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Liquid biopsy predicts checkpoint inhibitor response
The overall response rate to immune checkpoint inhibitors was 45% among cancer patients who had more than three variants of unknown significance in their circulating tumor DNA; among those with three or fewer, the response rate was 15%, according to a University of California, San Diego, investigation with 69 subjects.
Higher mutation burdens in circulating tumor DNA (ctDNA) also correlated with improved progression-free and overall survival across 20 cancer types, the investigators reported (Clin Cancer Res. 2017 Oct. 1. doi: 10.1158/1078-0432.CCR-17-1439).
Tumor mutation burdens can predict response to checkpoint inhibitors, but they are usually assessed by tissue biopsy, which is costly and invasive. The findings suggest that blood tests could replace tissue biopsies to green-light immune checkpoint inhibitor treatment.
“Our current results may be clinically exploitable. ... Liquid biopsies that assess blood-derived ctDNA are noninvasive, easily acquired, and inexpensive. The ctDNA derived from blood may also represent shed DNA from multiple metastatic sites, whereas tissue genomics reflects only the piece of tissue removed,” said investigators led by Yulian Khagi, MD, a hematology-oncology fellow at the university.
In a press statement, Dr. Khagi said “If verified by further studies, clinicians will be able to utilize the ... results of this simple blood test to make determinations about whether to use checkpoint inhibitor–based immune therapy in a variety of tumor types.”
The 69 patients were a median of 56 years old, and 43 (62.3%) were men. Melanoma, lung cancer, and head and neck cancer were the most common malignancies. The majority of patients had anti–PD-1 or PD-L1 monotherapy.
For most patients, blood samples were drawn a month or 2 before treatment. Next-generation sequencing (Guardant360) was done on ctDNA to detect alterations in cancer genes. Of the 69 patients, 20 (29%) had more than three variants of unknown significance (VUS); the rest had three or fewer.
The median overall survival was 15.3 months from the start of immunotherapy. For patients with three or fewer VUS, median overall survival was 10.72 months; for patients with more, median overall survival could not be calculated because more than half were alive at the study’s conclusion.
Median progression-fee survival was 2.07 months with three or fewer VUS, versus 3.84 months with more. The findings were statistically significant.
Similar results were found when all genomic alterations, not just VUS, were examined and dichotomized as six or more versus fewer than six.
“The number of genes assayed in our ctDNA analysis was only between 54 and 70. Unlike targeted NGS [next-generation sequencing] of tumor tissue, which often tests for hundreds of genes and allows a relatively accurate estimate of total mutational burden, targeted NGS of plasma ctDNA provides only a limited snapshot of the cancer genome. More extensive ctDNA gene panels merit investigation to determine if they increase the correlative value of our findings,” the investigators said.
The work was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Dr. Khagi had no industry disclosures. Three authors reported financial ties to a number of companies, including Boehringer, Merck, Guardant, and Pfizer. The senior author has ownership interests in CureMatch.
The overall response rate to immune checkpoint inhibitors was 45% among cancer patients who had more than three variants of unknown significance in their circulating tumor DNA; among those with three or fewer, the response rate was 15%, according to a University of California, San Diego, investigation with 69 subjects.
Higher mutation burdens in circulating tumor DNA (ctDNA) also correlated with improved progression-free and overall survival across 20 cancer types, the investigators reported (Clin Cancer Res. 2017 Oct. 1. doi: 10.1158/1078-0432.CCR-17-1439).
Tumor mutation burdens can predict response to checkpoint inhibitors, but they are usually assessed by tissue biopsy, which is costly and invasive. The findings suggest that blood tests could replace tissue biopsies to green-light immune checkpoint inhibitor treatment.
“Our current results may be clinically exploitable. ... Liquid biopsies that assess blood-derived ctDNA are noninvasive, easily acquired, and inexpensive. The ctDNA derived from blood may also represent shed DNA from multiple metastatic sites, whereas tissue genomics reflects only the piece of tissue removed,” said investigators led by Yulian Khagi, MD, a hematology-oncology fellow at the university.
In a press statement, Dr. Khagi said “If verified by further studies, clinicians will be able to utilize the ... results of this simple blood test to make determinations about whether to use checkpoint inhibitor–based immune therapy in a variety of tumor types.”
The 69 patients were a median of 56 years old, and 43 (62.3%) were men. Melanoma, lung cancer, and head and neck cancer were the most common malignancies. The majority of patients had anti–PD-1 or PD-L1 monotherapy.
For most patients, blood samples were drawn a month or 2 before treatment. Next-generation sequencing (Guardant360) was done on ctDNA to detect alterations in cancer genes. Of the 69 patients, 20 (29%) had more than three variants of unknown significance (VUS); the rest had three or fewer.
The median overall survival was 15.3 months from the start of immunotherapy. For patients with three or fewer VUS, median overall survival was 10.72 months; for patients with more, median overall survival could not be calculated because more than half were alive at the study’s conclusion.
Median progression-fee survival was 2.07 months with three or fewer VUS, versus 3.84 months with more. The findings were statistically significant.
Similar results were found when all genomic alterations, not just VUS, were examined and dichotomized as six or more versus fewer than six.
“The number of genes assayed in our ctDNA analysis was only between 54 and 70. Unlike targeted NGS [next-generation sequencing] of tumor tissue, which often tests for hundreds of genes and allows a relatively accurate estimate of total mutational burden, targeted NGS of plasma ctDNA provides only a limited snapshot of the cancer genome. More extensive ctDNA gene panels merit investigation to determine if they increase the correlative value of our findings,” the investigators said.
The work was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Dr. Khagi had no industry disclosures. Three authors reported financial ties to a number of companies, including Boehringer, Merck, Guardant, and Pfizer. The senior author has ownership interests in CureMatch.
The overall response rate to immune checkpoint inhibitors was 45% among cancer patients who had more than three variants of unknown significance in their circulating tumor DNA; among those with three or fewer, the response rate was 15%, according to a University of California, San Diego, investigation with 69 subjects.
Higher mutation burdens in circulating tumor DNA (ctDNA) also correlated with improved progression-free and overall survival across 20 cancer types, the investigators reported (Clin Cancer Res. 2017 Oct. 1. doi: 10.1158/1078-0432.CCR-17-1439).
Tumor mutation burdens can predict response to checkpoint inhibitors, but they are usually assessed by tissue biopsy, which is costly and invasive. The findings suggest that blood tests could replace tissue biopsies to green-light immune checkpoint inhibitor treatment.
“Our current results may be clinically exploitable. ... Liquid biopsies that assess blood-derived ctDNA are noninvasive, easily acquired, and inexpensive. The ctDNA derived from blood may also represent shed DNA from multiple metastatic sites, whereas tissue genomics reflects only the piece of tissue removed,” said investigators led by Yulian Khagi, MD, a hematology-oncology fellow at the university.
In a press statement, Dr. Khagi said “If verified by further studies, clinicians will be able to utilize the ... results of this simple blood test to make determinations about whether to use checkpoint inhibitor–based immune therapy in a variety of tumor types.”
The 69 patients were a median of 56 years old, and 43 (62.3%) were men. Melanoma, lung cancer, and head and neck cancer were the most common malignancies. The majority of patients had anti–PD-1 or PD-L1 monotherapy.
For most patients, blood samples were drawn a month or 2 before treatment. Next-generation sequencing (Guardant360) was done on ctDNA to detect alterations in cancer genes. Of the 69 patients, 20 (29%) had more than three variants of unknown significance (VUS); the rest had three or fewer.
The median overall survival was 15.3 months from the start of immunotherapy. For patients with three or fewer VUS, median overall survival was 10.72 months; for patients with more, median overall survival could not be calculated because more than half were alive at the study’s conclusion.
Median progression-fee survival was 2.07 months with three or fewer VUS, versus 3.84 months with more. The findings were statistically significant.
Similar results were found when all genomic alterations, not just VUS, were examined and dichotomized as six or more versus fewer than six.
“The number of genes assayed in our ctDNA analysis was only between 54 and 70. Unlike targeted NGS [next-generation sequencing] of tumor tissue, which often tests for hundreds of genes and allows a relatively accurate estimate of total mutational burden, targeted NGS of plasma ctDNA provides only a limited snapshot of the cancer genome. More extensive ctDNA gene panels merit investigation to determine if they increase the correlative value of our findings,” the investigators said.
The work was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Dr. Khagi had no industry disclosures. Three authors reported financial ties to a number of companies, including Boehringer, Merck, Guardant, and Pfizer. The senior author has ownership interests in CureMatch.
FROM CLINICAL CANCER RESEARCH
Key clinical point:
Major finding: The overall response rate to immune checkpoint inhibitors was 45% among cancer patients who had more than three variants of unknown significance in their circulating tumor DNA; among those with three or fewer, the response rate was 15%.
Data source: Review of 69 cancer patients.
Disclosures: The work was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Three investigators reported financial ties to a number of companies, including Boehringer, Merck, Guardant, and Pfizer. The senior author has ownership interests in CureMatch.
Checkmate 214: Upfront nivo/ipi bests TKI in advanced RCC
MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported
Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.
Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).
“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.
Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .
The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.
The results for the coprimary endpoints are noted above.
Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.
For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.
The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).
In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.
There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.
In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.
“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.
“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.
The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported
Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.
Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).
“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.
Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .
The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.
The results for the coprimary endpoints are noted above.
Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.
For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.
The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).
In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.
There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.
In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.
“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.
“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.
The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
MADRID – A combination of two immune checkpoint inhibitors was superior to the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) in first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC), investigators reported
Median overall survival (OS) among 425 patients with intermediate- or poor-risk treatment-naive advanced/metastatic clear-cell RCC treated with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was not reached after 32 months of follow-up. In contrast, the median OS for 422 patients treated with sunitinib was 26 months, reported Bernard Escudier, MD from the Institut Gustave Roussy in Villejuif, France.
Similarly tipping the balance toward the combination, the ORR was 42%, compared with 27% in the sunitinib group (P less than .0001).
“These results support the use of nivo/ipi [nivolumab/ipilimumab] as a new first-line standard of care option for patients with advanced renal cell carcinoma,” Dr. Escudier said at a briefing prior to presenting the data in a presidential symposium.
Patients with treatment-naive advanced or metastatic clear-cell RCC with measurable disease, a Karnofsky Performance Score of at least 70%, and tumor tissue available for programmed death ligand 1 (PD-L1) typing were enrolled in Checkmate 214, .
The patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and by region (U.S. versus Canada/Europe versus the rest of the world) and then randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses then 3 mg/kg nivolumab every other week or to receive 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Patients remained on treatment until progression or unacceptable toxicity.
The results for the coprimary endpoints are noted above.
Duration of response trended toward superior with the checkpoint inhibitor duo. At 2-year follow-up, the median duration of response was not reached with nivo/ipi, vs. 18.2 months with sunitinib. In all, 72% of patients on the combination had an ongoing response at 2 years, compared with 63% of patients on the TKI, but the upper level of the confidence interval in both trial arms had not been reached at the time of the data cutoff, so statistical significance of the difference in duration cannot be determined.
For the secondary endpoints of overall survival in the intention-to-treat population, which included 550 patients assigned to nivo/ipi and 546 to sunitinib, the ORR was 39% for patients assigned to the checkpoint inhibitors, compared with 32% for sunitinib (P = .0191). The median respective PFS numbers, however, were virtually identical at 12.4 vs. 12.3 months.
The median OS in the intention-to-treat population was not reached with the combination, versus 32.9 months with the TKI (hazard ratio, 0.68; P = .0003).
In the intermediate- or poor-risk population, PFS was significantly better with nivo/ipi among patients with PD-L1 expression in 1% or more of cells but not in patients with lower levels of PD-L1 expression.
There were more adverse events leading to discontinuation among patients on the dual checkpoint inhibitors at 22% vs. 12% with sunitinib. The most common grade 3 or greater adverse events in the combination group were fatigue and diarrhea in 4% each and rash and nausea in 2% each, while incidences of pruritus, hypothyroidism, vomiting, and hypertension occurred in fewer than 1% of patients.
In the sunitinib group, the most common grade 3 or greater events were hypertension in 16%, fatigue in 9%, palmar-plantar erythrodysesthesia syndrome in 9%, stomatitis in 3%, mucosal inflammation in 3%, and vomiting in 2%. Nausea, decreased appetite, hypothyroidism, and dysgeusia occurred in 1% or fewer of patients in this arm.
“The combination, I think, is really beneficial, because with immunotherapy we have seen that patients who respond usually have long-term benefit, and in this case high-response rate seems to be important and translates into a long-term for patients,” commented Maria de Santis, MD, from the University of Warwick, U.K., who was an invited discussant at the briefing.
“This data is clearly important and practice changing, and it challenges the former standard of care with TKI monotherapy treatment,” she added.
The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
AT ESMO 2017
Key clinical point: The combination of the PD-1 inhibitor nivolumab and CTLA-4 inhibitor ipilimumab was efficacious in frontline therapyfor advanced or metastatic renal cell carcinoma.
Major finding: The trial met its coprimary endpoints of overall response rate and progression-free survival, as well as its secondary endpoint of overall survival.
Data source: Randomized open-label study in 1096 patients with advanced/metastatic RCC, including 847 with intermediate- to poor-risk disease.
Disclosures: The study was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical; Dr. Escudier disclosed honoraria from BMS. Dr. de Santis did not disclose potential conflicts of interest.
FDA approves pembrolizumab for gastric and GEJ adenocarcinoma
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in cases where tests confirm that the tumors contain programmed death–ligand 1 and where the disease is progressing on or after two or more prior lines of therapy.
Pembrolizumab has been approved in the United States since 2014 for the treatment of melanoma, with subsequent approvals for treatment of non–small-cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, and several other advanced cancers.
The approval comes on the basis of the nonrandomized, open label KEYNOTE-059 trial, which enrolled 259 patients with gastric or GEJ adenocarcinoma that progressed on at least two prior systemic treatments for advanced disease. Of the enrollees, 143 patients had tumors with a PD-L1 Combined Positive Score of 1 or greater. The primary trial outcome, the objective response rate for these 143 patients, was 13.3% (95% confidence interval; 8.2-20), with a complete response rate of 1.4% and a partial response rate of 11.9%. The duration of response ranged from at least 2.8 months to at least 19.4 months.
Continued approval for the new indication will depend upon further demonstration of a clinical benefit in confirmatory trials.
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in cases where tests confirm that the tumors contain programmed death–ligand 1 and where the disease is progressing on or after two or more prior lines of therapy.
Pembrolizumab has been approved in the United States since 2014 for the treatment of melanoma, with subsequent approvals for treatment of non–small-cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, and several other advanced cancers.
The approval comes on the basis of the nonrandomized, open label KEYNOTE-059 trial, which enrolled 259 patients with gastric or GEJ adenocarcinoma that progressed on at least two prior systemic treatments for advanced disease. Of the enrollees, 143 patients had tumors with a PD-L1 Combined Positive Score of 1 or greater. The primary trial outcome, the objective response rate for these 143 patients, was 13.3% (95% confidence interval; 8.2-20), with a complete response rate of 1.4% and a partial response rate of 11.9%. The duration of response ranged from at least 2.8 months to at least 19.4 months.
Continued approval for the new indication will depend upon further demonstration of a clinical benefit in confirmatory trials.
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in cases where tests confirm that the tumors contain programmed death–ligand 1 and where the disease is progressing on or after two or more prior lines of therapy.
Pembrolizumab has been approved in the United States since 2014 for the treatment of melanoma, with subsequent approvals for treatment of non–small-cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, and several other advanced cancers.
The approval comes on the basis of the nonrandomized, open label KEYNOTE-059 trial, which enrolled 259 patients with gastric or GEJ adenocarcinoma that progressed on at least two prior systemic treatments for advanced disease. Of the enrollees, 143 patients had tumors with a PD-L1 Combined Positive Score of 1 or greater. The primary trial outcome, the objective response rate for these 143 patients, was 13.3% (95% confidence interval; 8.2-20), with a complete response rate of 1.4% and a partial response rate of 11.9%. The duration of response ranged from at least 2.8 months to at least 19.4 months.
Continued approval for the new indication will depend upon further demonstration of a clinical benefit in confirmatory trials.
Retrospective review: No difference in PFS, OS with radiation before PD-1/PD-L1 inhibition
CHICAGO – Exposure to radiation therapy prior to PD-1/PD-L1 therapy was not associated with improved outcomes in a retrospective review of 66 lung cancer patients.
The patients had stage IIIB or IV non–small cell lung cancer, median age of 64 years, received at least 6 weeks of single-agent anti-PD-1/PD-L1 therapy in the second-line setting or beyond, and had survived at least 8 weeks from immunotherapy initiation. Compared with 13 patients who received no radiation therapy, the 53 who received any prior radiation therapy – including 44 with extracranial radiation and 22 with intracranial radiation – did not differ significantly with respect to progression-free survival (median 4-5 months; hazard ratio, 0.83), or overall survival (median of about 12 months in both groups; HR, 0.96), Christopher Strouse, MD, of the University of Iowa, Iowa City, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
There also were no significant differences in the outcomes between those who had extracranial radiation and those who had intracranial radiation (HRs for PFS and OS, respectively, 0.91 and 1.19), or (on univariate analysis), between those receiving any vs. no intracranial radiation therapy (HRs for PFS and OS, respectively, 0.92 and 0.98), Dr. Strouse said.
The patients who received extracranial radiation therapy had lower lymphocyte counts at the time of anti-PD-1/PD-L1 therapy initiation vs. those who received only radiation therapy (mean lymphocyte count, 809 vs. 1,519), and those who received intracranial radiation therapy were younger than those who did not (median age, 59 vs. 65 years), but the groups were similar with respect to other variables, including gender, histology, performance status, smoking history, KRAS mutation, and number of prior lines of systemic therapies. Anti-PD-1/PD-L1 therapies are promising treatment options for metastatic non–small cell lung cancer, and combining these agents with other immune-modulating therapies may enhance their efficacy and lead to a greater proportion of patients with responses to these treatments, Dr. Strouse noted.
“It’s known that immune response depends on a lot of steps, even beyond the PD-1/PD-L1 axis, and one possible explanation for some of these patients [not responding] may be that there is some failure along the way in some other step,” he said. “Our hypothesis was that radiation therapy would be helpful in overcoming some of these barriers.”
However, in this study, which is limited by small sample size and single-institution retrospective design, no such effect was identified.
The findings conflict with some larger studies, including the recently-reported PACIFIC study, which showed a significant PFS benefit in lung cancer patients who received chemoradiation therapy followed by treatment with the PD-L1 inhibitor durvalumab.
Dr. Strouse said he looks forward to seeing further reports looking into the effects of radiation therapy at different doses and timing.
Invited discussant Heather Wakelee, MD, of Stanford (Calif.) University, also stressed the limitations of the University of Iowa study, and noted that while there are many unanswered questions, findings such as those from the PACIFIC trial show that radiation and PD-L1 inhibition is here to stay.
“It appears safe; there will be more coming,” she said.
Dr. Strouse reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
CHICAGO – Exposure to radiation therapy prior to PD-1/PD-L1 therapy was not associated with improved outcomes in a retrospective review of 66 lung cancer patients.
The patients had stage IIIB or IV non–small cell lung cancer, median age of 64 years, received at least 6 weeks of single-agent anti-PD-1/PD-L1 therapy in the second-line setting or beyond, and had survived at least 8 weeks from immunotherapy initiation. Compared with 13 patients who received no radiation therapy, the 53 who received any prior radiation therapy – including 44 with extracranial radiation and 22 with intracranial radiation – did not differ significantly with respect to progression-free survival (median 4-5 months; hazard ratio, 0.83), or overall survival (median of about 12 months in both groups; HR, 0.96), Christopher Strouse, MD, of the University of Iowa, Iowa City, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
There also were no significant differences in the outcomes between those who had extracranial radiation and those who had intracranial radiation (HRs for PFS and OS, respectively, 0.91 and 1.19), or (on univariate analysis), between those receiving any vs. no intracranial radiation therapy (HRs for PFS and OS, respectively, 0.92 and 0.98), Dr. Strouse said.
The patients who received extracranial radiation therapy had lower lymphocyte counts at the time of anti-PD-1/PD-L1 therapy initiation vs. those who received only radiation therapy (mean lymphocyte count, 809 vs. 1,519), and those who received intracranial radiation therapy were younger than those who did not (median age, 59 vs. 65 years), but the groups were similar with respect to other variables, including gender, histology, performance status, smoking history, KRAS mutation, and number of prior lines of systemic therapies. Anti-PD-1/PD-L1 therapies are promising treatment options for metastatic non–small cell lung cancer, and combining these agents with other immune-modulating therapies may enhance their efficacy and lead to a greater proportion of patients with responses to these treatments, Dr. Strouse noted.
“It’s known that immune response depends on a lot of steps, even beyond the PD-1/PD-L1 axis, and one possible explanation for some of these patients [not responding] may be that there is some failure along the way in some other step,” he said. “Our hypothesis was that radiation therapy would be helpful in overcoming some of these barriers.”
However, in this study, which is limited by small sample size and single-institution retrospective design, no such effect was identified.
The findings conflict with some larger studies, including the recently-reported PACIFIC study, which showed a significant PFS benefit in lung cancer patients who received chemoradiation therapy followed by treatment with the PD-L1 inhibitor durvalumab.
Dr. Strouse said he looks forward to seeing further reports looking into the effects of radiation therapy at different doses and timing.
Invited discussant Heather Wakelee, MD, of Stanford (Calif.) University, also stressed the limitations of the University of Iowa study, and noted that while there are many unanswered questions, findings such as those from the PACIFIC trial show that radiation and PD-L1 inhibition is here to stay.
“It appears safe; there will be more coming,” she said.
Dr. Strouse reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
CHICAGO – Exposure to radiation therapy prior to PD-1/PD-L1 therapy was not associated with improved outcomes in a retrospective review of 66 lung cancer patients.
The patients had stage IIIB or IV non–small cell lung cancer, median age of 64 years, received at least 6 weeks of single-agent anti-PD-1/PD-L1 therapy in the second-line setting or beyond, and had survived at least 8 weeks from immunotherapy initiation. Compared with 13 patients who received no radiation therapy, the 53 who received any prior radiation therapy – including 44 with extracranial radiation and 22 with intracranial radiation – did not differ significantly with respect to progression-free survival (median 4-5 months; hazard ratio, 0.83), or overall survival (median of about 12 months in both groups; HR, 0.96), Christopher Strouse, MD, of the University of Iowa, Iowa City, reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
There also were no significant differences in the outcomes between those who had extracranial radiation and those who had intracranial radiation (HRs for PFS and OS, respectively, 0.91 and 1.19), or (on univariate analysis), between those receiving any vs. no intracranial radiation therapy (HRs for PFS and OS, respectively, 0.92 and 0.98), Dr. Strouse said.
The patients who received extracranial radiation therapy had lower lymphocyte counts at the time of anti-PD-1/PD-L1 therapy initiation vs. those who received only radiation therapy (mean lymphocyte count, 809 vs. 1,519), and those who received intracranial radiation therapy were younger than those who did not (median age, 59 vs. 65 years), but the groups were similar with respect to other variables, including gender, histology, performance status, smoking history, KRAS mutation, and number of prior lines of systemic therapies. Anti-PD-1/PD-L1 therapies are promising treatment options for metastatic non–small cell lung cancer, and combining these agents with other immune-modulating therapies may enhance their efficacy and lead to a greater proportion of patients with responses to these treatments, Dr. Strouse noted.
“It’s known that immune response depends on a lot of steps, even beyond the PD-1/PD-L1 axis, and one possible explanation for some of these patients [not responding] may be that there is some failure along the way in some other step,” he said. “Our hypothesis was that radiation therapy would be helpful in overcoming some of these barriers.”
However, in this study, which is limited by small sample size and single-institution retrospective design, no such effect was identified.
The findings conflict with some larger studies, including the recently-reported PACIFIC study, which showed a significant PFS benefit in lung cancer patients who received chemoradiation therapy followed by treatment with the PD-L1 inhibitor durvalumab.
Dr. Strouse said he looks forward to seeing further reports looking into the effects of radiation therapy at different doses and timing.
Invited discussant Heather Wakelee, MD, of Stanford (Calif.) University, also stressed the limitations of the University of Iowa study, and noted that while there are many unanswered questions, findings such as those from the PACIFIC trial show that radiation and PD-L1 inhibition is here to stay.
“It appears safe; there will be more coming,” she said.
Dr. Strouse reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
AT A SYMPOSIUM IN THORACIC ONCOLOGY
Key clinical point:
Major finding: PFS and OS did not differ significantly between patients who did and did not receive prior radiation therapy (HRs for PFS and OS, respectively, 0.83 and 0.96).
Data source: A retrospective review of 66 patients.
Disclosures: Dr. Strouse reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
FDA approves nivolumab for HCC patients
The Food and Drug Administration has granted accelerated approval to nivolumab (Optivo) for the treatment of patients with hepatocellular carcinoma (HCC) who have been treated previously with sorafenib.
Approval was based on tumor response rate and durability of response from the phase 1/2 Checkmate 040 trial. Of 154 patients with HCC in the trial who received nivolumab following progression on sorafenib, 3 experienced complete response, and 19 experienced partial response. Median time to response was 2.8 months, and 91% of patients who responded to treatment had a response length longer than 6 months, with 55% of patients having a response length longer than 1 year.
“In recent years, there has been growing interest in leveraging immuno-oncology knowledge and discoveries to add to the treatment options available for patients with advanced-stage liver cancer. The approval of Opdivo provides us with an encouraging approach and a new treatment option for appropriate patients with HCC following prior systemic therapy,” Anthony B. El-Khoueiry, MD, a medical oncologist and phase 1 program director at the University of Southern California, Los Angeles, and the USC Norris Comprehensive Cancer Center, said in the press release.
The Food and Drug Administration has granted accelerated approval to nivolumab (Optivo) for the treatment of patients with hepatocellular carcinoma (HCC) who have been treated previously with sorafenib.
Approval was based on tumor response rate and durability of response from the phase 1/2 Checkmate 040 trial. Of 154 patients with HCC in the trial who received nivolumab following progression on sorafenib, 3 experienced complete response, and 19 experienced partial response. Median time to response was 2.8 months, and 91% of patients who responded to treatment had a response length longer than 6 months, with 55% of patients having a response length longer than 1 year.
“In recent years, there has been growing interest in leveraging immuno-oncology knowledge and discoveries to add to the treatment options available for patients with advanced-stage liver cancer. The approval of Opdivo provides us with an encouraging approach and a new treatment option for appropriate patients with HCC following prior systemic therapy,” Anthony B. El-Khoueiry, MD, a medical oncologist and phase 1 program director at the University of Southern California, Los Angeles, and the USC Norris Comprehensive Cancer Center, said in the press release.
The Food and Drug Administration has granted accelerated approval to nivolumab (Optivo) for the treatment of patients with hepatocellular carcinoma (HCC) who have been treated previously with sorafenib.
Approval was based on tumor response rate and durability of response from the phase 1/2 Checkmate 040 trial. Of 154 patients with HCC in the trial who received nivolumab following progression on sorafenib, 3 experienced complete response, and 19 experienced partial response. Median time to response was 2.8 months, and 91% of patients who responded to treatment had a response length longer than 6 months, with 55% of patients having a response length longer than 1 year.
“In recent years, there has been growing interest in leveraging immuno-oncology knowledge and discoveries to add to the treatment options available for patients with advanced-stage liver cancer. The approval of Opdivo provides us with an encouraging approach and a new treatment option for appropriate patients with HCC following prior systemic therapy,” Anthony B. El-Khoueiry, MD, a medical oncologist and phase 1 program director at the University of Southern California, Los Angeles, and the USC Norris Comprehensive Cancer Center, said in the press release.
CRP may predict survival after immunotherapy for lung cancer
CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.
In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.
The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.
Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.
The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.
However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.
Dr. Naqash reported having no disclosures.
CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.
In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.
The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.
Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.
The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.
However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.
Dr. Naqash reported having no disclosures.
CHICAGO – A baseline C-reactive protein (CRP) level above 50 mg/L independently predicted worse overall survival after immunotherapy in patients with advanced non–small cell lung cancer and small cell lung cancer in a retrospective study.
In 99 patients treated with nivolumab after a first-line platinum doublet, the median baseline CRP level was 22 mg/L. After a median follow-up of 8.5 months, 50% of patients were alive, and, based on univariate and multivariate analysis, both liver involvement and having a CRP level greater than 50 mg/L were significantly associated with inferior overall survival after immunotherapy.
The median overall survival after immunotherapy was 9.3 months versus 2.7 months with a CRP level of 50 mg/L or less versus above 50 mg/L, Abdul Rafeh Naqash, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
Notably, significant increases in CRP level, compared with baseline, were seen at the time of grade 2 to grade 4 immune-related adverse events, which occurred in 38.4% of patients. This is a hypothesis-generating finding in that it suggests there is dysregulation of the immune system, in the context of immune checkpoint blockade, that leads to a more proinflammatory state, which ultimately leads to immune-related adverse events, Dr. Naqash said.
Study subjects were adults with a median age of 65 years who were treated during April 2015-March 2017. Most were white (64.7%), were male (64.6%), and had non–small cell lung cancer (88%). Most had stage IV disease (70.7%), and the most common site for metastases was the bones (35.4%) and the liver (24.2%). Patients’ CRP levels were measured at anti-PD-1–treatment initiation and serially with subsequent doses.
The findings are important because the identification of predictive biomarkers in patients treated with anti-PD-1 therapy could provide valuable insights into underlying mechanisms regulating patient responses, elucidate resistance mechanisms, and help with optimal selection of patients for treatment with and development of patient-tailored treatment, Dr. Naqash said, noting that identifying such biomarkers has thus far been a challenge.
However, this study is limited by its retrospective design and limited follow-up; the findings require validation in prospective lung cancer trials, he concluded.
Dr. Naqash reported having no disclosures.
AT A SYMPOSIUM IN THORACIC ONCOLOGY
Key clinical point:
Major finding: Median overall survival after immunotherapy: 9.3 months vs. 2.7 months with CRP of 50 mg/L or less vs. above 50 mg/L.
Data source: A retrospective study of 99 patients.
Disclosures: Dr. Naqash reported having no disclosures.
Tocilizumab looks promising for corticosteroid refractory anti-PD-1-related adverse events
CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.
Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.
There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.
“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.
At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.
Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.
“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.
The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.
Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.
C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.
Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.
“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.
Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”
Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.
“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.
However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”
Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.
Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.
There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.
“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.
At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.
Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.
“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.
The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.
Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.
C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.
Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.
“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.
Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”
Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.
“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.
However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”
Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
CHICAGO – Tocilizumab may be a therapeutic option for steroid-refractory immune-related adverse events that are secondary to PD-1 blockade, according to findings from a review of patients treated with nivolumab for various malignancies.
Of 87 patients who were treated with the PD-1 inhibitor between April 2015 and October 2016, 34 received tocilizumab for high-grade immune-related adverse events (irAEs) that were refractory to corticosteroids. Of those, 27 experienced clinical improvement, which was defined as documentation of symptom resolution or hospital discharge within 7 days, Aparna Hegde, MD, of East Carolina University, Greenville, N.C., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.
The median time to discharge was 4 days, and no adverse effect on median overall survival was seen between those who received tocilizumab and those who did not (6.1 vs, 6.7 months, respectively), Dr. Hegde said.
There was, however, a trend toward inferior overall survival in patients who required more than one dose of tocilizumab, but the difference was not statistically significant (hazard ratio, 1.72), she noted.
“Immune checkpoint inhibitors are associated with an unprecedented clinical benefit in patients with lung cancer. However, they are also associated with a unique spectrum of immune-mediated adverse events. While the standard of care for initial management of these adverse events is corticosteroids, the management of steroid-refractory events is poorly defined,” she said, adding that data from randomized trials on which consensus guidelines could be based are lacking.
At East Carolina University, a significant proportion of patients treated with PD-1 inhibitors were presenting with systemic inflammatory response syndrome (SIRS)-like symptoms and immune-related organ toxicities similar to what has been described in cytokine release syndrome, Dr. Hegde said.
Such symptoms have also been reported with other types of immune therapy, such as CAR T-cell therapy and bispecific T-cell receptor–engaging antibodies in hematologic malignancies, she noted.
“In our experience, when we treated these patients with tocilizumab, which is an [anti-interleukin-6] receptor monoclonal antibody, we saw dramatic and rapid responses, not only in the SIRS symptoms, but also in other immune-related organ toxicities. Therefore, we adopted the use of tocilizumab as our standard treatment for high-grade immune-related adverse events,” she said, explaining that it has been well documented that interleukin (IL)-6 levels increase during cytokine release syndrome and are mediators of inflammation, suggesting that blocking IL-6 may treat irAEs without compromising the efficacy of immune therapy.
The current study was undertaken to look more closely at the responses to tocilizumab and to assess overall survival in those who received tocilizumab.
Study participants were being prospectively followed as part of another ongoing study looking at the relationship between systemic inflammation and cancer-related symptom burden. Most (77) were being treated for lung cancer and 10 had other types of malignancy. They received nivolumab at a dose of 3 mg/kg (or a flat dose of 240 mg after September 2016) every 2 weeks, and received tocilizumab at a dose of 4 mg/kg given over 1 hour. Those with grade 3 or 4 irAEs also received supportive care and corticosteroids. Median follow-up was 10.6 months.
C-reactive protein (CRP), a reliable surrogate marker of IL-6, was drawn at the first nivolumab infusion and before each subsequent infusion as part of the study in which the patients were enrolled, and for the current analysis was measured in relation to irAEs.
Significant reductions were seen in CRP levels after tocilizumab treatment; similar responses have been described in cytokine release syndrome, Dr. Hegde noted.
“Tocilizumab is a therapeutic option for management of immune-related adverse events in patients who are already on corticosteroids. CRP may be of clinical utility in detecting immune-related adverse events as well as monitoring the response to tocilizumab,” she said, adding that the current analysis is limited by the small patient number, single-center setting, use of tocilizumab outside of a clinical trial setting, and short follow-up.
Therefore, the findings require confirmation in multicenter randomized trials to determine “the definitive utility of tocilizumab, as well as CRP as an accompanying biomarker in the management of high-grade steroid refractory immune-related adverse events.”
Heather Wakelee, MD, an invited discussant at the symposium, commended Dr. Hegde and her colleagues for “coming up with a novel idea about how to treat [irAEs],” but also stressed the need for further study.
“This is a novel agent that has the potential ability to manage toxicity, and that’s important, because when you get beyond the steroids that we use as a first-line approach ... there’s not a whole lot else. We definitely have a clear unmet need,” said Dr. Wakelee of Stanford (Calif.) University.
However, she stressed that the approach must be evaluated in multicenter randomized trials “before we can be widely discussing this as a good thing to be doing.”
Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
AT A SYMPOSIUM IN THORACIC ONCOLOGY
Key clinical point:
Major finding: Twenty-seven of 34 patients treated with tocilizumab experienced clinical improvement.
Data source: A review of 87 patients.
Disclosures: Dr. Hegde reported having no disclosures. Dr. Wakelee has been the institutional principal investigator for studies of nivolumab, tocilizumab, and other agents. She has consulted for Peregrine, ACEA, Pfizer, Helsinn, Genentech/Roche, Clovis, and Lilly, and received research/grant support from Clovis, Exelixis, AstraZeneca/Medimmune, Genentech/Roche, BMS, Gilead, Novartis, Xcovery, Pfizer, Celgene, Gilead, Pharmacyclics, and Lilly.
Adding T-vec might help surmount PD-1 resistance in melanoma
Almost two-thirds of patients with advanced melanoma responded to combination therapy with pembrolizumab and talimogene laherparepvec (T-vec) in a small phase 1b trial, investigators reported.
A third of patients achieved a complete response and median progression-free and overall survival were not reached after typically 18.6 (range, 17.7 to 20.8) months of follow-up, said Antoni Ribas, MD, of the University of California, Los Angeles, and his coinvestigators. In contrast to single-agent pembrolizumab therapy, responders to the combination regimen included patients with very low levels of CD8+ T cell infiltrates or negative interferon-gamma (IFN-gamma) gene signatures in baseline tumor biopsies, suggesting that oncolytic virotherapy might make anti-PD-1 therapy more effective by altering the tumor microenvironment, the researchers concluded. Serious adverse events were uncommon in this study, and there were no dose-limiting toxicities, they wrote (Cell. 2017 Sept. 7 doi: 10.1016/j.cell.2017.08.027).
To see if attracting CD8+ T cells into tumors helped surmount this obstacle, the researchers treated 21 patients with advanced melanoma with pembrolizumab and T-vec, an intratumorally administered, genetically modified clinical herpes simplex virus-1 strain approved for treating melanoma. Patients first received up to 4 mL T-vec (106 plaque-forming units [pfu] per mL) to induce a protective immune response. Three weeks later, they started receiving to 4 mL (108 pfu/mL) T-vec plus 200 mg intravenous pembrolizumab every 2 weeks.
Thirteen patients (62%) showed at least a partial response, and seven (33%) had a complete response based on immune criteria. Notably, 9 of 13 (69%) patients with baseline tumor CD8+ densities below 1,000 cells/mm2 responded to combination treatment, as did three of five patients with low baseline IFN-gamma signatures.
“There was only one baseline biopsy that was scored as PD-L1 negative, but that patient went on to have a complete response to the combined therapy,” the researchers wrote. “Patients who responded to combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression, [and] IFN-gamma gene expression on several cell subsets in tumors after [T-vec] treatment. Response to combination therapy did not appear to be associated with baseline CD8+ T cell infiltration or baseline IFN-gamma signature.” Increased levels of circulating immune cells and shrinkage of untreated tumors both suggested that intratumoral T-vec injections led to systemic effects, they added.
Amgen and Merck provided funding. Dr. Ribas disclosed consulting fees from both companies.
Almost two-thirds of patients with advanced melanoma responded to combination therapy with pembrolizumab and talimogene laherparepvec (T-vec) in a small phase 1b trial, investigators reported.
A third of patients achieved a complete response and median progression-free and overall survival were not reached after typically 18.6 (range, 17.7 to 20.8) months of follow-up, said Antoni Ribas, MD, of the University of California, Los Angeles, and his coinvestigators. In contrast to single-agent pembrolizumab therapy, responders to the combination regimen included patients with very low levels of CD8+ T cell infiltrates or negative interferon-gamma (IFN-gamma) gene signatures in baseline tumor biopsies, suggesting that oncolytic virotherapy might make anti-PD-1 therapy more effective by altering the tumor microenvironment, the researchers concluded. Serious adverse events were uncommon in this study, and there were no dose-limiting toxicities, they wrote (Cell. 2017 Sept. 7 doi: 10.1016/j.cell.2017.08.027).
To see if attracting CD8+ T cells into tumors helped surmount this obstacle, the researchers treated 21 patients with advanced melanoma with pembrolizumab and T-vec, an intratumorally administered, genetically modified clinical herpes simplex virus-1 strain approved for treating melanoma. Patients first received up to 4 mL T-vec (106 plaque-forming units [pfu] per mL) to induce a protective immune response. Three weeks later, they started receiving to 4 mL (108 pfu/mL) T-vec plus 200 mg intravenous pembrolizumab every 2 weeks.
Thirteen patients (62%) showed at least a partial response, and seven (33%) had a complete response based on immune criteria. Notably, 9 of 13 (69%) patients with baseline tumor CD8+ densities below 1,000 cells/mm2 responded to combination treatment, as did three of five patients with low baseline IFN-gamma signatures.
“There was only one baseline biopsy that was scored as PD-L1 negative, but that patient went on to have a complete response to the combined therapy,” the researchers wrote. “Patients who responded to combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression, [and] IFN-gamma gene expression on several cell subsets in tumors after [T-vec] treatment. Response to combination therapy did not appear to be associated with baseline CD8+ T cell infiltration or baseline IFN-gamma signature.” Increased levels of circulating immune cells and shrinkage of untreated tumors both suggested that intratumoral T-vec injections led to systemic effects, they added.
Amgen and Merck provided funding. Dr. Ribas disclosed consulting fees from both companies.
Almost two-thirds of patients with advanced melanoma responded to combination therapy with pembrolizumab and talimogene laherparepvec (T-vec) in a small phase 1b trial, investigators reported.
A third of patients achieved a complete response and median progression-free and overall survival were not reached after typically 18.6 (range, 17.7 to 20.8) months of follow-up, said Antoni Ribas, MD, of the University of California, Los Angeles, and his coinvestigators. In contrast to single-agent pembrolizumab therapy, responders to the combination regimen included patients with very low levels of CD8+ T cell infiltrates or negative interferon-gamma (IFN-gamma) gene signatures in baseline tumor biopsies, suggesting that oncolytic virotherapy might make anti-PD-1 therapy more effective by altering the tumor microenvironment, the researchers concluded. Serious adverse events were uncommon in this study, and there were no dose-limiting toxicities, they wrote (Cell. 2017 Sept. 7 doi: 10.1016/j.cell.2017.08.027).
To see if attracting CD8+ T cells into tumors helped surmount this obstacle, the researchers treated 21 patients with advanced melanoma with pembrolizumab and T-vec, an intratumorally administered, genetically modified clinical herpes simplex virus-1 strain approved for treating melanoma. Patients first received up to 4 mL T-vec (106 plaque-forming units [pfu] per mL) to induce a protective immune response. Three weeks later, they started receiving to 4 mL (108 pfu/mL) T-vec plus 200 mg intravenous pembrolizumab every 2 weeks.
Thirteen patients (62%) showed at least a partial response, and seven (33%) had a complete response based on immune criteria. Notably, 9 of 13 (69%) patients with baseline tumor CD8+ densities below 1,000 cells/mm2 responded to combination treatment, as did three of five patients with low baseline IFN-gamma signatures.
“There was only one baseline biopsy that was scored as PD-L1 negative, but that patient went on to have a complete response to the combined therapy,” the researchers wrote. “Patients who responded to combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression, [and] IFN-gamma gene expression on several cell subsets in tumors after [T-vec] treatment. Response to combination therapy did not appear to be associated with baseline CD8+ T cell infiltration or baseline IFN-gamma signature.” Increased levels of circulating immune cells and shrinkage of untreated tumors both suggested that intratumoral T-vec injections led to systemic effects, they added.
Amgen and Merck provided funding. Dr. Ribas disclosed consulting fees from both companies.
FROM CELL
Key clinical point: Adding talimogene laherparepvec (T-vec) might help overcome resistance to anti-PD-1 antibodies in patients with advanced melanoma.
Major finding: In all, 62% of patients had at least a partial response and 33% had a complete response. Median progression-free and overall survival were not reached after a median of 18.6 weeks of follow-up.
Data source: A phase 1b clinical trial of 21 adults with advanced melanoma who received T-vec and pembrolizumab.
Disclosures: Amgen and Merck provided funding. Dr. Ribas disclosed consulting fees from both companies.
Checkmate 238: Nivolumab bests ipilimumab for resectable stage III or IV melanoma
MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.
Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.
However, longer follow-up will be needed to see whether the RFS advantage of nivolumab translates into an overall survival advantage, he acknowledged.
In the trial, patients with high-risk, completely resected stage IIIB, IIIC, or IV melanoma were stratified by disease stage and PD-L1 status at baseline and randomly assigned in cohorts of 453 patients each to receive either nivolumab 3 mg/kg intravenously every 2 weeks and ipilimumab placebo every 3 weeks for four doses, or to ipilimumab 10 mg/kg IV every 3 weeks for four doses, then every 12 weeks from week 24, and nivolumab placebo IV every 2 weeks.
The maximum duration of therapy was 1 year.
For the primary RFS endpoint, the hazard ratio (HR) favoring nivolumab was 0.65 (P less than .0001).
The benefit for nivolumab was observed across the majority of prespecified subgroups tested, including PD-L1 and BRAF mutational status, Dr. Weber said.
Nivolumab also had a better safety profile, with a 14.4% incidence of grade 3 or 4 treatment-related adverse events, compared with 45.9% for ipilimumab. Grade 3 or 4 treatment-related adverse events leading to discontinuation of therapy occurred in 4.6% of patients on nivolumab, compared with 30.9% of those on ipilimumab.
Two patients in the ipilimumab arm died from toxicities related to therapy, one from marrow aplasia, and one from colitis. Both of these deaths occurred more than 100 days after the patients received their last dose of ipilimumab. There were no treatment-related deaths in the nivolumab arm.
Commenting on both the Checkmate 238 trial and a second trial reported at ESMO (COMBI-AD) looking at a combination of dabrafenib and trametinib for patients with stage III melanoma with a BRAF V600 mutation, Olivier Michielin, MD, PhD, said that “we now have, with the data, two fantastic new options. We couldn’t dream those studies to be so positive. This is really something that will open new futures for our patients.”
Dr. Michielin and Dr. Dummer were invited commentators at the briefing. Dr. Michielin was not involved in either trial. Dr. Dummer was a coinvestigator for the COMBI-AD trial.
The study was published simultaneously online by the New England Journal of Medicine.
Checkmate 238 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Weber disclosed honoraria, consulting fees, and travel accommodations/expenses from BMS and multiple other companies. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK. Dr. Dummer reported advising/consulting roles with BMS and others.
MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.
Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.
However, longer follow-up will be needed to see whether the RFS advantage of nivolumab translates into an overall survival advantage, he acknowledged.
In the trial, patients with high-risk, completely resected stage IIIB, IIIC, or IV melanoma were stratified by disease stage and PD-L1 status at baseline and randomly assigned in cohorts of 453 patients each to receive either nivolumab 3 mg/kg intravenously every 2 weeks and ipilimumab placebo every 3 weeks for four doses, or to ipilimumab 10 mg/kg IV every 3 weeks for four doses, then every 12 weeks from week 24, and nivolumab placebo IV every 2 weeks.
The maximum duration of therapy was 1 year.
For the primary RFS endpoint, the hazard ratio (HR) favoring nivolumab was 0.65 (P less than .0001).
The benefit for nivolumab was observed across the majority of prespecified subgroups tested, including PD-L1 and BRAF mutational status, Dr. Weber said.
Nivolumab also had a better safety profile, with a 14.4% incidence of grade 3 or 4 treatment-related adverse events, compared with 45.9% for ipilimumab. Grade 3 or 4 treatment-related adverse events leading to discontinuation of therapy occurred in 4.6% of patients on nivolumab, compared with 30.9% of those on ipilimumab.
Two patients in the ipilimumab arm died from toxicities related to therapy, one from marrow aplasia, and one from colitis. Both of these deaths occurred more than 100 days after the patients received their last dose of ipilimumab. There were no treatment-related deaths in the nivolumab arm.
Commenting on both the Checkmate 238 trial and a second trial reported at ESMO (COMBI-AD) looking at a combination of dabrafenib and trametinib for patients with stage III melanoma with a BRAF V600 mutation, Olivier Michielin, MD, PhD, said that “we now have, with the data, two fantastic new options. We couldn’t dream those studies to be so positive. This is really something that will open new futures for our patients.”
Dr. Michielin and Dr. Dummer were invited commentators at the briefing. Dr. Michielin was not involved in either trial. Dr. Dummer was a coinvestigator for the COMBI-AD trial.
The study was published simultaneously online by the New England Journal of Medicine.
Checkmate 238 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Weber disclosed honoraria, consulting fees, and travel accommodations/expenses from BMS and multiple other companies. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK. Dr. Dummer reported advising/consulting roles with BMS and others.
MADRID – For patients with resectable stage III melanoma, adjuvant therapy with the programmed death 1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo) was associated with significantly longer relapse-free survival compared with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy), results of a randomized phase 3 trial show.
Among 906 patients who underwent complete resection of stage IIIB, IIIC, or stage IV melanoma in the Checkmate 238 trial, the rates of relapse-free survival (RFS), the primary endpoint, were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab. At 18 months, the respective RFS rates were 66% and 53%, reported Jeffrey Weber, MD, PhD, of NYU Langone Health’s Perlmutter Cancer Center in New York City.
However, longer follow-up will be needed to see whether the RFS advantage of nivolumab translates into an overall survival advantage, he acknowledged.
In the trial, patients with high-risk, completely resected stage IIIB, IIIC, or IV melanoma were stratified by disease stage and PD-L1 status at baseline and randomly assigned in cohorts of 453 patients each to receive either nivolumab 3 mg/kg intravenously every 2 weeks and ipilimumab placebo every 3 weeks for four doses, or to ipilimumab 10 mg/kg IV every 3 weeks for four doses, then every 12 weeks from week 24, and nivolumab placebo IV every 2 weeks.
The maximum duration of therapy was 1 year.
For the primary RFS endpoint, the hazard ratio (HR) favoring nivolumab was 0.65 (P less than .0001).
The benefit for nivolumab was observed across the majority of prespecified subgroups tested, including PD-L1 and BRAF mutational status, Dr. Weber said.
Nivolumab also had a better safety profile, with a 14.4% incidence of grade 3 or 4 treatment-related adverse events, compared with 45.9% for ipilimumab. Grade 3 or 4 treatment-related adverse events leading to discontinuation of therapy occurred in 4.6% of patients on nivolumab, compared with 30.9% of those on ipilimumab.
Two patients in the ipilimumab arm died from toxicities related to therapy, one from marrow aplasia, and one from colitis. Both of these deaths occurred more than 100 days after the patients received their last dose of ipilimumab. There were no treatment-related deaths in the nivolumab arm.
Commenting on both the Checkmate 238 trial and a second trial reported at ESMO (COMBI-AD) looking at a combination of dabrafenib and trametinib for patients with stage III melanoma with a BRAF V600 mutation, Olivier Michielin, MD, PhD, said that “we now have, with the data, two fantastic new options. We couldn’t dream those studies to be so positive. This is really something that will open new futures for our patients.”
Dr. Michielin and Dr. Dummer were invited commentators at the briefing. Dr. Michielin was not involved in either trial. Dr. Dummer was a coinvestigator for the COMBI-AD trial.
The study was published simultaneously online by the New England Journal of Medicine.
Checkmate 238 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Weber disclosed honoraria, consulting fees, and travel accommodations/expenses from BMS and multiple other companies. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK. Dr. Dummer reported advising/consulting roles with BMS and others.
AT ESMO 2017
Key clinical point: Nivolumab improved relapse-free survival over ipilimumab in patients with stage III or IV resectable melanoma.
Major finding: The rates of relapse-free survival were 71% at 12 months for patients assigned to adjuvant nivolumab, compared with 61% for adjuvant ipilimumab.
Data source: Randomized clinical trial in 906 patients with completely resectable stage III melanoma.
Disclosures: Checkmate 238 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Weber disclosed honoraria, consulting fees, and travel accommodations/expenses from BMS and other companies. Dr. Michielin disclosed consulting and/or honoraria from Amgen, BMS, Roche, MSD, Novartis, and GSK.. Dr. Dummer reported advising/consulting roles with BMS and others.
PACIFIC: Durvalumab extends PFS in stage 3 NSCLC
MADRID – For patients with locally advanced, unresectable non-small cell lung cancer, consolidation therapy with the anti-programmed death ligand 1 (PD-L1) inhibitor durvalumab after chemoradiation was associated with significantly better progression-free survival (PFS) than placebo, results of an interim analysis of the phase 3 PACIFIC trial showed.
Among 713 patients with stage III NSCLC treated with definitive chemoradiotherapy, the median PFS from randomization was 16.8 months for patients assigned to durvalumab compared with 5.6 months for patients assigned to placebo, reported Luis Paz-Ares, MD, from the University of Madrid, Spain.
“Overall, we think durvalumab is a promising option for patients with stage III non-small cell lung cancer treated with chemoradiation,” he said at a briefing at the European Society of Medical Oncology (ESMO) Congress.
Approximately 25% to 30% of patients with NSCLC have locally advanced disease at the time of presentation. Patients with unresectable disease and good performance status are treated with chemoradiotheraoy consisting of a platinum doublet with concurrent radiation, but median PFS in these patients is generally short, on the order of 8 months. The 5-year overall survival (OS) rate is 15%, he said.
Given the lack of major advances in the care of patients with stage 3 disease, investigators have been looking to newer therapies such as immune checkpoint inhibitors to see whether they could improve outcomes.
PACIFIC is a phase 3 trial in which patients with stage III NSCLC who did not have disease progression after a minimum of two cycles of platinum-based chemotherapy were assigned on a 2:1 basis to receive intravenous durvalumab 10 mg/kg or placebo every 2 weeks for up to 12 months. Patients were stratified by age, sex, and smoking history.
Dr. Paz-Ares presented PFS results from the interim analysis, planned when about 367 events had occurred. Data on the co-primary endpoint of OS were not mature at the time of the data cutoff.
Median PFS from randomization according to blinded independent central review for 476 patients treated with durvalumab was 16.8 months, compared with 5.6 months for 237 patients who received the placebo. This translated into a stratified hazard ratio (HR) of 0.52 (P less than .0001).
The respective PFS rates for durvalumab and placebo, were 59.9% vs. 35.3% at 12 months, and 44.2% vs. 27% at 18 months.
Among 443 patients on durvalumab and 213 on placebo who were evaluable for objective responses (OR), the respective OR rates were 28.4% vs. 16.
There were 6 complete responses (CR), 120 partial responses (PR), and 233 cases of stable disease in the durvalumab arm, compared with one CR, 33 PR, and 119 cases of stable disease in the placebo arm. In the durvalumab arm, 73 patients (16.5%) had progressive disease, compared with 59 patients (27.7%) in the placebo arm.
The median duration of response was not reached in the durvalumab arm, compared with 13.8 months in the placebo arm.
The PD-L1 inhibitor was also associated with a lower incidence of any new lesion among the intention-to-treat population (20.4% vs. 32.1%).
Grade 3 or 4 toxicities from any cause were slightly higher with durvalumab, at 29.9% vs. 26.1%. Events leading to discontinuation were also higher with the active drug, at 15.4% vs. 9.8% for placebo.
There were 21 deaths (4.4%) of patients treated with durvalumab, and 13 deaths (5.6%) of patients treated with placebo.
“In my opinion, this is a very well-designed study, and the results are very promising,” commented Enriqueta Felip, MD, who was not involved in the PACIFIC trial.
“We need to wait for the overall survival results, but in my opinion this is a very valuable trial in a group of patients [for whom] we need new strategies,” she said.
Dr. Felip was invited to the briefing as an independent commentator.
Results of the interim analysis of the PACIFIC trial were also published online in the New England Journal of Medicine.
The PACIFIC trial was funded by AstraZeneca. Dr. Paz-Ares has received consultancy fees from the company. Dr. Felip disclosed financial relationships with multiple companies not including AstraZeneca.
MADRID – For patients with locally advanced, unresectable non-small cell lung cancer, consolidation therapy with the anti-programmed death ligand 1 (PD-L1) inhibitor durvalumab after chemoradiation was associated with significantly better progression-free survival (PFS) than placebo, results of an interim analysis of the phase 3 PACIFIC trial showed.
Among 713 patients with stage III NSCLC treated with definitive chemoradiotherapy, the median PFS from randomization was 16.8 months for patients assigned to durvalumab compared with 5.6 months for patients assigned to placebo, reported Luis Paz-Ares, MD, from the University of Madrid, Spain.
“Overall, we think durvalumab is a promising option for patients with stage III non-small cell lung cancer treated with chemoradiation,” he said at a briefing at the European Society of Medical Oncology (ESMO) Congress.
Approximately 25% to 30% of patients with NSCLC have locally advanced disease at the time of presentation. Patients with unresectable disease and good performance status are treated with chemoradiotheraoy consisting of a platinum doublet with concurrent radiation, but median PFS in these patients is generally short, on the order of 8 months. The 5-year overall survival (OS) rate is 15%, he said.
Given the lack of major advances in the care of patients with stage 3 disease, investigators have been looking to newer therapies such as immune checkpoint inhibitors to see whether they could improve outcomes.
PACIFIC is a phase 3 trial in which patients with stage III NSCLC who did not have disease progression after a minimum of two cycles of platinum-based chemotherapy were assigned on a 2:1 basis to receive intravenous durvalumab 10 mg/kg or placebo every 2 weeks for up to 12 months. Patients were stratified by age, sex, and smoking history.
Dr. Paz-Ares presented PFS results from the interim analysis, planned when about 367 events had occurred. Data on the co-primary endpoint of OS were not mature at the time of the data cutoff.
Median PFS from randomization according to blinded independent central review for 476 patients treated with durvalumab was 16.8 months, compared with 5.6 months for 237 patients who received the placebo. This translated into a stratified hazard ratio (HR) of 0.52 (P less than .0001).
The respective PFS rates for durvalumab and placebo, were 59.9% vs. 35.3% at 12 months, and 44.2% vs. 27% at 18 months.
Among 443 patients on durvalumab and 213 on placebo who were evaluable for objective responses (OR), the respective OR rates were 28.4% vs. 16.
There were 6 complete responses (CR), 120 partial responses (PR), and 233 cases of stable disease in the durvalumab arm, compared with one CR, 33 PR, and 119 cases of stable disease in the placebo arm. In the durvalumab arm, 73 patients (16.5%) had progressive disease, compared with 59 patients (27.7%) in the placebo arm.
The median duration of response was not reached in the durvalumab arm, compared with 13.8 months in the placebo arm.
The PD-L1 inhibitor was also associated with a lower incidence of any new lesion among the intention-to-treat population (20.4% vs. 32.1%).
Grade 3 or 4 toxicities from any cause were slightly higher with durvalumab, at 29.9% vs. 26.1%. Events leading to discontinuation were also higher with the active drug, at 15.4% vs. 9.8% for placebo.
There were 21 deaths (4.4%) of patients treated with durvalumab, and 13 deaths (5.6%) of patients treated with placebo.
“In my opinion, this is a very well-designed study, and the results are very promising,” commented Enriqueta Felip, MD, who was not involved in the PACIFIC trial.
“We need to wait for the overall survival results, but in my opinion this is a very valuable trial in a group of patients [for whom] we need new strategies,” she said.
Dr. Felip was invited to the briefing as an independent commentator.
Results of the interim analysis of the PACIFIC trial were also published online in the New England Journal of Medicine.
The PACIFIC trial was funded by AstraZeneca. Dr. Paz-Ares has received consultancy fees from the company. Dr. Felip disclosed financial relationships with multiple companies not including AstraZeneca.
MADRID – For patients with locally advanced, unresectable non-small cell lung cancer, consolidation therapy with the anti-programmed death ligand 1 (PD-L1) inhibitor durvalumab after chemoradiation was associated with significantly better progression-free survival (PFS) than placebo, results of an interim analysis of the phase 3 PACIFIC trial showed.
Among 713 patients with stage III NSCLC treated with definitive chemoradiotherapy, the median PFS from randomization was 16.8 months for patients assigned to durvalumab compared with 5.6 months for patients assigned to placebo, reported Luis Paz-Ares, MD, from the University of Madrid, Spain.
“Overall, we think durvalumab is a promising option for patients with stage III non-small cell lung cancer treated with chemoradiation,” he said at a briefing at the European Society of Medical Oncology (ESMO) Congress.
Approximately 25% to 30% of patients with NSCLC have locally advanced disease at the time of presentation. Patients with unresectable disease and good performance status are treated with chemoradiotheraoy consisting of a platinum doublet with concurrent radiation, but median PFS in these patients is generally short, on the order of 8 months. The 5-year overall survival (OS) rate is 15%, he said.
Given the lack of major advances in the care of patients with stage 3 disease, investigators have been looking to newer therapies such as immune checkpoint inhibitors to see whether they could improve outcomes.
PACIFIC is a phase 3 trial in which patients with stage III NSCLC who did not have disease progression after a minimum of two cycles of platinum-based chemotherapy were assigned on a 2:1 basis to receive intravenous durvalumab 10 mg/kg or placebo every 2 weeks for up to 12 months. Patients were stratified by age, sex, and smoking history.
Dr. Paz-Ares presented PFS results from the interim analysis, planned when about 367 events had occurred. Data on the co-primary endpoint of OS were not mature at the time of the data cutoff.
Median PFS from randomization according to blinded independent central review for 476 patients treated with durvalumab was 16.8 months, compared with 5.6 months for 237 patients who received the placebo. This translated into a stratified hazard ratio (HR) of 0.52 (P less than .0001).
The respective PFS rates for durvalumab and placebo, were 59.9% vs. 35.3% at 12 months, and 44.2% vs. 27% at 18 months.
Among 443 patients on durvalumab and 213 on placebo who were evaluable for objective responses (OR), the respective OR rates were 28.4% vs. 16.
There were 6 complete responses (CR), 120 partial responses (PR), and 233 cases of stable disease in the durvalumab arm, compared with one CR, 33 PR, and 119 cases of stable disease in the placebo arm. In the durvalumab arm, 73 patients (16.5%) had progressive disease, compared with 59 patients (27.7%) in the placebo arm.
The median duration of response was not reached in the durvalumab arm, compared with 13.8 months in the placebo arm.
The PD-L1 inhibitor was also associated with a lower incidence of any new lesion among the intention-to-treat population (20.4% vs. 32.1%).
Grade 3 or 4 toxicities from any cause were slightly higher with durvalumab, at 29.9% vs. 26.1%. Events leading to discontinuation were also higher with the active drug, at 15.4% vs. 9.8% for placebo.
There were 21 deaths (4.4%) of patients treated with durvalumab, and 13 deaths (5.6%) of patients treated with placebo.
“In my opinion, this is a very well-designed study, and the results are very promising,” commented Enriqueta Felip, MD, who was not involved in the PACIFIC trial.
“We need to wait for the overall survival results, but in my opinion this is a very valuable trial in a group of patients [for whom] we need new strategies,” she said.
Dr. Felip was invited to the briefing as an independent commentator.
Results of the interim analysis of the PACIFIC trial were also published online in the New England Journal of Medicine.
The PACIFIC trial was funded by AstraZeneca. Dr. Paz-Ares has received consultancy fees from the company. Dr. Felip disclosed financial relationships with multiple companies not including AstraZeneca.
AT ESMO 2017