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Immune-modified RECIST can help identify survival benefit from cancer immunotherapy
Cancer immunotherapy-specific response criteria not only provide improved estimates of treatment response versus standard criteria, but may also better identify patients who achieve an overall survival benefit from therapy.
Compared to standard Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, the immune-modified RECIST provided a 1%-2% greater overall response and an 8%-13% greater rate of disease control, and added 0.5-1.5 months to median progression-free survival among patients treated with the PD-L1 inhibitor atezolizumab, according to analyses of different phase 1 and 2 trials.
In addition, overall survival (OS) benefit in some of the trials could be better delineated using the immune-modified criteria, which account for unique patterns of progression sometimes experienced by patients on cancer immunotherapy, noted the study authors. The report was published in the Journal of Clinical Oncology.
Using immune-specific criteria to evaluate response to cancer immunotherapy is not a new concept. However, there are only limited data on how those criteria might apply to predictions of OS, according to lead author F. Stephen Hodi, MD, of Dana-Farber Cancer Institute, Boston, and his coauthors.
“These analyses reveal aspects of immune-modified RECIST that seem to predict OS better than RECIST v1.1, and aspects needing refinement to improve the ability to predict clinical benefit,” wrote Dr. Hodi and his colleagues.
Typical response criteria may not adequately predict the potential OS benefit of cancer immunotherapy, since patients receiving cancer immunotherapy may exhibit response patterns outside of the “classic response patterns” seen with other anticancer treatments, they noted.
In particular, some patients may experience an initial transient increase in tumor burden before responding, while in other cases, patients with responding baseline lesions might develop new lesions.
Immune-modified criteria have been developed to account for those “other patterns” that can manifest with cancer immunotherapy, the authors said.
Dr. Hodi and his colleagues sought to evaluate outcomes by RECIST vs. immune-related RECIST criteria among patients treated with atezolizumab in studies of non–small-cell lung cancer (NSCLC) and metastatic urothelial carcinoma.
In the phase 2 BIRCH study of first-line atezolizumab for NSCLC, they found that immune-related RECIST criteria appeared to predict OS better than RECIST. Median overall survival was 4.0 months longer among patients who had progressive disease (PD) by RECIST criteria within 90 days of study enrollment, versus patients who had PD by both RECIST and immune-modified RECIST at that time point, Dr. Hodi and his colleagues reported.
In the POPLAR trial of atezolizumab in NSCLC, median overall survival was 1.4 months longer for patients with PD by RECIST vs. patients with PD by both RECIST and immune-modified RECIST at 90 days, they reported.
For patients with metastatic urothelial bladder cancer treated with atezolizumab in the IMvigor210 study, median overall survival was 4.4 months longer for patients with PD by RECIST only vs. PD by both RECIST and immune-related RECIST within 180 days of enrollment, the researchers noted.
An international effort is underway to compare data sets from larger trial sets and multiple cancer immunotherapy agents, they wrote.
SOURCE: Hodi FS et al., J Clin Oncol. 2018 Jan 17. doi: 10.1200/JCO.2017.75.1644
Cancer immunotherapy-specific response criteria not only provide improved estimates of treatment response versus standard criteria, but may also better identify patients who achieve an overall survival benefit from therapy.
Compared to standard Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, the immune-modified RECIST provided a 1%-2% greater overall response and an 8%-13% greater rate of disease control, and added 0.5-1.5 months to median progression-free survival among patients treated with the PD-L1 inhibitor atezolizumab, according to analyses of different phase 1 and 2 trials.
In addition, overall survival (OS) benefit in some of the trials could be better delineated using the immune-modified criteria, which account for unique patterns of progression sometimes experienced by patients on cancer immunotherapy, noted the study authors. The report was published in the Journal of Clinical Oncology.
Using immune-specific criteria to evaluate response to cancer immunotherapy is not a new concept. However, there are only limited data on how those criteria might apply to predictions of OS, according to lead author F. Stephen Hodi, MD, of Dana-Farber Cancer Institute, Boston, and his coauthors.
“These analyses reveal aspects of immune-modified RECIST that seem to predict OS better than RECIST v1.1, and aspects needing refinement to improve the ability to predict clinical benefit,” wrote Dr. Hodi and his colleagues.
Typical response criteria may not adequately predict the potential OS benefit of cancer immunotherapy, since patients receiving cancer immunotherapy may exhibit response patterns outside of the “classic response patterns” seen with other anticancer treatments, they noted.
In particular, some patients may experience an initial transient increase in tumor burden before responding, while in other cases, patients with responding baseline lesions might develop new lesions.
Immune-modified criteria have been developed to account for those “other patterns” that can manifest with cancer immunotherapy, the authors said.
Dr. Hodi and his colleagues sought to evaluate outcomes by RECIST vs. immune-related RECIST criteria among patients treated with atezolizumab in studies of non–small-cell lung cancer (NSCLC) and metastatic urothelial carcinoma.
In the phase 2 BIRCH study of first-line atezolizumab for NSCLC, they found that immune-related RECIST criteria appeared to predict OS better than RECIST. Median overall survival was 4.0 months longer among patients who had progressive disease (PD) by RECIST criteria within 90 days of study enrollment, versus patients who had PD by both RECIST and immune-modified RECIST at that time point, Dr. Hodi and his colleagues reported.
In the POPLAR trial of atezolizumab in NSCLC, median overall survival was 1.4 months longer for patients with PD by RECIST vs. patients with PD by both RECIST and immune-modified RECIST at 90 days, they reported.
For patients with metastatic urothelial bladder cancer treated with atezolizumab in the IMvigor210 study, median overall survival was 4.4 months longer for patients with PD by RECIST only vs. PD by both RECIST and immune-related RECIST within 180 days of enrollment, the researchers noted.
An international effort is underway to compare data sets from larger trial sets and multiple cancer immunotherapy agents, they wrote.
SOURCE: Hodi FS et al., J Clin Oncol. 2018 Jan 17. doi: 10.1200/JCO.2017.75.1644
Cancer immunotherapy-specific response criteria not only provide improved estimates of treatment response versus standard criteria, but may also better identify patients who achieve an overall survival benefit from therapy.
Compared to standard Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, the immune-modified RECIST provided a 1%-2% greater overall response and an 8%-13% greater rate of disease control, and added 0.5-1.5 months to median progression-free survival among patients treated with the PD-L1 inhibitor atezolizumab, according to analyses of different phase 1 and 2 trials.
In addition, overall survival (OS) benefit in some of the trials could be better delineated using the immune-modified criteria, which account for unique patterns of progression sometimes experienced by patients on cancer immunotherapy, noted the study authors. The report was published in the Journal of Clinical Oncology.
Using immune-specific criteria to evaluate response to cancer immunotherapy is not a new concept. However, there are only limited data on how those criteria might apply to predictions of OS, according to lead author F. Stephen Hodi, MD, of Dana-Farber Cancer Institute, Boston, and his coauthors.
“These analyses reveal aspects of immune-modified RECIST that seem to predict OS better than RECIST v1.1, and aspects needing refinement to improve the ability to predict clinical benefit,” wrote Dr. Hodi and his colleagues.
Typical response criteria may not adequately predict the potential OS benefit of cancer immunotherapy, since patients receiving cancer immunotherapy may exhibit response patterns outside of the “classic response patterns” seen with other anticancer treatments, they noted.
In particular, some patients may experience an initial transient increase in tumor burden before responding, while in other cases, patients with responding baseline lesions might develop new lesions.
Immune-modified criteria have been developed to account for those “other patterns” that can manifest with cancer immunotherapy, the authors said.
Dr. Hodi and his colleagues sought to evaluate outcomes by RECIST vs. immune-related RECIST criteria among patients treated with atezolizumab in studies of non–small-cell lung cancer (NSCLC) and metastatic urothelial carcinoma.
In the phase 2 BIRCH study of first-line atezolizumab for NSCLC, they found that immune-related RECIST criteria appeared to predict OS better than RECIST. Median overall survival was 4.0 months longer among patients who had progressive disease (PD) by RECIST criteria within 90 days of study enrollment, versus patients who had PD by both RECIST and immune-modified RECIST at that time point, Dr. Hodi and his colleagues reported.
In the POPLAR trial of atezolizumab in NSCLC, median overall survival was 1.4 months longer for patients with PD by RECIST vs. patients with PD by both RECIST and immune-modified RECIST at 90 days, they reported.
For patients with metastatic urothelial bladder cancer treated with atezolizumab in the IMvigor210 study, median overall survival was 4.4 months longer for patients with PD by RECIST only vs. PD by both RECIST and immune-related RECIST within 180 days of enrollment, the researchers noted.
An international effort is underway to compare data sets from larger trial sets and multiple cancer immunotherapy agents, they wrote.
SOURCE: Hodi FS et al., J Clin Oncol. 2018 Jan 17. doi: 10.1200/JCO.2017.75.1644
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Compared to standard criteria for response evaluation, criteria developed specifically to evaluate response to cancer immunotherapy better identified patients with an overall survival (OS) benefit.
Major finding: Median OS was 4.0 and 1.4 months longer, respectively, in the BIRCH and POPLAR non–small-cell lung cancer trial among patients who had progressive disease (PD) by standard criteria only, as opposed to patients who also had PD according to the immunotherapy-specific response criteria.
Data source: Analysis of patients treated with single-agent atezolizumab in phase 1 and 2 clinical trials.
Disclosures: The study was supported by F. Hoffmann-La Roche. Authors reported disclosures related to Merck Sharp & Dohme, Novartis, Genentech/Roche, Bristol-Myers Squibb, and others.
Source: Hodi FS et al., J Clin Oncol. 2018 Jan 17. doi: 10.1200/JCO.2017.75.1644.
CRB-410 update: Multiple myeloma response rates remain high with bb2121 CAR T-cell therapy
ATLANTA – A novel chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen showed promising efficacy with a manageable adverse event profile in heavily pretreated patients with relapsed/refractory multiple myeloma in the CRB-410 multicenter phase 1 dose escalation trial.
The product, known as bb2121, received breakthrough therapy designation from the Food and Drug Administration in November 2017 based on preliminary data from the ongoing trial. Those data showed that as of May 2017, the overall response rate at 1 month in 18 evaluable patients was 89%, whereas the response in those who received active dosing (150 x 106 CAR+ T cells or higher) was 100%.
Multiple myeloma currently is “essentially incurable,” and new treatments are desperately needed; B-cell maturation antigen (BCMA) – which is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells – is a promising target, said Dr. Kochenderfer of the National Cancer Institute, Bethesda, Md.
The bb2121 product is a second-generation CAR construct targeting BCMA to redirect T cells to multiple myeloma cells. It was tested at doses of 50, 150, 450, and 800 x 106 CAR+ T cells in patients who first underwent chemotherapy as a conditioning regimen to enhance the activity of the CAR T cells.
A total of 24 patients were enrolled, but three had clinical deterioration and were not dosed. The remaining 21 patients had a median age of 58 years, performance scores of 0 or 1, and a median of 5 years since multiple myeloma diagnosis. A high percentage (43%) had high-risk cytogenetics. The median number of prior lines of therapy was seven, and all patients had undergone prior autologous stem cell transplant.
“Generally, this was a very well tolerated CAR T-cell product, especially in comparison to other protocols that I’ve participated in,” he said, noting that the incidence of adverse events, including dose-limiting toxicities, was the primary outcome measure of this phase of the study.
Cytokine release syndrome occurred in 71% of the 21 patients evaluable for response with a median follow-up of 35 weeks at the Oct. 2, 2017, data cutoff, but was grade 3 or greater in just 10% of those patients. Neurological toxicity occurred in 24% of patients, as well, but no cases were grade 3 or above, he said.
“The neurotoxicity was generally much milder and less prevalent than what I’ve seen in previous anti-CD19 CAR studies,” he said.
Neutropenia, thrombocytopenia, and anemia also occurred, but there were no dose-limiting toxicities observed during dose escalation.
Five deaths occurred. Three were due to disease progression and occurred in patients on the lowest dose (50 x 106 CAR+ T cells), which was deemed inactive. The other deaths occurred in patients receiving higher (active) doses; one was a result of myelodysplastic syndrome, and one from cardiac arrest, he said.
One or more serious adverse events occurred in 14 patients, and in some cases were characterized as such due to strict study protocols, Dr. Kochenderfer said.
Of note, one patient out of 12 in an ongoing dose expansion phase of the study, for which data have not yet been fully reported, experienced a delayed onset reversible grade 4 neurological toxicity associated with tumor lysis syndrome and cytokine release syndrome. The patient, who had the highest disease burden in the trial, completely recovered and has obtained a very good partial response despite low BCMA expression on the myeloma cells, Dr. Kochenderfer said.
In terms of response rates, 17 of 18 patients who received doses above 50 x 106 CAR+ T cells had overall responses, and 10 of the 18 achieved complete remission.
The median time to first response was 1 month, and the times to best response and complete response were 3.74 and 3.84 months, respectively. The rates of progression-free survival were 81% at 6 months, and 71% at 9 months, and responses deepened over time: as of May, the complete response rate was 27%, and as of October, it was 56%.
“Five of these patients so far have met the 1-year progression-free survival standard,” Dr. Kochenderfer said, adding that responses have endured for more than a year in several patients. The longest was 68 weeks at the time of the data presentation, and responses continued to improve as late as 15 months, with very good partial remission to complete remission transitions.
The median progression-free survival had not been reached in the active dose cohorts.
“So, in general, very impressive responses compared to my previous experience treating multiple myeloma,” he said.
The findings support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed/refractory multiple myeloma, he concluded, noting that a global pivotal trial of bb2121 (the phase 2 KarMMa trial) is now enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells. Under the breakthrough therapy designation granted for bb2121, the product will receive expedited review by the FDA.The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
ATLANTA – A novel chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen showed promising efficacy with a manageable adverse event profile in heavily pretreated patients with relapsed/refractory multiple myeloma in the CRB-410 multicenter phase 1 dose escalation trial.
The product, known as bb2121, received breakthrough therapy designation from the Food and Drug Administration in November 2017 based on preliminary data from the ongoing trial. Those data showed that as of May 2017, the overall response rate at 1 month in 18 evaluable patients was 89%, whereas the response in those who received active dosing (150 x 106 CAR+ T cells or higher) was 100%.
Multiple myeloma currently is “essentially incurable,” and new treatments are desperately needed; B-cell maturation antigen (BCMA) – which is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells – is a promising target, said Dr. Kochenderfer of the National Cancer Institute, Bethesda, Md.
The bb2121 product is a second-generation CAR construct targeting BCMA to redirect T cells to multiple myeloma cells. It was tested at doses of 50, 150, 450, and 800 x 106 CAR+ T cells in patients who first underwent chemotherapy as a conditioning regimen to enhance the activity of the CAR T cells.
A total of 24 patients were enrolled, but three had clinical deterioration and were not dosed. The remaining 21 patients had a median age of 58 years, performance scores of 0 or 1, and a median of 5 years since multiple myeloma diagnosis. A high percentage (43%) had high-risk cytogenetics. The median number of prior lines of therapy was seven, and all patients had undergone prior autologous stem cell transplant.
“Generally, this was a very well tolerated CAR T-cell product, especially in comparison to other protocols that I’ve participated in,” he said, noting that the incidence of adverse events, including dose-limiting toxicities, was the primary outcome measure of this phase of the study.
Cytokine release syndrome occurred in 71% of the 21 patients evaluable for response with a median follow-up of 35 weeks at the Oct. 2, 2017, data cutoff, but was grade 3 or greater in just 10% of those patients. Neurological toxicity occurred in 24% of patients, as well, but no cases were grade 3 or above, he said.
“The neurotoxicity was generally much milder and less prevalent than what I’ve seen in previous anti-CD19 CAR studies,” he said.
Neutropenia, thrombocytopenia, and anemia also occurred, but there were no dose-limiting toxicities observed during dose escalation.
Five deaths occurred. Three were due to disease progression and occurred in patients on the lowest dose (50 x 106 CAR+ T cells), which was deemed inactive. The other deaths occurred in patients receiving higher (active) doses; one was a result of myelodysplastic syndrome, and one from cardiac arrest, he said.
One or more serious adverse events occurred in 14 patients, and in some cases were characterized as such due to strict study protocols, Dr. Kochenderfer said.
Of note, one patient out of 12 in an ongoing dose expansion phase of the study, for which data have not yet been fully reported, experienced a delayed onset reversible grade 4 neurological toxicity associated with tumor lysis syndrome and cytokine release syndrome. The patient, who had the highest disease burden in the trial, completely recovered and has obtained a very good partial response despite low BCMA expression on the myeloma cells, Dr. Kochenderfer said.
In terms of response rates, 17 of 18 patients who received doses above 50 x 106 CAR+ T cells had overall responses, and 10 of the 18 achieved complete remission.
The median time to first response was 1 month, and the times to best response and complete response were 3.74 and 3.84 months, respectively. The rates of progression-free survival were 81% at 6 months, and 71% at 9 months, and responses deepened over time: as of May, the complete response rate was 27%, and as of October, it was 56%.
“Five of these patients so far have met the 1-year progression-free survival standard,” Dr. Kochenderfer said, adding that responses have endured for more than a year in several patients. The longest was 68 weeks at the time of the data presentation, and responses continued to improve as late as 15 months, with very good partial remission to complete remission transitions.
The median progression-free survival had not been reached in the active dose cohorts.
“So, in general, very impressive responses compared to my previous experience treating multiple myeloma,” he said.
The findings support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed/refractory multiple myeloma, he concluded, noting that a global pivotal trial of bb2121 (the phase 2 KarMMa trial) is now enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells. Under the breakthrough therapy designation granted for bb2121, the product will receive expedited review by the FDA.The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
ATLANTA – A novel chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen showed promising efficacy with a manageable adverse event profile in heavily pretreated patients with relapsed/refractory multiple myeloma in the CRB-410 multicenter phase 1 dose escalation trial.
The product, known as bb2121, received breakthrough therapy designation from the Food and Drug Administration in November 2017 based on preliminary data from the ongoing trial. Those data showed that as of May 2017, the overall response rate at 1 month in 18 evaluable patients was 89%, whereas the response in those who received active dosing (150 x 106 CAR+ T cells or higher) was 100%.
Multiple myeloma currently is “essentially incurable,” and new treatments are desperately needed; B-cell maturation antigen (BCMA) – which is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells – is a promising target, said Dr. Kochenderfer of the National Cancer Institute, Bethesda, Md.
The bb2121 product is a second-generation CAR construct targeting BCMA to redirect T cells to multiple myeloma cells. It was tested at doses of 50, 150, 450, and 800 x 106 CAR+ T cells in patients who first underwent chemotherapy as a conditioning regimen to enhance the activity of the CAR T cells.
A total of 24 patients were enrolled, but three had clinical deterioration and were not dosed. The remaining 21 patients had a median age of 58 years, performance scores of 0 or 1, and a median of 5 years since multiple myeloma diagnosis. A high percentage (43%) had high-risk cytogenetics. The median number of prior lines of therapy was seven, and all patients had undergone prior autologous stem cell transplant.
“Generally, this was a very well tolerated CAR T-cell product, especially in comparison to other protocols that I’ve participated in,” he said, noting that the incidence of adverse events, including dose-limiting toxicities, was the primary outcome measure of this phase of the study.
Cytokine release syndrome occurred in 71% of the 21 patients evaluable for response with a median follow-up of 35 weeks at the Oct. 2, 2017, data cutoff, but was grade 3 or greater in just 10% of those patients. Neurological toxicity occurred in 24% of patients, as well, but no cases were grade 3 or above, he said.
“The neurotoxicity was generally much milder and less prevalent than what I’ve seen in previous anti-CD19 CAR studies,” he said.
Neutropenia, thrombocytopenia, and anemia also occurred, but there were no dose-limiting toxicities observed during dose escalation.
Five deaths occurred. Three were due to disease progression and occurred in patients on the lowest dose (50 x 106 CAR+ T cells), which was deemed inactive. The other deaths occurred in patients receiving higher (active) doses; one was a result of myelodysplastic syndrome, and one from cardiac arrest, he said.
One or more serious adverse events occurred in 14 patients, and in some cases were characterized as such due to strict study protocols, Dr. Kochenderfer said.
Of note, one patient out of 12 in an ongoing dose expansion phase of the study, for which data have not yet been fully reported, experienced a delayed onset reversible grade 4 neurological toxicity associated with tumor lysis syndrome and cytokine release syndrome. The patient, who had the highest disease burden in the trial, completely recovered and has obtained a very good partial response despite low BCMA expression on the myeloma cells, Dr. Kochenderfer said.
In terms of response rates, 17 of 18 patients who received doses above 50 x 106 CAR+ T cells had overall responses, and 10 of the 18 achieved complete remission.
The median time to first response was 1 month, and the times to best response and complete response were 3.74 and 3.84 months, respectively. The rates of progression-free survival were 81% at 6 months, and 71% at 9 months, and responses deepened over time: as of May, the complete response rate was 27%, and as of October, it was 56%.
“Five of these patients so far have met the 1-year progression-free survival standard,” Dr. Kochenderfer said, adding that responses have endured for more than a year in several patients. The longest was 68 weeks at the time of the data presentation, and responses continued to improve as late as 15 months, with very good partial remission to complete remission transitions.
The median progression-free survival had not been reached in the active dose cohorts.
“So, in general, very impressive responses compared to my previous experience treating multiple myeloma,” he said.
The findings support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed/refractory multiple myeloma, he concluded, noting that a global pivotal trial of bb2121 (the phase 2 KarMMa trial) is now enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells. Under the breakthrough therapy designation granted for bb2121, the product will receive expedited review by the FDA.The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: The overall response rate was 94%.
Study details: An update from the phase 1 CRB-410 dose trial of 21 patients.
Disclosures: The CRB-410 trial is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported receiving research funding from bluebird bio and Kite Pharma, and having multiple patents in the CAR field.
Source: Berdeja J et al. ASH 2017 Abstract 740.
VIDEO - New lymphoma drug approvals: Clinical use, future directions
ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.
At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.
In this video interview,
“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.
“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.
However, while the findings are encouraging, only 30%-40% are having a durable response, she added.
“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.
With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.
Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.
“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.
She reported having no relevant financial disclosures.
ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.
At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.
In this video interview,
“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.
“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.
However, while the findings are encouraging, only 30%-40% are having a durable response, she added.
“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.
With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.
Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.
“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.
She reported having no relevant financial disclosures.
ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.
At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.
In this video interview,
“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.
“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.
However, while the findings are encouraging, only 30%-40% are having a durable response, she added.
“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.
With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.
Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.
“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.
She reported having no relevant financial disclosures.
REPORTING FROM ASH 2017
PANACEA: pembrolizumab overcomes trastuzumab resistance for some
SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab overcomes trastuzumab resistance in HER2-positive advanced breast cancer provided that the tumor expresses programmed death ligand 1 (PD-L1), a trial reported at the San Antonio Breast Cancer Symposium suggests. But presence of immune cells in the tumor is a major additional determinant of benefit.
The single-arm phase 1b/2 trial, called PANACEA (also KEYNOTE-014), enrolled 58 patients with HER2-positive advanced breast cancer that had progressed on trastuzumab (Herceptin) or trastuzumab emtansine (Kadcyla). All were given pembrolizumab (Keytruda), which unleashes antitumor immunity by targeting the programmed death-1 receptor on immune cells, in combination with trastuzumab.
With a median follow-up of 13.6 months, the cohort of patients having tumors positive for PD-L1 achieved an overall response rate of 15.2% and a disease control rate of 24%,” Dr. Loi reported in a press briefing and session, on behalf of the International Breast Cancer Study Group and Breast International Group. In contrast, there were no responses in the PD-L1–negative cohort.
Within the PD-L1–positive cohort, stromal levels of TILs in the metastatic lesion – which were low overall – influenced likelihood of benefit. The response rate was almost eight times higher in patients who had at least 5% of the stromal area densely infiltrated with TILs.
“The PANACEA study met its primary endpoint in the PD-L1–positive cohort. For responders, this combination offers durable control without chemotherapy,” Dr. Loi summarized.
“Metastatic HER2-positive breast cancer in this [heavily pretreated] setting is poorly immunogenic, as evidenced by the majority of patients having low TILs in their metastatic lesions. Saying that, however, we did observe a higher response rate in this study as compared to the equivalent triple-negative breast cancer studied in KEYNOTE-086,” she noted. “Future directions in this disease space should focus on combinations with effective anti-HER2 therapy, particularly in low-TIL patients.”
Predicting benefit
The trial is noteworthy for its efforts to identify the subset of patients most likely to benefit from immune checkpoint inhibition, according to press briefing moderator Virginia Kaklamani, MD, a professor of medicine in the division of hematology/oncology at the University of Texas Health Science Center, San Antonio, and a leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center.
In similar studies among patients with HER2-negative breast cancer, PD-L1 did not pan out as a strong predictive biomarker. “What do you think the difference is between that subset and the HER2-positive subset?” Dr. Kaklamani asked.
“First off, I think that there are technical issues with the PD-L1 assay. And we find that patients with high TILs or immune infiltration usually have high levels of PD-L1 expression on their TILs,” Dr. Loi replied. “So I think that PD-L1 can be expressed on the tumor as well as the TIL, and it certainly seems to be the TIL infiltrate that probably enriches for responders to a PD-L1 checkpoint inhibitor on its own or in this case with trastuzumab.”
Study details
In the PANACEA trial (additionally known as IBCSG 45-13 and BIG 4-13), the most common adverse event of any grade and type with the pembrolizumab-trastuzumab combination was fatigue, seen in 21% of patients, Dr. Loi reported. For immune-related adverse events specifically, 19.0% of patients experienced an event, 10.3% experienced an event of grade 3 or worse, and 6.9% stopped treatment because of these events.
“These frequencies are consistent with what has been reported in other solid tumor types with pembrolizumab,” she commented. There were no cardiac events reported.
Efficacy analyses were restricted largely to the PD-L1–positive cohort, given the lack of any response in the negative cohort.
Median duration of response in the positive cohort was 3.5 months, and median duration of disease control was 11.1 months. Five patients (10.8%) remain on treatment with no progression; three of them have completed 2 years of pembrolizumab.
Median progression-free and overall survival were 2.7 and 16.1 months, respectively; corresponding 12-month rates were 13% and 65%. “There is a tantalizing suggestion of a tail on the curve. ... Obviously, this requires further follow-up, and the numbers are small,” Dr. Loi commented.
The median baseline stromal TIL level in metastatic lesions was just 1%. “This is 20 times less than what we observe in primary HER2-positive breast cancers,” she pointed out.
Compared with the PD-L1–negative cohort, the PD-L1–positive cohort had higher TIL levels. Additionally, within that latter cohort, TIL level was higher among patients achieving response versus not (P = .006) and patients achieving disease control versus not (P = .0006).
“We then went on to try to identify a TIL cutoff that could enrich the population for responders. This has been done in other solid tumor types,” Dr. Loi explained.
Analyses in the PD-L1-positive cohort showed that TIL levels down to 5% predicted benefit. The 41% of patients having 5% or more TILs were dramatically more likely to have a response (39% vs. 5%) and disease control (47% vs. 5%).
TIL levels varied widely according to site of the metastasis, with higher levels seen in metastases from lung and lymph nodes, and lower levels seen in those from liver and skin.
“At this stage, we are not sure which is the chicken and the egg: Patients could have disease in their lung and their lymph nodes because their immune system is better controlling their disease,” Dr. Loi commented. “How we treat these patients is still an open question. In patients with liver metastases, perhaps we need to be more aggressive with the primary or tumor-control anti-HER2 therapy.”
Improving efficacy
Going forward, one strategy for improving pembrolizumab efficacy in this patient population might be priming the immune response, according to Dr. Loi.
“In HER2 disease, it’s very clear that oncogenic signaling is the driver, so targeting HER2 potently also will help relieve tumor-mediated immune suppression,” she elaborated. “In this particular context, targeting HER2 well is the key. Whether you need the addition of a little bit of chemo or some radiation, all this needs to be studied.”
Another strategy for improving pembrolizumab efficacy might be moving the drug to earlier disease settings, Dr. Loi proposed.
“By the time you get to advanced stage and have had multiple treatments, you actually have low levels of T-cell infiltration in your metastatic lesion, for whatever reasons – tumor burden, immunosuppression, multiple lines of treatment. That all reduces your chance of responding to pembrolizumab, for example, as monotherapy,” she elaborated. “We don’t know yet if chemotherapy in addition to pembrolizumab could change that tumor microenvironment. But still, I think the earlier in lines you go, the more chance you are going to have of preexisting effective antitumor immunity that can be reactivated with the addition of pembrolizumab.”
Dr. Loi disclosed that her institution receives research funding from Novartis, Pfizer, Merck, Genentech/Roche, and Puma. Merck provided study drug and support for PANACEA.
SOURCE: Loi S et al. SABCS 2017 Abstract GS2-06.
SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab overcomes trastuzumab resistance in HER2-positive advanced breast cancer provided that the tumor expresses programmed death ligand 1 (PD-L1), a trial reported at the San Antonio Breast Cancer Symposium suggests. But presence of immune cells in the tumor is a major additional determinant of benefit.
The single-arm phase 1b/2 trial, called PANACEA (also KEYNOTE-014), enrolled 58 patients with HER2-positive advanced breast cancer that had progressed on trastuzumab (Herceptin) or trastuzumab emtansine (Kadcyla). All were given pembrolizumab (Keytruda), which unleashes antitumor immunity by targeting the programmed death-1 receptor on immune cells, in combination with trastuzumab.
With a median follow-up of 13.6 months, the cohort of patients having tumors positive for PD-L1 achieved an overall response rate of 15.2% and a disease control rate of 24%,” Dr. Loi reported in a press briefing and session, on behalf of the International Breast Cancer Study Group and Breast International Group. In contrast, there were no responses in the PD-L1–negative cohort.
Within the PD-L1–positive cohort, stromal levels of TILs in the metastatic lesion – which were low overall – influenced likelihood of benefit. The response rate was almost eight times higher in patients who had at least 5% of the stromal area densely infiltrated with TILs.
“The PANACEA study met its primary endpoint in the PD-L1–positive cohort. For responders, this combination offers durable control without chemotherapy,” Dr. Loi summarized.
“Metastatic HER2-positive breast cancer in this [heavily pretreated] setting is poorly immunogenic, as evidenced by the majority of patients having low TILs in their metastatic lesions. Saying that, however, we did observe a higher response rate in this study as compared to the equivalent triple-negative breast cancer studied in KEYNOTE-086,” she noted. “Future directions in this disease space should focus on combinations with effective anti-HER2 therapy, particularly in low-TIL patients.”
Predicting benefit
The trial is noteworthy for its efforts to identify the subset of patients most likely to benefit from immune checkpoint inhibition, according to press briefing moderator Virginia Kaklamani, MD, a professor of medicine in the division of hematology/oncology at the University of Texas Health Science Center, San Antonio, and a leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center.
In similar studies among patients with HER2-negative breast cancer, PD-L1 did not pan out as a strong predictive biomarker. “What do you think the difference is between that subset and the HER2-positive subset?” Dr. Kaklamani asked.
“First off, I think that there are technical issues with the PD-L1 assay. And we find that patients with high TILs or immune infiltration usually have high levels of PD-L1 expression on their TILs,” Dr. Loi replied. “So I think that PD-L1 can be expressed on the tumor as well as the TIL, and it certainly seems to be the TIL infiltrate that probably enriches for responders to a PD-L1 checkpoint inhibitor on its own or in this case with trastuzumab.”
Study details
In the PANACEA trial (additionally known as IBCSG 45-13 and BIG 4-13), the most common adverse event of any grade and type with the pembrolizumab-trastuzumab combination was fatigue, seen in 21% of patients, Dr. Loi reported. For immune-related adverse events specifically, 19.0% of patients experienced an event, 10.3% experienced an event of grade 3 or worse, and 6.9% stopped treatment because of these events.
“These frequencies are consistent with what has been reported in other solid tumor types with pembrolizumab,” she commented. There were no cardiac events reported.
Efficacy analyses were restricted largely to the PD-L1–positive cohort, given the lack of any response in the negative cohort.
Median duration of response in the positive cohort was 3.5 months, and median duration of disease control was 11.1 months. Five patients (10.8%) remain on treatment with no progression; three of them have completed 2 years of pembrolizumab.
Median progression-free and overall survival were 2.7 and 16.1 months, respectively; corresponding 12-month rates were 13% and 65%. “There is a tantalizing suggestion of a tail on the curve. ... Obviously, this requires further follow-up, and the numbers are small,” Dr. Loi commented.
The median baseline stromal TIL level in metastatic lesions was just 1%. “This is 20 times less than what we observe in primary HER2-positive breast cancers,” she pointed out.
Compared with the PD-L1–negative cohort, the PD-L1–positive cohort had higher TIL levels. Additionally, within that latter cohort, TIL level was higher among patients achieving response versus not (P = .006) and patients achieving disease control versus not (P = .0006).
“We then went on to try to identify a TIL cutoff that could enrich the population for responders. This has been done in other solid tumor types,” Dr. Loi explained.
Analyses in the PD-L1-positive cohort showed that TIL levels down to 5% predicted benefit. The 41% of patients having 5% or more TILs were dramatically more likely to have a response (39% vs. 5%) and disease control (47% vs. 5%).
TIL levels varied widely according to site of the metastasis, with higher levels seen in metastases from lung and lymph nodes, and lower levels seen in those from liver and skin.
“At this stage, we are not sure which is the chicken and the egg: Patients could have disease in their lung and their lymph nodes because their immune system is better controlling their disease,” Dr. Loi commented. “How we treat these patients is still an open question. In patients with liver metastases, perhaps we need to be more aggressive with the primary or tumor-control anti-HER2 therapy.”
Improving efficacy
Going forward, one strategy for improving pembrolizumab efficacy in this patient population might be priming the immune response, according to Dr. Loi.
“In HER2 disease, it’s very clear that oncogenic signaling is the driver, so targeting HER2 potently also will help relieve tumor-mediated immune suppression,” she elaborated. “In this particular context, targeting HER2 well is the key. Whether you need the addition of a little bit of chemo or some radiation, all this needs to be studied.”
Another strategy for improving pembrolizumab efficacy might be moving the drug to earlier disease settings, Dr. Loi proposed.
“By the time you get to advanced stage and have had multiple treatments, you actually have low levels of T-cell infiltration in your metastatic lesion, for whatever reasons – tumor burden, immunosuppression, multiple lines of treatment. That all reduces your chance of responding to pembrolizumab, for example, as monotherapy,” she elaborated. “We don’t know yet if chemotherapy in addition to pembrolizumab could change that tumor microenvironment. But still, I think the earlier in lines you go, the more chance you are going to have of preexisting effective antitumor immunity that can be reactivated with the addition of pembrolizumab.”
Dr. Loi disclosed that her institution receives research funding from Novartis, Pfizer, Merck, Genentech/Roche, and Puma. Merck provided study drug and support for PANACEA.
SOURCE: Loi S et al. SABCS 2017 Abstract GS2-06.
SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab overcomes trastuzumab resistance in HER2-positive advanced breast cancer provided that the tumor expresses programmed death ligand 1 (PD-L1), a trial reported at the San Antonio Breast Cancer Symposium suggests. But presence of immune cells in the tumor is a major additional determinant of benefit.
The single-arm phase 1b/2 trial, called PANACEA (also KEYNOTE-014), enrolled 58 patients with HER2-positive advanced breast cancer that had progressed on trastuzumab (Herceptin) or trastuzumab emtansine (Kadcyla). All were given pembrolizumab (Keytruda), which unleashes antitumor immunity by targeting the programmed death-1 receptor on immune cells, in combination with trastuzumab.
With a median follow-up of 13.6 months, the cohort of patients having tumors positive for PD-L1 achieved an overall response rate of 15.2% and a disease control rate of 24%,” Dr. Loi reported in a press briefing and session, on behalf of the International Breast Cancer Study Group and Breast International Group. In contrast, there were no responses in the PD-L1–negative cohort.
Within the PD-L1–positive cohort, stromal levels of TILs in the metastatic lesion – which were low overall – influenced likelihood of benefit. The response rate was almost eight times higher in patients who had at least 5% of the stromal area densely infiltrated with TILs.
“The PANACEA study met its primary endpoint in the PD-L1–positive cohort. For responders, this combination offers durable control without chemotherapy,” Dr. Loi summarized.
“Metastatic HER2-positive breast cancer in this [heavily pretreated] setting is poorly immunogenic, as evidenced by the majority of patients having low TILs in their metastatic lesions. Saying that, however, we did observe a higher response rate in this study as compared to the equivalent triple-negative breast cancer studied in KEYNOTE-086,” she noted. “Future directions in this disease space should focus on combinations with effective anti-HER2 therapy, particularly in low-TIL patients.”
Predicting benefit
The trial is noteworthy for its efforts to identify the subset of patients most likely to benefit from immune checkpoint inhibition, according to press briefing moderator Virginia Kaklamani, MD, a professor of medicine in the division of hematology/oncology at the University of Texas Health Science Center, San Antonio, and a leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center.
In similar studies among patients with HER2-negative breast cancer, PD-L1 did not pan out as a strong predictive biomarker. “What do you think the difference is between that subset and the HER2-positive subset?” Dr. Kaklamani asked.
“First off, I think that there are technical issues with the PD-L1 assay. And we find that patients with high TILs or immune infiltration usually have high levels of PD-L1 expression on their TILs,” Dr. Loi replied. “So I think that PD-L1 can be expressed on the tumor as well as the TIL, and it certainly seems to be the TIL infiltrate that probably enriches for responders to a PD-L1 checkpoint inhibitor on its own or in this case with trastuzumab.”
Study details
In the PANACEA trial (additionally known as IBCSG 45-13 and BIG 4-13), the most common adverse event of any grade and type with the pembrolizumab-trastuzumab combination was fatigue, seen in 21% of patients, Dr. Loi reported. For immune-related adverse events specifically, 19.0% of patients experienced an event, 10.3% experienced an event of grade 3 or worse, and 6.9% stopped treatment because of these events.
“These frequencies are consistent with what has been reported in other solid tumor types with pembrolizumab,” she commented. There were no cardiac events reported.
Efficacy analyses were restricted largely to the PD-L1–positive cohort, given the lack of any response in the negative cohort.
Median duration of response in the positive cohort was 3.5 months, and median duration of disease control was 11.1 months. Five patients (10.8%) remain on treatment with no progression; three of them have completed 2 years of pembrolizumab.
Median progression-free and overall survival were 2.7 and 16.1 months, respectively; corresponding 12-month rates were 13% and 65%. “There is a tantalizing suggestion of a tail on the curve. ... Obviously, this requires further follow-up, and the numbers are small,” Dr. Loi commented.
The median baseline stromal TIL level in metastatic lesions was just 1%. “This is 20 times less than what we observe in primary HER2-positive breast cancers,” she pointed out.
Compared with the PD-L1–negative cohort, the PD-L1–positive cohort had higher TIL levels. Additionally, within that latter cohort, TIL level was higher among patients achieving response versus not (P = .006) and patients achieving disease control versus not (P = .0006).
“We then went on to try to identify a TIL cutoff that could enrich the population for responders. This has been done in other solid tumor types,” Dr. Loi explained.
Analyses in the PD-L1-positive cohort showed that TIL levels down to 5% predicted benefit. The 41% of patients having 5% or more TILs were dramatically more likely to have a response (39% vs. 5%) and disease control (47% vs. 5%).
TIL levels varied widely according to site of the metastasis, with higher levels seen in metastases from lung and lymph nodes, and lower levels seen in those from liver and skin.
“At this stage, we are not sure which is the chicken and the egg: Patients could have disease in their lung and their lymph nodes because their immune system is better controlling their disease,” Dr. Loi commented. “How we treat these patients is still an open question. In patients with liver metastases, perhaps we need to be more aggressive with the primary or tumor-control anti-HER2 therapy.”
Improving efficacy
Going forward, one strategy for improving pembrolizumab efficacy in this patient population might be priming the immune response, according to Dr. Loi.
“In HER2 disease, it’s very clear that oncogenic signaling is the driver, so targeting HER2 potently also will help relieve tumor-mediated immune suppression,” she elaborated. “In this particular context, targeting HER2 well is the key. Whether you need the addition of a little bit of chemo or some radiation, all this needs to be studied.”
Another strategy for improving pembrolizumab efficacy might be moving the drug to earlier disease settings, Dr. Loi proposed.
“By the time you get to advanced stage and have had multiple treatments, you actually have low levels of T-cell infiltration in your metastatic lesion, for whatever reasons – tumor burden, immunosuppression, multiple lines of treatment. That all reduces your chance of responding to pembrolizumab, for example, as monotherapy,” she elaborated. “We don’t know yet if chemotherapy in addition to pembrolizumab could change that tumor microenvironment. But still, I think the earlier in lines you go, the more chance you are going to have of preexisting effective antitumor immunity that can be reactivated with the addition of pembrolizumab.”
Dr. Loi disclosed that her institution receives research funding from Novartis, Pfizer, Merck, Genentech/Roche, and Puma. Merck provided study drug and support for PANACEA.
SOURCE: Loi S et al. SABCS 2017 Abstract GS2-06.
REPORTING FROM SABCS 2017
Key clinical point:
Major finding: The PD-L1–positive cohort had an overall response rate of 15.2% and a disease control rate of 24%.
Data source: A single-arm phase 1b/2 trial among 58 women with trastuzumab-resistant HER2-positive advanced breast cancer (PANACEA study).
Disclosures: Dr. Loi disclosed that her institution receives research funding from Novartis, Pfizer, Merck, Genentech/Roche, and Puma. Merck provided study drug and support.
Source: Loi S et al. SABCS 2017 Abstract GS2-06.
VIDEO: CAR T cell axi-cel drives B-cell lymphomas into remission
ATLANTA – In the ZUMA-1 trial, more than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta; axi-cel) had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion.
Updated combined phase 1 and 2 results in 108 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma showed an objective response rate of 82% of patients – including 58% showing complete responses – after a median follow-up of 15.4 months.
In a video interview at the annual meeting of the American Society of Hematology, Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston discusses the use of CAR T cells directed against the CD19 antigen in patients with relapsed/refractory B-cell lymphomas and describes efforts to improve responses while managing adverse events common to CAR T-cell therapies, notably cytokine release syndrome.
ZUMA-1 is supported by Kite Pharma, which developed axicabtagene ciloleucel, and the Leukemia & Lymphoma Society’s Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ATLANTA – In the ZUMA-1 trial, more than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta; axi-cel) had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion.
Updated combined phase 1 and 2 results in 108 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma showed an objective response rate of 82% of patients – including 58% showing complete responses – after a median follow-up of 15.4 months.
In a video interview at the annual meeting of the American Society of Hematology, Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston discusses the use of CAR T cells directed against the CD19 antigen in patients with relapsed/refractory B-cell lymphomas and describes efforts to improve responses while managing adverse events common to CAR T-cell therapies, notably cytokine release syndrome.
ZUMA-1 is supported by Kite Pharma, which developed axicabtagene ciloleucel, and the Leukemia & Lymphoma Society’s Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
ATLANTA – In the ZUMA-1 trial, more than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta; axi-cel) had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion.
Updated combined phase 1 and 2 results in 108 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma showed an objective response rate of 82% of patients – including 58% showing complete responses – after a median follow-up of 15.4 months.
In a video interview at the annual meeting of the American Society of Hematology, Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston discusses the use of CAR T cells directed against the CD19 antigen in patients with relapsed/refractory B-cell lymphomas and describes efforts to improve responses while managing adverse events common to CAR T-cell therapies, notably cytokine release syndrome.
ZUMA-1 is supported by Kite Pharma, which developed axicabtagene ciloleucel, and the Leukemia & Lymphoma Society’s Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
REPORTING FROM ASH 2017
Three-month response to CAR T-cells looks durable in DLBCL
ATLANTA – Responses 3 months after chimeric antigen receptor (CAR) T-cell therapy look durable in adults with transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to updated results from the single-arm, global, phase 2 JULIET trial.
Fully 95% of patients who had a complete response to CTL019 (tisagenlecleucel; Kymriah) at 3 months maintained that complete response at 6 months, Stephen J. Schuster, MD, said at the annual meeting of the American Society of Hematology.
Patients with relapsed/refractory DLBCL tend to face a very poor prognosis, noted Dr. Schuster of Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia. High-dose chemotherapy followed by autologous stem cell transplantation “is capable of long-term survival, but in very few patients,” he said. A dismal 8% of patients completely respond to salvage treatment and only about one in five partially respond. Both levels of response are short-lived, with a median survival of about 4 months.
Meanwhile, CTL019 therapy has produced durable complete remissions in children with lymphoblastic leukemia and in adults with chronic lymphocytic leukemia, Dr. Schuster and his associates wrote in an article simultaneously published in the New England Journal of Medicine (2017 Dec 10. doi: 10.1056/NEJMoa1708566).
To test the CAR T-cell therapy in relapsed/refractory DLBCL, they enrolled affected adults who had received at least two prior lines of antineoplastic treatment and who were not candidates for autologous stem cell transplantation.
Treatment consisted of a single CTL019 infusion (median dose, 3.1 × 108 cells; range, 0.1 × 108 to 6.0 × 108 cells), usually after lymphodepleting chemotherapy. Previously, patients had received a median of three lines of therapy, and about half had undergone autologous stem cell transplantation.
Median time from infusion to data cutoff in March 2017 was 5.6 months. Among 81 patients followed for at least 3 months before data cutoff, best overall response rate was 53% and 40% had a complete response. Overall response rates were 38% at 3 months and 37% at 6 months. Rates of complete response as confirmed by 18F-fluorodeoxyglucose–positron-emission tomography (PET) were 32% at 3 months and 30% at 6 months.These findings highlight the predictive power of 3-month response to CTL019 therapy in relapsed/refractory DLBCL, Dr. Schuster said. Among all responders, 74% remained relapse free at 6 months, meaning that median duration of response and median overall survival were not reached at data cutoff.
Dr. Schuster also reported that 26% of patients were infused as outpatients, which he called “easy to do” and appropriate as long as patients who become febrile are admitted and monitored for cytokine release syndrome. Three-quarters of patients who were infused as outpatients were able to remain home for at least 3 days afterward, he said.
Adverse events typified those of CAR T-cell therapy, including cytokine release syndrome (all grades: 58%; grade 3-4: 23%) and neurological toxicities (all grades: 21%; grade 3-4: 12%). The current labeling for CTL019 in children and young adults with acute lymphoblastic leukemia also includes a boxed warning for these toxicities.Tisagenlecleucel, the first-ever approved CAR T-cell therapy, is made by using a lentiviral vector to genetically engineer a patient’s own T-cells to express a CAR for the pan-B-cell CD19 antigen. These anti-CD19 CAR T-cells are then expanded in the laboratory, frozen for shipping purposes, and infused back into patients. In October 2017, Novartis submitted a biologics license application to the Food and Drug Administration to expand the label for CTL019 to include transplant-ineligible relapsed/refractory DLBCL.
Novartis Pharmaceuticals anticipates large-scale production in 2018, Dr. Schuster said. Manufacturing time has been cut to 22 days from the 30-day turnaround used in the trial, he reported.
Dr. Schuster also said that he sees no point in retreating patients whose relapsed/refractory DLBCL doesn’t respond to tisagenlecleucel, and that JULIET did not test this approach. “If someone fails therapy and you retreat, you don’t see success, in my experience,” he said. “If patients respond and then fail later, then you retreat and you may succeed.”
Novartis Pharmaceuticals sponsored JULIET. Dr. Schuster disclosed consultancy and research funding from Novartis and ties to Celgene, Gilead, Genentech, and several other pharmaceutical companies.
SOURCE: Schuster S et al. ASH 2017 Abstract 577.
ATLANTA – Responses 3 months after chimeric antigen receptor (CAR) T-cell therapy look durable in adults with transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to updated results from the single-arm, global, phase 2 JULIET trial.
Fully 95% of patients who had a complete response to CTL019 (tisagenlecleucel; Kymriah) at 3 months maintained that complete response at 6 months, Stephen J. Schuster, MD, said at the annual meeting of the American Society of Hematology.
Patients with relapsed/refractory DLBCL tend to face a very poor prognosis, noted Dr. Schuster of Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia. High-dose chemotherapy followed by autologous stem cell transplantation “is capable of long-term survival, but in very few patients,” he said. A dismal 8% of patients completely respond to salvage treatment and only about one in five partially respond. Both levels of response are short-lived, with a median survival of about 4 months.
Meanwhile, CTL019 therapy has produced durable complete remissions in children with lymphoblastic leukemia and in adults with chronic lymphocytic leukemia, Dr. Schuster and his associates wrote in an article simultaneously published in the New England Journal of Medicine (2017 Dec 10. doi: 10.1056/NEJMoa1708566).
To test the CAR T-cell therapy in relapsed/refractory DLBCL, they enrolled affected adults who had received at least two prior lines of antineoplastic treatment and who were not candidates for autologous stem cell transplantation.
Treatment consisted of a single CTL019 infusion (median dose, 3.1 × 108 cells; range, 0.1 × 108 to 6.0 × 108 cells), usually after lymphodepleting chemotherapy. Previously, patients had received a median of three lines of therapy, and about half had undergone autologous stem cell transplantation.
Median time from infusion to data cutoff in March 2017 was 5.6 months. Among 81 patients followed for at least 3 months before data cutoff, best overall response rate was 53% and 40% had a complete response. Overall response rates were 38% at 3 months and 37% at 6 months. Rates of complete response as confirmed by 18F-fluorodeoxyglucose–positron-emission tomography (PET) were 32% at 3 months and 30% at 6 months.These findings highlight the predictive power of 3-month response to CTL019 therapy in relapsed/refractory DLBCL, Dr. Schuster said. Among all responders, 74% remained relapse free at 6 months, meaning that median duration of response and median overall survival were not reached at data cutoff.
Dr. Schuster also reported that 26% of patients were infused as outpatients, which he called “easy to do” and appropriate as long as patients who become febrile are admitted and monitored for cytokine release syndrome. Three-quarters of patients who were infused as outpatients were able to remain home for at least 3 days afterward, he said.
Adverse events typified those of CAR T-cell therapy, including cytokine release syndrome (all grades: 58%; grade 3-4: 23%) and neurological toxicities (all grades: 21%; grade 3-4: 12%). The current labeling for CTL019 in children and young adults with acute lymphoblastic leukemia also includes a boxed warning for these toxicities.Tisagenlecleucel, the first-ever approved CAR T-cell therapy, is made by using a lentiviral vector to genetically engineer a patient’s own T-cells to express a CAR for the pan-B-cell CD19 antigen. These anti-CD19 CAR T-cells are then expanded in the laboratory, frozen for shipping purposes, and infused back into patients. In October 2017, Novartis submitted a biologics license application to the Food and Drug Administration to expand the label for CTL019 to include transplant-ineligible relapsed/refractory DLBCL.
Novartis Pharmaceuticals anticipates large-scale production in 2018, Dr. Schuster said. Manufacturing time has been cut to 22 days from the 30-day turnaround used in the trial, he reported.
Dr. Schuster also said that he sees no point in retreating patients whose relapsed/refractory DLBCL doesn’t respond to tisagenlecleucel, and that JULIET did not test this approach. “If someone fails therapy and you retreat, you don’t see success, in my experience,” he said. “If patients respond and then fail later, then you retreat and you may succeed.”
Novartis Pharmaceuticals sponsored JULIET. Dr. Schuster disclosed consultancy and research funding from Novartis and ties to Celgene, Gilead, Genentech, and several other pharmaceutical companies.
SOURCE: Schuster S et al. ASH 2017 Abstract 577.
ATLANTA – Responses 3 months after chimeric antigen receptor (CAR) T-cell therapy look durable in adults with transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to updated results from the single-arm, global, phase 2 JULIET trial.
Fully 95% of patients who had a complete response to CTL019 (tisagenlecleucel; Kymriah) at 3 months maintained that complete response at 6 months, Stephen J. Schuster, MD, said at the annual meeting of the American Society of Hematology.
Patients with relapsed/refractory DLBCL tend to face a very poor prognosis, noted Dr. Schuster of Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia. High-dose chemotherapy followed by autologous stem cell transplantation “is capable of long-term survival, but in very few patients,” he said. A dismal 8% of patients completely respond to salvage treatment and only about one in five partially respond. Both levels of response are short-lived, with a median survival of about 4 months.
Meanwhile, CTL019 therapy has produced durable complete remissions in children with lymphoblastic leukemia and in adults with chronic lymphocytic leukemia, Dr. Schuster and his associates wrote in an article simultaneously published in the New England Journal of Medicine (2017 Dec 10. doi: 10.1056/NEJMoa1708566).
To test the CAR T-cell therapy in relapsed/refractory DLBCL, they enrolled affected adults who had received at least two prior lines of antineoplastic treatment and who were not candidates for autologous stem cell transplantation.
Treatment consisted of a single CTL019 infusion (median dose, 3.1 × 108 cells; range, 0.1 × 108 to 6.0 × 108 cells), usually after lymphodepleting chemotherapy. Previously, patients had received a median of three lines of therapy, and about half had undergone autologous stem cell transplantation.
Median time from infusion to data cutoff in March 2017 was 5.6 months. Among 81 patients followed for at least 3 months before data cutoff, best overall response rate was 53% and 40% had a complete response. Overall response rates were 38% at 3 months and 37% at 6 months. Rates of complete response as confirmed by 18F-fluorodeoxyglucose–positron-emission tomography (PET) were 32% at 3 months and 30% at 6 months.These findings highlight the predictive power of 3-month response to CTL019 therapy in relapsed/refractory DLBCL, Dr. Schuster said. Among all responders, 74% remained relapse free at 6 months, meaning that median duration of response and median overall survival were not reached at data cutoff.
Dr. Schuster also reported that 26% of patients were infused as outpatients, which he called “easy to do” and appropriate as long as patients who become febrile are admitted and monitored for cytokine release syndrome. Three-quarters of patients who were infused as outpatients were able to remain home for at least 3 days afterward, he said.
Adverse events typified those of CAR T-cell therapy, including cytokine release syndrome (all grades: 58%; grade 3-4: 23%) and neurological toxicities (all grades: 21%; grade 3-4: 12%). The current labeling for CTL019 in children and young adults with acute lymphoblastic leukemia also includes a boxed warning for these toxicities.Tisagenlecleucel, the first-ever approved CAR T-cell therapy, is made by using a lentiviral vector to genetically engineer a patient’s own T-cells to express a CAR for the pan-B-cell CD19 antigen. These anti-CD19 CAR T-cells are then expanded in the laboratory, frozen for shipping purposes, and infused back into patients. In October 2017, Novartis submitted a biologics license application to the Food and Drug Administration to expand the label for CTL019 to include transplant-ineligible relapsed/refractory DLBCL.
Novartis Pharmaceuticals anticipates large-scale production in 2018, Dr. Schuster said. Manufacturing time has been cut to 22 days from the 30-day turnaround used in the trial, he reported.
Dr. Schuster also said that he sees no point in retreating patients whose relapsed/refractory DLBCL doesn’t respond to tisagenlecleucel, and that JULIET did not test this approach. “If someone fails therapy and you retreat, you don’t see success, in my experience,” he said. “If patients respond and then fail later, then you retreat and you may succeed.”
Novartis Pharmaceuticals sponsored JULIET. Dr. Schuster disclosed consultancy and research funding from Novartis and ties to Celgene, Gilead, Genentech, and several other pharmaceutical companies.
SOURCE: Schuster S et al. ASH 2017 Abstract 577.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: Among 81 patients with at least 3 months of follow-up, best overall response rate was 53% (95% CI, 42%-64%; P less than .0001) and rates of complete response were 32% at 3 months and 30% at 6 months.
Study details: JULIET is an international, single-arm, phase 2 study of adults with relapsed/refractory DLBCL.
Disclosures: Novartis Pharmaceuticals sponsored JULIET. Dr. Schuster reported consultancy and research funding from Novartis and ties to Celgene, Gilead, Genentech, and several other pharmaceutical companies.
Source: Schuster S et al. ASH 2017 Abstract 577.
Updated ZUMA-1 data show durable CAR-T responses in B-cell lymphomas
ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.
Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.
“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.
The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 106 cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.
The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.
Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.
The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.
In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.
The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.
At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.
The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.
The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.
Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.
Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.
In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”
They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).
In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.
ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.
SOURCE: Neelapu S et al. ASH 2017 Abstract 578.
ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.
Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.
“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.
The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 106 cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.
The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.
Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.
The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.
In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.
The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.
At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.
The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.
The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.
Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.
Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.
In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”
They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).
In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.
ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.
SOURCE: Neelapu S et al. ASH 2017 Abstract 578.
ATLANTA – More than one-third of patients with refractory large B-cell lymphomas treated with the chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (Yescarta), often called axi-cel, had durable responses, with some patients having complete responses lasting more than 1 year after a single infusion, according to investigators in the ZUMA-1 trial.
Updated combined phase 1 and phase 2 results in 108 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) showed an objective response rate (ORR) of 82%, including 58% complete responses, after a median follow-up of 15.4 months, reported Sattva S. Neelapu, MD, from the University of Texas MD Anderson Cancer Center in Houston.
“Axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options,” he said in a briefing at the annual meeting of the American Society of Hematology, prior to his presentation of the data in an oral session.
The trial results were also published simultaneously in the New England Journal of Medicine.As previously reported, in the multicenter phase 2 ZUMA-1 trial, 111 patients with treatment refractory DLBCL, PMBCL, or TFL were enrolled and treated with axi-cel at a target dose of 2 x 106 cells/kg, following a conditioning regimen with low-dose cyclophosphamide and fludarabine.
The median patient age was 58 years. Patients had stage III or IV disease, 48% had International Prognostic Index scores of 3-4, 76% had disease that was refractory to third-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant
Axi-cel was successfully manufactured with sufficient cells for transfusion in all but one of the 111 patients, and 101 patients eventually received infusions in phase 2 (modified intention-to-treat population). The average turnaround time from apheresis to the clinical site was 17 days.
Dr. Neelapu also presented data on seven patients enrolled in phase 1; the data were combined with the phase 2 results for an updated analysis of those patients who had at least 1 year of follow-up.
The phase 2 trial met its primary endpoint at the time of the primary analysis, with an 82% ORR, consisting of 54% complete responses and 28% partial responses at a median follow-up of 8.7 months.
In the updated analysis, the ORR and respective remission rates were 82%, 58%, and 34%, at a median of 15.4 months follow-up.
The median duration of response in the updated analysis was 11.1 months. The median duration of complete responses had not been reached at the time of data cutoff in August 2017. The median duration of partial responses was 1.9 months.
At the 15.4-month mark, 42% of patients remained free of disease progression, and 56% were alive, with the median overall survival not yet reached.
The treatment had generally acceptable toxicities, with only 13% of patients in phase 2 experiencing grade 3 or greater cytokine release syndrome (CRS), although one patient with CRS died from hemophagocytic lymphohistiocytosis, and one with CRS died from cardiac arrest. Grade 3 or greater neurologic events occurred in 28% of patients, and included encephalopathy, confusional state, aphasia, and somnolence.
The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
Since the primary analysis with at least 6 months of follow-up, there have been no new axi-cel–related cases of CRS, neurologic events, or deaths.
Dr. Neelapu also presented safety data on serious adverse events occurring more than 6 months after therapy in 10 patients who developed symptoms after the data cutoff.
Grade 3 events in these patients included lung infection, recurrent upper respiratory viral infection, and rotavirus infection, pneumonias, atrial fibrillation with rapid ventricular response, lung infection, febrile neutropenia, and influenza B infection. One patient had grade 4 sepsis.
In an editorial accompanying the study in the New England Journal of Medicine, Eric Tran, PhD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland (Ore.) Medical Center, and Dan L. Longo, MD, deputy editor of the journal, praised ZUMA-1 as “a landmark study because it involved 22 institutions and showed that a personalized gene-engineered T-cell product could be rapidly generated at a centralized cell-manufacturing facility and safely administered to patients at transplantation-capable medical centers.”
They noted, however, that about half of all patients with relapsed or refractory large B-cell lymphomas will not have durable responses to CAR T-cell therapy directed against CD19, and that new strategies will be needed to improve responses (N Engl J Med. 2017 Dec 10; doi: 10.1056/NEJMe1714680).
In the question and answer session at the end of the briefing, Dr. Neelapu said the preliminary observations of mechanisms of relapse or disease progression in some patients may be related to the loss of the CD19 antigen, which occurs in about one-third of patients who experience relapse, and to high expression of the programmed death ligand-1, which can potentially inhibit CAR-T cell function. A clinical trial is currently underway to evaluate potential strategies for improving response rates to CAR-T therapies, he said.
ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.
SOURCE: Neelapu S et al. ASH 2017 Abstract 578.
REPORTING FROM ASH 2017
Key clinical point:.
Major finding: The objective response rate was 82%, including 58% complete responses at a median of 15.4 months of follow-up.
Data source: Update analysis of phase 1 and 2 data from the ZUMA-1 trial in 108 patients with large B-cell lymphomas.
Disclosures: ZUMA-1 is supported by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. Dr. Neelapu reported receiving advisory board fees from the company. Myriad coauthors also reported financial relationship with multiple companies.
Source: Neelapu S et al. ASH 2017 Abstract 578
DNA vaccine + PD-1 blockade shows promise in mCRPC
NATIONAL HARBOR, MD. – Combining programmed death (PD)-1 blockade with tumor-targeted T-cell activation by a novel DNA vaccine safely enhanced antitumor immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients in a randomized clinical study.
Of 26 patients with mCRPC who were evaluable for response, 13 received treatment with an investigational DNA vaccine (pTVG-HP) that encodes prostatic acid phosphatase (PAP) and concurrent PD-1 blockade, and 13 received sequential vaccination and PD-1 blockade. No difference was seen between the groups with respect to progression-free survival at 6 months, but of eight patients in the concurrent therapy arm who had measurable disease, one experienced a partial response and two experienced a reduction in tumor volume, Douglas G. McNeel, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We did not see objective responses in [six patients with measurable disease in the sequential treatment arm], said Dr. McNeel, a professor at the University of Wisconsin, Madison.
Prostate specific antigen (PSA) responses, which may be a more sensitive marker, were also more common in the concurrent treatment group; 8 of 13 patients in that group had a PSA decline from baseline, and 4 of those had a decline of greater than 25% from baseline, whereas only 1 of the 13 patients in the sequential treatment arm experienced any decline in PSA vs. baseline, Dr. McNeel said.
Responses to the vaccine’s target antigen, prostatic acid phosphatase, were seen in both arms, but only those who received the combined treatment and who had evidence of immune response experienced PSA decline, he added.
Pre- and postvaccination biopsies of metastatic sites showed that concurrent treatment, compared with sequential treatment, elicited tumor-infiltrating CD8+ T cells, PD-L1 expression in tumors, and changes associated with CD8+ T-cell activation, he said, adding that immunization with concurrent PD-1 blockade also elicits changes in proliferation detected by (18F) fluorothymidine PET/CT.
“We’ve been interested in vaccines for cancer, because we know that having the right kind of T cells in the tumor microenvironment is associated with better long-term outcomes,” Dr. McNeel said, noting that the ability of vaccines to activate T cells and augment cytolytic T cells, in particular, should have anticancer activity.
However, the clinical activity of single-agent tumor vaccines has been underwhelming, he noted.
PAP has been a focus in vaccine development, because it is essentially restricted to prostate tissue in humans. A nearly identical prostate-specific rat homologue was used in early studies, and PAP permits evaluation of serum PSA as an independent assessment of response in human trials, he explained.
“It’s the same target as the sipuleucel-T vaccine,” he said, referring to a Food and Drug Administration–approved vaccine for prostate cancer(Provenge).
Two prior phase 1/2 trials looking at DNA vaccine encoding PAP in patients with early biochemically recurrent prostate cancer showed that PAP-specific T-cell immune responses were elicited and that no significant adverse events occurred.
In both trials, the development of persistent PAP-specific, interferon-gamma–secreting T cells was associated with favorable change in PSA doubling time (suggesting a possible impact on the disease), and with PD-L1 expression in circulating tumor cells (suggesting a potential mechanism of resistance), he said.
Laboratory studies helped identify mechanisms of immune resistance following DNA immunization, he said, explaining that immunization elicits T cells secreting interferon-gamma, which leads to an increase in PD-L1 expression on tumor cells.
Encoding epitopes with increased major histocompatibility complex class 1 affinity elicited CD+ t cells with increased and persistent PD-1 expression, and blockade of PD-1 or PD-L1 with vaccination led to improved antitumor responses, he said.
The findings led to the new model focused on timing of PD-1 blockade with vaccine T-cell activation studied in the current trial.
It was hypothesized that PD-1 blockade at the time of T-cell activation with vaccination would be more effective than was blockade of PD-1-regulated T cells previously elicited with vaccination.
Study subjects had mCRPC and evidence of disease progression. Previous treatment with abiraterone(Zytiga), enzalutamide(Xtandi), or chemotherapy, was allowed, but patients with prior sipuleucel-T vaccine exposure were excluded.
Patients in the concurrent treatment arm received both the vaccine and PD-1 blockade with pembrolizumab (Keytruda)over 12 weeks, and those in the sequential therapy arm received vaccination first followed by PD-1 blockade, each for 12 weeks.
Both approaches were well tolerated.
“Essentially, we saw nothing that was unexpected,” Dr. McNeel said.
Adverse events greater than grade 2 included fatigue in one patient, diarrhea in one patient, and autoimmune hepatitis in one patient. No patients discontinued treatment from toxicity, he noted.
One death occurred during follow-up in a patient who had evidence of progression and refused further follow-up, therefore it could not be determined if the death was related to treatment.
The current findings, which are notable in part because PD-1 pathway inhibitors have demonstrated little clinical activity when used as single agents for prostate cancer and which expand upon data presented in a scientific poster at SITC 2016, demonstrate that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells – as detectable within the peripheral blood and by imaging – and can result in objective antitumor changes.
“To summarize, plasmid DNA vaccines can elicit antigen-specific CD8+ T cells; immunization can increase PD-L1 expression on tumor cells – and we’ve demonstrated, in mice anyway, that this is mediated by the T cells elicited with immunization; PD-1 expression increases on CD8+ T cells following vaccination; and we think this is an opportunity to use checkpoint blockade at the point of vaccination to improve antitumor responses,” Dr. McNeel said.
“So we can look at this as PD-1 blockade to improve the effect of vaccination, but we can also look at it the other way around, and that is that anti-tumor vaccines can elicit the tumor-specific CD8+ T cells needed to enable PD-1 blockade to work,” he said. “ I think this has implications for the choice of vaccine approach, the antigen, and the timing of PD-1 blockade.”
Based on these results, an expansion arm has been opened to evaluate the safety and clinical efficacy of combination treatment beyond 12 weeks, and future studies will look at the combination of two different vaccines to improve antitumor response, he said.
Dr. McNeel disclosed financial relationships (intellectual property rights/patent holder, consultant, ownership interest) with Madison Vaccines Inc. The study is funded by a 2014 Movember PCF Challenge Award and Madison Vaccines.
sworcester@frontlinemedcom.com
SOURCE: McNeel D et al., J Immunother Cancer. 2017 5(Suppl 2):86 Abstract O11.
NATIONAL HARBOR, MD. – Combining programmed death (PD)-1 blockade with tumor-targeted T-cell activation by a novel DNA vaccine safely enhanced antitumor immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients in a randomized clinical study.
Of 26 patients with mCRPC who were evaluable for response, 13 received treatment with an investigational DNA vaccine (pTVG-HP) that encodes prostatic acid phosphatase (PAP) and concurrent PD-1 blockade, and 13 received sequential vaccination and PD-1 blockade. No difference was seen between the groups with respect to progression-free survival at 6 months, but of eight patients in the concurrent therapy arm who had measurable disease, one experienced a partial response and two experienced a reduction in tumor volume, Douglas G. McNeel, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We did not see objective responses in [six patients with measurable disease in the sequential treatment arm], said Dr. McNeel, a professor at the University of Wisconsin, Madison.
Prostate specific antigen (PSA) responses, which may be a more sensitive marker, were also more common in the concurrent treatment group; 8 of 13 patients in that group had a PSA decline from baseline, and 4 of those had a decline of greater than 25% from baseline, whereas only 1 of the 13 patients in the sequential treatment arm experienced any decline in PSA vs. baseline, Dr. McNeel said.
Responses to the vaccine’s target antigen, prostatic acid phosphatase, were seen in both arms, but only those who received the combined treatment and who had evidence of immune response experienced PSA decline, he added.
Pre- and postvaccination biopsies of metastatic sites showed that concurrent treatment, compared with sequential treatment, elicited tumor-infiltrating CD8+ T cells, PD-L1 expression in tumors, and changes associated with CD8+ T-cell activation, he said, adding that immunization with concurrent PD-1 blockade also elicits changes in proliferation detected by (18F) fluorothymidine PET/CT.
“We’ve been interested in vaccines for cancer, because we know that having the right kind of T cells in the tumor microenvironment is associated with better long-term outcomes,” Dr. McNeel said, noting that the ability of vaccines to activate T cells and augment cytolytic T cells, in particular, should have anticancer activity.
However, the clinical activity of single-agent tumor vaccines has been underwhelming, he noted.
PAP has been a focus in vaccine development, because it is essentially restricted to prostate tissue in humans. A nearly identical prostate-specific rat homologue was used in early studies, and PAP permits evaluation of serum PSA as an independent assessment of response in human trials, he explained.
“It’s the same target as the sipuleucel-T vaccine,” he said, referring to a Food and Drug Administration–approved vaccine for prostate cancer(Provenge).
Two prior phase 1/2 trials looking at DNA vaccine encoding PAP in patients with early biochemically recurrent prostate cancer showed that PAP-specific T-cell immune responses were elicited and that no significant adverse events occurred.
In both trials, the development of persistent PAP-specific, interferon-gamma–secreting T cells was associated with favorable change in PSA doubling time (suggesting a possible impact on the disease), and with PD-L1 expression in circulating tumor cells (suggesting a potential mechanism of resistance), he said.
Laboratory studies helped identify mechanisms of immune resistance following DNA immunization, he said, explaining that immunization elicits T cells secreting interferon-gamma, which leads to an increase in PD-L1 expression on tumor cells.
Encoding epitopes with increased major histocompatibility complex class 1 affinity elicited CD+ t cells with increased and persistent PD-1 expression, and blockade of PD-1 or PD-L1 with vaccination led to improved antitumor responses, he said.
The findings led to the new model focused on timing of PD-1 blockade with vaccine T-cell activation studied in the current trial.
It was hypothesized that PD-1 blockade at the time of T-cell activation with vaccination would be more effective than was blockade of PD-1-regulated T cells previously elicited with vaccination.
Study subjects had mCRPC and evidence of disease progression. Previous treatment with abiraterone(Zytiga), enzalutamide(Xtandi), or chemotherapy, was allowed, but patients with prior sipuleucel-T vaccine exposure were excluded.
Patients in the concurrent treatment arm received both the vaccine and PD-1 blockade with pembrolizumab (Keytruda)over 12 weeks, and those in the sequential therapy arm received vaccination first followed by PD-1 blockade, each for 12 weeks.
Both approaches were well tolerated.
“Essentially, we saw nothing that was unexpected,” Dr. McNeel said.
Adverse events greater than grade 2 included fatigue in one patient, diarrhea in one patient, and autoimmune hepatitis in one patient. No patients discontinued treatment from toxicity, he noted.
One death occurred during follow-up in a patient who had evidence of progression and refused further follow-up, therefore it could not be determined if the death was related to treatment.
The current findings, which are notable in part because PD-1 pathway inhibitors have demonstrated little clinical activity when used as single agents for prostate cancer and which expand upon data presented in a scientific poster at SITC 2016, demonstrate that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells – as detectable within the peripheral blood and by imaging – and can result in objective antitumor changes.
“To summarize, plasmid DNA vaccines can elicit antigen-specific CD8+ T cells; immunization can increase PD-L1 expression on tumor cells – and we’ve demonstrated, in mice anyway, that this is mediated by the T cells elicited with immunization; PD-1 expression increases on CD8+ T cells following vaccination; and we think this is an opportunity to use checkpoint blockade at the point of vaccination to improve antitumor responses,” Dr. McNeel said.
“So we can look at this as PD-1 blockade to improve the effect of vaccination, but we can also look at it the other way around, and that is that anti-tumor vaccines can elicit the tumor-specific CD8+ T cells needed to enable PD-1 blockade to work,” he said. “ I think this has implications for the choice of vaccine approach, the antigen, and the timing of PD-1 blockade.”
Based on these results, an expansion arm has been opened to evaluate the safety and clinical efficacy of combination treatment beyond 12 weeks, and future studies will look at the combination of two different vaccines to improve antitumor response, he said.
Dr. McNeel disclosed financial relationships (intellectual property rights/patent holder, consultant, ownership interest) with Madison Vaccines Inc. The study is funded by a 2014 Movember PCF Challenge Award and Madison Vaccines.
sworcester@frontlinemedcom.com
SOURCE: McNeel D et al., J Immunother Cancer. 2017 5(Suppl 2):86 Abstract O11.
NATIONAL HARBOR, MD. – Combining programmed death (PD)-1 blockade with tumor-targeted T-cell activation by a novel DNA vaccine safely enhanced antitumor immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients in a randomized clinical study.
Of 26 patients with mCRPC who were evaluable for response, 13 received treatment with an investigational DNA vaccine (pTVG-HP) that encodes prostatic acid phosphatase (PAP) and concurrent PD-1 blockade, and 13 received sequential vaccination and PD-1 blockade. No difference was seen between the groups with respect to progression-free survival at 6 months, but of eight patients in the concurrent therapy arm who had measurable disease, one experienced a partial response and two experienced a reduction in tumor volume, Douglas G. McNeel, MD, PhD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“We did not see objective responses in [six patients with measurable disease in the sequential treatment arm], said Dr. McNeel, a professor at the University of Wisconsin, Madison.
Prostate specific antigen (PSA) responses, which may be a more sensitive marker, were also more common in the concurrent treatment group; 8 of 13 patients in that group had a PSA decline from baseline, and 4 of those had a decline of greater than 25% from baseline, whereas only 1 of the 13 patients in the sequential treatment arm experienced any decline in PSA vs. baseline, Dr. McNeel said.
Responses to the vaccine’s target antigen, prostatic acid phosphatase, were seen in both arms, but only those who received the combined treatment and who had evidence of immune response experienced PSA decline, he added.
Pre- and postvaccination biopsies of metastatic sites showed that concurrent treatment, compared with sequential treatment, elicited tumor-infiltrating CD8+ T cells, PD-L1 expression in tumors, and changes associated with CD8+ T-cell activation, he said, adding that immunization with concurrent PD-1 blockade also elicits changes in proliferation detected by (18F) fluorothymidine PET/CT.
“We’ve been interested in vaccines for cancer, because we know that having the right kind of T cells in the tumor microenvironment is associated with better long-term outcomes,” Dr. McNeel said, noting that the ability of vaccines to activate T cells and augment cytolytic T cells, in particular, should have anticancer activity.
However, the clinical activity of single-agent tumor vaccines has been underwhelming, he noted.
PAP has been a focus in vaccine development, because it is essentially restricted to prostate tissue in humans. A nearly identical prostate-specific rat homologue was used in early studies, and PAP permits evaluation of serum PSA as an independent assessment of response in human trials, he explained.
“It’s the same target as the sipuleucel-T vaccine,” he said, referring to a Food and Drug Administration–approved vaccine for prostate cancer(Provenge).
Two prior phase 1/2 trials looking at DNA vaccine encoding PAP in patients with early biochemically recurrent prostate cancer showed that PAP-specific T-cell immune responses were elicited and that no significant adverse events occurred.
In both trials, the development of persistent PAP-specific, interferon-gamma–secreting T cells was associated with favorable change in PSA doubling time (suggesting a possible impact on the disease), and with PD-L1 expression in circulating tumor cells (suggesting a potential mechanism of resistance), he said.
Laboratory studies helped identify mechanisms of immune resistance following DNA immunization, he said, explaining that immunization elicits T cells secreting interferon-gamma, which leads to an increase in PD-L1 expression on tumor cells.
Encoding epitopes with increased major histocompatibility complex class 1 affinity elicited CD+ t cells with increased and persistent PD-1 expression, and blockade of PD-1 or PD-L1 with vaccination led to improved antitumor responses, he said.
The findings led to the new model focused on timing of PD-1 blockade with vaccine T-cell activation studied in the current trial.
It was hypothesized that PD-1 blockade at the time of T-cell activation with vaccination would be more effective than was blockade of PD-1-regulated T cells previously elicited with vaccination.
Study subjects had mCRPC and evidence of disease progression. Previous treatment with abiraterone(Zytiga), enzalutamide(Xtandi), or chemotherapy, was allowed, but patients with prior sipuleucel-T vaccine exposure were excluded.
Patients in the concurrent treatment arm received both the vaccine and PD-1 blockade with pembrolizumab (Keytruda)over 12 weeks, and those in the sequential therapy arm received vaccination first followed by PD-1 blockade, each for 12 weeks.
Both approaches were well tolerated.
“Essentially, we saw nothing that was unexpected,” Dr. McNeel said.
Adverse events greater than grade 2 included fatigue in one patient, diarrhea in one patient, and autoimmune hepatitis in one patient. No patients discontinued treatment from toxicity, he noted.
One death occurred during follow-up in a patient who had evidence of progression and refused further follow-up, therefore it could not be determined if the death was related to treatment.
The current findings, which are notable in part because PD-1 pathway inhibitors have demonstrated little clinical activity when used as single agents for prostate cancer and which expand upon data presented in a scientific poster at SITC 2016, demonstrate that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells – as detectable within the peripheral blood and by imaging – and can result in objective antitumor changes.
“To summarize, plasmid DNA vaccines can elicit antigen-specific CD8+ T cells; immunization can increase PD-L1 expression on tumor cells – and we’ve demonstrated, in mice anyway, that this is mediated by the T cells elicited with immunization; PD-1 expression increases on CD8+ T cells following vaccination; and we think this is an opportunity to use checkpoint blockade at the point of vaccination to improve antitumor responses,” Dr. McNeel said.
“So we can look at this as PD-1 blockade to improve the effect of vaccination, but we can also look at it the other way around, and that is that anti-tumor vaccines can elicit the tumor-specific CD8+ T cells needed to enable PD-1 blockade to work,” he said. “ I think this has implications for the choice of vaccine approach, the antigen, and the timing of PD-1 blockade.”
Based on these results, an expansion arm has been opened to evaluate the safety and clinical efficacy of combination treatment beyond 12 weeks, and future studies will look at the combination of two different vaccines to improve antitumor response, he said.
Dr. McNeel disclosed financial relationships (intellectual property rights/patent holder, consultant, ownership interest) with Madison Vaccines Inc. The study is funded by a 2014 Movember PCF Challenge Award and Madison Vaccines.
sworcester@frontlinemedcom.com
SOURCE: McNeel D et al., J Immunother Cancer. 2017 5(Suppl 2):86 Abstract O11.
REPORTING FROM SITC 2017
Key clinical point: Concurrent PD-1 blockade enhanced DNA vaccine activity in mCRPC.
Major finding: A partial response and tumor volume reduction occurred in one and two patients, respectively.
Study details: A randomized clinical study of 26 patients.
Disclosures: Dr. McNeel disclosed financial relationships (intellectual property rights/patent holder, consultant, ownership interest) with Madison Vaccines. The study is funded by a 2014 Movember PCF Challenge Award and Madison Vaccines.
Source: Douglas McNeel D et al. J Immunother Cancer. 2017 Nov; 5(Suppl 2):86 Abstract O11.
VIDEO: Dr. Sherene Loi discusses PANACEA trial and implications for pembrolizumab use
SAN ANTONIO – The phase 1b/2 PANACEA trial of pembrolizumab and trastuzumab in trastuzumab-resistant HER2-positive advanced breast cancer met its primary endpoint, showing an overall response rate of 15.2% in the PD-L1-positive cohort and controlling disease for almost a year without chemotherapy, Sherene Loi, MD, PhD, of the Peter MacCallum Cancer Centre in Melbourne reported on behalf of the International Breast Cancer Study Group (IBCSG). But level of antitumor immunity was key. In an interview at the San Antonio Breast Cancer Symposium, Dr. Loi discussed the findings and possible implications for use of pembrolizumab earlier in the disease course.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – The phase 1b/2 PANACEA trial of pembrolizumab and trastuzumab in trastuzumab-resistant HER2-positive advanced breast cancer met its primary endpoint, showing an overall response rate of 15.2% in the PD-L1-positive cohort and controlling disease for almost a year without chemotherapy, Sherene Loi, MD, PhD, of the Peter MacCallum Cancer Centre in Melbourne reported on behalf of the International Breast Cancer Study Group (IBCSG). But level of antitumor immunity was key. In an interview at the San Antonio Breast Cancer Symposium, Dr. Loi discussed the findings and possible implications for use of pembrolizumab earlier in the disease course.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – The phase 1b/2 PANACEA trial of pembrolizumab and trastuzumab in trastuzumab-resistant HER2-positive advanced breast cancer met its primary endpoint, showing an overall response rate of 15.2% in the PD-L1-positive cohort and controlling disease for almost a year without chemotherapy, Sherene Loi, MD, PhD, of the Peter MacCallum Cancer Centre in Melbourne reported on behalf of the International Breast Cancer Study Group (IBCSG). But level of antitumor immunity was key. In an interview at the San Antonio Breast Cancer Symposium, Dr. Loi discussed the findings and possible implications for use of pembrolizumab earlier in the disease course.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
REPORTING FROM SABCS 2017
First-in-class glutaminase inhibitor combats anti-PD-1/PD-L1 resistance
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
AT SITC 2017
Key clinical point:
Major finding: The objective response rate in advanced melanoma patients refractory to anti-PD-1/PD-L1 therapy was 19%.
Data source: A phase 1/2 study of 82 patients.
Disclosures: Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel or as a board member for multiple companies.