reflected the approach used in the treatment of lung cancer, historically, Dr. Flaig said.
Cisplatin, while effective, is a challenging therapy to administer and is not an option for all bladder cancer patients because of potential adverse effects, he noted. Antibody drug conjugates and immune checkpoint inhibitors are new alternatives for some who are not able to receive cisplatin.
What are the New Options for Treating Metastatic Urothelial Bladder Cancer?
The approval of antibody drug conjugates offers new treatment with a “specific target and therapeutic payload,” said Dr. Flaig in his presentation. Two antibody drug conjugates, enfortumab vedotin and sacituzumab govitecan, have been approved by the US Food and Drug Administration (FDA), he said. Enforumab vedotin was approved by the FDA in 2021 for adults with locally advanced or metastatic urothelial cancer for subsequent line therapy in select patients. In a 2021 study published in The New England Journal of Medicine, the primary outcome of overall response rate was significantly greater in patients with advanced urothelial carcinoma who were treated with enfortumab vedotin than in those treated with standard chemotherapy (overall response rate [ORR] 40.6% vs 17.9%, respectively).
Side effects associated with enfortumab vedotin “are intrinsic to the payload toxicity and the target distribution. Ideally, the target would be present on all of the cancer cells and none of the normal tissue,” said Dr. Flaig. With enfortumab, specific toxicities included neuropathy, skin reactions, and blood glucose elevation/diabetic ketoacidosis, he said.
A second agent, sacituzumab govitecan, was approved by the FDA for metastatic urothelial cancer patients in 2021, based on data from the TROPHY-U-O1 phase 2 open-label study of 113 individuals. In that study, the ORR was 27% at a median follow-up of 9.1 months. Adverse events included neutropenia, leukopenia, and diarrhea.
What Do the Latest Studies of Combination Therapy Show?
Immune checkpoint inhibitor combinations are significantly changing the landscape of bladder cancer treatment, Dr. Flaig explained.
A recent phase 3 study published in 2024 in The New England Journal of Medicine comparing enfortumab vedotin plus pembrolizumab to platinum-based combination chemotherapy showed an overall response rate of 67.7% vs 44.4% in favor of enfortumab/pembrolizumab, said Dr. Flaig. In addition, the risk of disease progression or death was approximately 55% lower in the enfortumab vedotin-pembrolizumab group vs the chemotherapy group (hazard ratio [HR], 0.45; P less than .001) and the median progression-free survival was approximately doubled (12.5 months vs 6.3 months).
Dr. Flaig described this study as “very notable”because “the enfortumab plus pembrolizumab arm was clearly more effective than the long-standing chemotherapy arm, now becoming the preferred, first-line treatment in the NCCN guidelines. Based on preliminary results of the study, this combination was approved by the FDA in 2023 for locally advanced or metastatic urothelial cancer patients regardless of their eligibility for cisplatin.
Another promising combination, nivolumab plus gemcitabine-cisplatin, was associated with significantly longer overall and progression-free survival in patients with previously untreated unresectable or metastatic urothelial carcinoma, Dr. Flaig said. The therapy was approved by the FDA in March 2024 for first-line therapy.
In a study of 608 patients published in The New England Journal of Medicine, median overall survival was 21.7 months for the nivolumab group vs 18.9 months for the gemcitabine-cisplatin alone group. The overall response rates were 57.6% in the nivolumab group vs 43.1% in the gemcitabine-cisplatin–alone group, and complete response rates were 21.7% and 11.8%, respectively. Serious adverse events (grade 3 or higher) were similar between the groups (61.8% and 51.7%, respectively).
What About Targeted Therapy?
Erdafitinib, a tyrosine kinase inhibitor of FGFR1–4, was approved by the FDA in January 2024 for adults with locally advanced or metastatic urothelial carcinoma who had susceptible FGFR3 genetic alterations, said Dr. Flaig, during his presentation. The limitation of this treatment to only those patients with an FGFR3 mutation is a recent update in its use, he noted.
“Up to 20% of patients with advanced urothelial carcinoma have FGFR alterations,” he said. In an open-label phase 2 study of 99 individuals with unresectable or metastatic urothelial carcinoma, past chemotherapy, and FGFR alterations, confirmed response to erdafitinib was 40% with a median overall survival of 13.8 months.
Dr. Flaig disclosed grant/research support from Agensys; Astellas Pharma US; AstraZeneca Pharmaceuticals LP; Bristol Myers Squibb; Genentech, Inc.; Janssen Pharmaceutica Products, LP; Merck & Co.; Sanofi-Aventis U.S.; and SeaGen. He also disclosed equity interest/stock options and intellectual property rights in Aurora Oncology, and serving as a consultant or scientific advisor for Janssen Pharmaceutica Product, LP, and Criterium, Inc.
according to Thomas W. Flaig, MD, vice chancellor for research at the University of Colorado Anschutz Medical Campus, Aurora.
Combination therapies involving enfortumab and nivolumab are demonstrating success in recent studies and have been incorporated into the latest guidelines, Dr. Flaig said in a presentation at the National Comprehensive Cancer Network (NCCN) annual conference.
What's New in The Updated Guidelines?
Advances in the treatment options for metastatic urothelial carcinoma in the last decade have been dramatic, with ongoing developments and new emerging treatment options, Dr. Flaig told the audience of his session.
This has led to the identification of new and effective immune checkpoint inhibitor combinations. Consequently, immune checkpoint inhibitors are currently included in all preferred/other recommended first-line treatment regimens, he said.
“Enfortumab vedotin plus pembrolizumab is now the sole preferred first-line regimen for locally advanced or metastatic disease.” Based on the recent research, the mindset regarding cisplatin-eligible patient selection may be changing, he added.
“We have used cisplatin eligibility as a key factor in determining first-line therapy for years, and that paradigm is now shifting with the emergence of enfortumab plus pembrolizumab, a new non–cisplatin containing regimen” Dr. Flaig noted.
Although the optimal choice for second- or third-line therapy after immune checkpoint inhibitors is not well-defined, options include platinum regimens, antibody-drug conjugate, and erdafitinib in eligible patients, he said.
Other Current Strategies for Localized Bladder Cancer Management
The incidence of bladder cancer has been stable for decades, with minimal therapeutic developments until the approval of immune checkpoint inhibitors in the last decade, Dr. Flaig said.
Bladder cancer is more common in older adults, with an average onset age of 73 years, and most patients (75%) are male, he said. Comorbid disease is common in these patients, and many have a history of smoking, Dr. Flaig added.
The traditional medical approach to treating bladder cancer has been based on combination therapies including cisplatin. This has also reflected the approach used in the treatment of lung cancer, historically, Dr. Flaig said.
Cisplatin, while effective, is a challenging therapy to administer and is not an option for all bladder cancer patients because of potential adverse effects, he noted. Antibody drug conjugates and immune checkpoint inhibitors are new alternatives for some who are not able to receive cisplatin.
What are the New Options for Treating Metastatic Urothelial Bladder Cancer?
The approval of antibody drug conjugates offers new treatment with a “specific target and therapeutic payload,” said Dr. Flaig in his presentation. Two antibody drug conjugates, enfortumab vedotin and sacituzumab govitecan, have been approved by the US Food and Drug Administration (FDA), he said. Enforumab vedotin was approved by the FDA in 2021 for adults with locally advanced or metastatic urothelial cancer for subsequent line therapy in select patients. In a 2021 study published in The New England Journal of Medicine, the primary outcome of overall response rate was significantly greater in patients with advanced urothelial carcinoma who were treated with enfortumab vedotin than in those treated with standard chemotherapy (overall response rate [ORR] 40.6% vs 17.9%, respectively).
Side effects associated with enfortumab vedotin “are intrinsic to the payload toxicity and the target distribution. Ideally, the target would be present on all of the cancer cells and none of the normal tissue,” said Dr. Flaig. With enfortumab, specific toxicities included neuropathy, skin reactions, and blood glucose elevation/diabetic ketoacidosis, he said.
A second agent, sacituzumab govitecan, was approved by the FDA for metastatic urothelial cancer patients in 2021, based on data from the TROPHY-U-O1 phase 2 open-label study of 113 individuals. In that study, the ORR was 27% at a median follow-up of 9.1 months. Adverse events included neutropenia, leukopenia, and diarrhea.
What Do the Latest Studies of Combination Therapy Show?
Immune checkpoint inhibitor combinations are significantly changing the landscape of bladder cancer treatment, Dr. Flaig explained.
A recent phase 3 study published in 2024 in The New England Journal of Medicine comparing enfortumab vedotin plus pembrolizumab to platinum-based combination chemotherapy showed an overall response rate of 67.7% vs 44.4% in favor of enfortumab/pembrolizumab, said Dr. Flaig. In addition, the risk of disease progression or death was approximately 55% lower in the enfortumab vedotin-pembrolizumab group vs the chemotherapy group (hazard ratio [HR], 0.45; P less than .001) and the median progression-free survival was approximately doubled (12.5 months vs 6.3 months).
Dr. Flaig described this study as “very notable”because “the enfortumab plus pembrolizumab arm was clearly more effective than the long-standing chemotherapy arm, now becoming the preferred, first-line treatment in the NCCN guidelines. Based on preliminary results of the study, this combination was approved by the FDA in 2023 for locally advanced or metastatic urothelial cancer patients regardless of their eligibility for cisplatin.
Another promising combination, nivolumab plus gemcitabine-cisplatin, was associated with significantly longer overall and progression-free survival in patients with previously untreated unresectable or metastatic urothelial carcinoma, Dr. Flaig said. The therapy was approved by the FDA in March 2024 for first-line therapy.
In a study of 608 patients published in The New England Journal of Medicine, median overall survival was 21.7 months for the nivolumab group vs 18.9 months for the gemcitabine-cisplatin alone group. The overall response rates were 57.6% in the nivolumab group vs 43.1% in the gemcitabine-cisplatin–alone group, and complete response rates were 21.7% and 11.8%, respectively. Serious adverse events (grade 3 or higher) were similar between the groups (61.8% and 51.7%, respectively).
What About Targeted Therapy?
Erdafitinib, a tyrosine kinase inhibitor of FGFR1–4, was approved by the FDA in January 2024 for adults with locally advanced or metastatic urothelial carcinoma who had susceptible FGFR3 genetic alterations, said Dr. Flaig, during his presentation. The limitation of this treatment to only those patients with an FGFR3 mutation is a recent update in its use, he noted.
“Up to 20% of patients with advanced urothelial carcinoma have FGFR alterations,” he said. In an open-label phase 2 study of 99 individuals with unresectable or metastatic urothelial carcinoma, past chemotherapy, and FGFR alterations, confirmed response to erdafitinib was 40% with a median overall survival of 13.8 months.
Dr. Flaig disclosed grant/research support from Agensys; Astellas Pharma US; AstraZeneca Pharmaceuticals LP; Bristol Myers Squibb; Genentech, Inc.; Janssen Pharmaceutica Products, LP; Merck & Co.; Sanofi-Aventis U.S.; and SeaGen. He also disclosed equity interest/stock options and intellectual property rights in Aurora Oncology, and serving as a consultant or scientific advisor for Janssen Pharmaceutica Product, LP, and Criterium, Inc.
FROM NCCN 2024
Less Than 50% of Accelerated Approvals Show Clinical Benefit
despite being on the US market for more than 5 years, according to a new study.
Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response.
Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.
The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.
In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.
To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits.
Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.
Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results.
The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff.
However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials.
In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”
There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit.
The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious.
In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial.
“There have been some promising steps,” Dr. Cliff said, but much work needs to be done.
Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.”
But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.
Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.”
Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.”
As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together.
The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures.
A version of this article appeared on Medscape.com.
despite being on the US market for more than 5 years, according to a new study.
Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response.
Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.
The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.
In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.
To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits.
Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.
Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results.
The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff.
However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials.
In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”
There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit.
The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious.
In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial.
“There have been some promising steps,” Dr. Cliff said, but much work needs to be done.
Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.”
But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.
Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.”
Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.”
As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together.
The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures.
A version of this article appeared on Medscape.com.
despite being on the US market for more than 5 years, according to a new study.
Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response.
Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.
The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.
In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.
To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits.
Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.
Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results.
The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff.
However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials.
In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”
There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit.
The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious.
In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial.
“There have been some promising steps,” Dr. Cliff said, but much work needs to be done.
Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.”
But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.
Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.”
Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.”
As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together.
The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures.
A version of this article appeared on Medscape.com.
Subcutaneous Immunotherapy Promises Better Life For Cancer Patients
The possibility is being driven by the development of subcutaneous formulations of commonly used immune checkpoint inhibitors for non–small cell lung cancer (NSCLC) and other indications, including pembrolizumab, nivolumab, durvalumab, atezolizumab, and amivantamab.
Instead of waiting anywhere from 30 minutes to several hours for infusions into their veins, patients would spend just a few minutes being injected under the loose skin of their abdomens or thighs. Clinicians would save time and money, and patients would leave the clinic much sooner than normal. The ease of subcutaneous injections also opens up an opportunity for home treatment, a potential boon for people who don’t want to spend their remaining time on hospital visits.
“In the future, I hope we can deliver these medicines at home,” said Hazel O’Sullivan, MBBCh, a medical lung cancer oncologist at Cork University, Ireland, who explained the issues during a session at the 2024 European Lung Cancer Congress.
She was the discussant on two studies at the meeting that highlighted the latest developments in the field, the IMscin002 study of subcutaneous atezolizumab and the PALOMA study of subcutaneous amivantamab, both mostly in NSCLC patients.
Subcutaneous atezolizumab was approved recently in Europe after its maker, Genentech/Roche, made a convincing case that its pharmacokinetics, efficacy, and safety are comparable to the intravenous (IV) version. The U.S. Food and Drug Administration is considering approval; Genentech/Roche anticipates a decision in 2024.
IMscin002 randomized 179 stage 2-4 NSCLC patients evenly to IV or subcutaneous atezolizumab for the first three cycles, then switched them for three more cycles.
Participants were then asked what version they preferred and what they wanted to continue with.
Seventy-one percent said they liked the subcutaneous version better and 80% opted to continue with it. Their main reasons were because they spent less time in the clinic and it was more comfortable.
When asked about the potential for home administration, presenter Federico Cappuzzo, MD, PhD, a medical lung cancer oncologist in Rome, said that it could be “an important option in the future,” particularly in isolated areas far away from hospitals.
The authors of new research are currently evaluating whether home administration is possible. Nurses are administering atezolizumab to patients in their homes with telemedicine monitoring.
The other subcutaneous study presented at the meeting, the PALOMA trial with amivantamab, had only 19 subjects. Administration took no more than 10 minutes, versus potentially hours, especially for the first dose. Subcutaneous amivantamab was given once a month, versus every 2 weeks for the IV formulation, during the maintenance phase of treatment.
The take-home from PALOMA is that the risk of infusion reactions is lower with subcutaneous administration (16% versus 67%) but the risk of mostly mild skin rashes is higher (79% versus 36%).
Investigation is ongoing to confirm safety, pharmacokinetic, and efficacy equivalence with the IV formulation, including in combination with other medications.
When asked about home administration of amivantamab, PALOMA lead investigator Natasha Leighl, MD, a lung, and breast cancer medical oncologist at the University of Toronto, stated that patients probably need to be watched in the clinic for the first 4 months.
The atezolizumab study was funded by maker Genentech/Roche. The amivantamab study was funded by its maker, Janssen. The amivantamab investigator, Dr. Leighl, reported grants, honoraria, and travel payments from Janssen. Dr. Cappuzzo, the investigator on the atezolizumab study, reported speaker and adviser payments from Genentech/Roche. The discussant, Dr. O’Sullivan, wasn’t involved with either company but reported payments from Amgen and AstraZeneca and travel costs covered by Takeda.
The possibility is being driven by the development of subcutaneous formulations of commonly used immune checkpoint inhibitors for non–small cell lung cancer (NSCLC) and other indications, including pembrolizumab, nivolumab, durvalumab, atezolizumab, and amivantamab.
Instead of waiting anywhere from 30 minutes to several hours for infusions into their veins, patients would spend just a few minutes being injected under the loose skin of their abdomens or thighs. Clinicians would save time and money, and patients would leave the clinic much sooner than normal. The ease of subcutaneous injections also opens up an opportunity for home treatment, a potential boon for people who don’t want to spend their remaining time on hospital visits.
“In the future, I hope we can deliver these medicines at home,” said Hazel O’Sullivan, MBBCh, a medical lung cancer oncologist at Cork University, Ireland, who explained the issues during a session at the 2024 European Lung Cancer Congress.
She was the discussant on two studies at the meeting that highlighted the latest developments in the field, the IMscin002 study of subcutaneous atezolizumab and the PALOMA study of subcutaneous amivantamab, both mostly in NSCLC patients.
Subcutaneous atezolizumab was approved recently in Europe after its maker, Genentech/Roche, made a convincing case that its pharmacokinetics, efficacy, and safety are comparable to the intravenous (IV) version. The U.S. Food and Drug Administration is considering approval; Genentech/Roche anticipates a decision in 2024.
IMscin002 randomized 179 stage 2-4 NSCLC patients evenly to IV or subcutaneous atezolizumab for the first three cycles, then switched them for three more cycles.
Participants were then asked what version they preferred and what they wanted to continue with.
Seventy-one percent said they liked the subcutaneous version better and 80% opted to continue with it. Their main reasons were because they spent less time in the clinic and it was more comfortable.
When asked about the potential for home administration, presenter Federico Cappuzzo, MD, PhD, a medical lung cancer oncologist in Rome, said that it could be “an important option in the future,” particularly in isolated areas far away from hospitals.
The authors of new research are currently evaluating whether home administration is possible. Nurses are administering atezolizumab to patients in their homes with telemedicine monitoring.
The other subcutaneous study presented at the meeting, the PALOMA trial with amivantamab, had only 19 subjects. Administration took no more than 10 minutes, versus potentially hours, especially for the first dose. Subcutaneous amivantamab was given once a month, versus every 2 weeks for the IV formulation, during the maintenance phase of treatment.
The take-home from PALOMA is that the risk of infusion reactions is lower with subcutaneous administration (16% versus 67%) but the risk of mostly mild skin rashes is higher (79% versus 36%).
Investigation is ongoing to confirm safety, pharmacokinetic, and efficacy equivalence with the IV formulation, including in combination with other medications.
When asked about home administration of amivantamab, PALOMA lead investigator Natasha Leighl, MD, a lung, and breast cancer medical oncologist at the University of Toronto, stated that patients probably need to be watched in the clinic for the first 4 months.
The atezolizumab study was funded by maker Genentech/Roche. The amivantamab study was funded by its maker, Janssen. The amivantamab investigator, Dr. Leighl, reported grants, honoraria, and travel payments from Janssen. Dr. Cappuzzo, the investigator on the atezolizumab study, reported speaker and adviser payments from Genentech/Roche. The discussant, Dr. O’Sullivan, wasn’t involved with either company but reported payments from Amgen and AstraZeneca and travel costs covered by Takeda.
The possibility is being driven by the development of subcutaneous formulations of commonly used immune checkpoint inhibitors for non–small cell lung cancer (NSCLC) and other indications, including pembrolizumab, nivolumab, durvalumab, atezolizumab, and amivantamab.
Instead of waiting anywhere from 30 minutes to several hours for infusions into their veins, patients would spend just a few minutes being injected under the loose skin of their abdomens or thighs. Clinicians would save time and money, and patients would leave the clinic much sooner than normal. The ease of subcutaneous injections also opens up an opportunity for home treatment, a potential boon for people who don’t want to spend their remaining time on hospital visits.
“In the future, I hope we can deliver these medicines at home,” said Hazel O’Sullivan, MBBCh, a medical lung cancer oncologist at Cork University, Ireland, who explained the issues during a session at the 2024 European Lung Cancer Congress.
She was the discussant on two studies at the meeting that highlighted the latest developments in the field, the IMscin002 study of subcutaneous atezolizumab and the PALOMA study of subcutaneous amivantamab, both mostly in NSCLC patients.
Subcutaneous atezolizumab was approved recently in Europe after its maker, Genentech/Roche, made a convincing case that its pharmacokinetics, efficacy, and safety are comparable to the intravenous (IV) version. The U.S. Food and Drug Administration is considering approval; Genentech/Roche anticipates a decision in 2024.
IMscin002 randomized 179 stage 2-4 NSCLC patients evenly to IV or subcutaneous atezolizumab for the first three cycles, then switched them for three more cycles.
Participants were then asked what version they preferred and what they wanted to continue with.
Seventy-one percent said they liked the subcutaneous version better and 80% opted to continue with it. Their main reasons were because they spent less time in the clinic and it was more comfortable.
When asked about the potential for home administration, presenter Federico Cappuzzo, MD, PhD, a medical lung cancer oncologist in Rome, said that it could be “an important option in the future,” particularly in isolated areas far away from hospitals.
The authors of new research are currently evaluating whether home administration is possible. Nurses are administering atezolizumab to patients in their homes with telemedicine monitoring.
The other subcutaneous study presented at the meeting, the PALOMA trial with amivantamab, had only 19 subjects. Administration took no more than 10 minutes, versus potentially hours, especially for the first dose. Subcutaneous amivantamab was given once a month, versus every 2 weeks for the IV formulation, during the maintenance phase of treatment.
The take-home from PALOMA is that the risk of infusion reactions is lower with subcutaneous administration (16% versus 67%) but the risk of mostly mild skin rashes is higher (79% versus 36%).
Investigation is ongoing to confirm safety, pharmacokinetic, and efficacy equivalence with the IV formulation, including in combination with other medications.
When asked about home administration of amivantamab, PALOMA lead investigator Natasha Leighl, MD, a lung, and breast cancer medical oncologist at the University of Toronto, stated that patients probably need to be watched in the clinic for the first 4 months.
The atezolizumab study was funded by maker Genentech/Roche. The amivantamab study was funded by its maker, Janssen. The amivantamab investigator, Dr. Leighl, reported grants, honoraria, and travel payments from Janssen. Dr. Cappuzzo, the investigator on the atezolizumab study, reported speaker and adviser payments from Genentech/Roche. The discussant, Dr. O’Sullivan, wasn’t involved with either company but reported payments from Amgen and AstraZeneca and travel costs covered by Takeda.
FROM ELCC 2024
Extraordinary Patients Inspired Father of Cancer Immunotherapy
His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.
To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.
Dr. Rosenberg, a senior investigator for the Center for Cancer Research at the National Cancer Institute (NCI), and chief of the NCI Surgery Branch, shared the history behind his novel research and the patient stories that inspired his discoveries, during an interview.
Tell us a little about yourself and where you grew up.
Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.
As a young boy, did you always want to become a doctor?
Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.
How did that experience impact your aspirations?
Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.
What led to your interest in cancer treatment?
Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.
Were there patients who inspired your research?
Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
Was the second patient’s case as impressive?
Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.
From there, how did your work evolve?
Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.
Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?
Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.
How did this finding impact your future discoveries?
Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.
What guidance would you have for other physician-investigators or young doctors who want to follow in your path?
Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.
His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.
To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.
Dr. Rosenberg, a senior investigator for the Center for Cancer Research at the National Cancer Institute (NCI), and chief of the NCI Surgery Branch, shared the history behind his novel research and the patient stories that inspired his discoveries, during an interview.
Tell us a little about yourself and where you grew up.
Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.
As a young boy, did you always want to become a doctor?
Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.
How did that experience impact your aspirations?
Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.
What led to your interest in cancer treatment?
Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.
Were there patients who inspired your research?
Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
Was the second patient’s case as impressive?
Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.
From there, how did your work evolve?
Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.
Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?
Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.
How did this finding impact your future discoveries?
Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.
What guidance would you have for other physician-investigators or young doctors who want to follow in your path?
Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.
His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.
To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.
Dr. Rosenberg, a senior investigator for the Center for Cancer Research at the National Cancer Institute (NCI), and chief of the NCI Surgery Branch, shared the history behind his novel research and the patient stories that inspired his discoveries, during an interview.
Tell us a little about yourself and where you grew up.
Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.
As a young boy, did you always want to become a doctor?
Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.
How did that experience impact your aspirations?
Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.
What led to your interest in cancer treatment?
Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.
Were there patients who inspired your research?
Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
Was the second patient’s case as impressive?
Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.
From there, how did your work evolve?
Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.
Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?
Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.
How did this finding impact your future discoveries?
Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.
What guidance would you have for other physician-investigators or young doctors who want to follow in your path?
Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.