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Treatment with checkpoint inhibitor pembrolizumab is associated with significant gains in overall survival among patients with treatment-refractory advanced urothelial carcinoma, according to new research.
Data from the KEYNOTE-045 trial was presented simultaneously at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, and published in the New England Journal of Medicine.
The open-label, international phase III trial involved 542 patients with advanced urothelial carcinoma that had recurred or progressed after platinum-based chemotherapy. Participants were randomized either to 200 mg pembrolizumab every 3 weeks, or the investigator’s choice of paclitaxel, docetaxel, or vinflunine chemotherapy.
After a median follow-up of 14.1 months, researchers saw a 27% lower hazard ratio for death among the pembrolizumab group, compared with the chemotherapy group (P = .002), with a median overall survival of 10.3 months with pembrolizumab, compared with 7.4 months with chemotherapy (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMoa1613683).
The estimated overall survival rate at 1 year was 43.9% among those treated with pembrolizumab and 30.7% in the chemotherapy group. The authors also saw no significant differences when each chemotherapy regimen was examined separately.
Patients treated with pembrolizumab also showed a significant higher objective response rate, compared with those treated with chemotherapy (21.1% vs. 11.4%, P = .001). At the time of data cut-off, 72% of patients in the pembrolizumab group showed a continued response, compared with 35% of the chemotherapy group.
“Most responses in patients in the pembrolizumab group occurred quickly and were reported at the first scheduled imaging assessment,” wrote Joaquim Bellmunt, MD, PhD, from the Dana-Farber Cancer Institute, Boston and his coauthors. “Continued disease regression over time in some patients resulted in radiologically confirmed responses that were reported as long as 6.3 months after the start of therapy.”
They also looked at how the level of programmed death 1 ligand (PD-L1) expression in the tumor influenced response by examining outcomes in a subgroup of patients whose tumor PD-L1 combined positive score – the percentage of PD-L1 expressing tumor and infiltrating immune cells relative to the total number of tumor cells – exceeded 10%.
In this group, median overall survival was 8 months with pembrolizumab, compared with 5.2 months with chemotherapy, representing a significant 43% reduction in mortality with immunotherapy.
There was an interaction between smoking status and response, with current smokers showing a significantly greater response that favored pembrolizumab. The authors pointed out that this effect has also been observed in other advanced cancers, and may reflect the impact of a greater mutational load in the cancers of smokers.
The study did not find any difference in the duration of progression-free survival between the two groups, nor among participants with a PD-L1 combined positive score of 10% of more. Median progression-free survival was 2.1 months in the pembrolizumab group and 3.3 months in the chemotherapy group.
Researchers also noted a lower rate of adverse events among patients treated with pembrolizumab, compared with chemotherapy. Treatment-related adverse events of grade 3-5 occurred in 49.4% of patients on chemotherapy, compared with 15% of those on pembrolizumab.
There was one death from treatment-related pneumonitis in the pembrolizumab group, and three deaths attributed to the study treatment; one urinary tract obstruction, one malignant neoplasm, and one unspecified cause. In the chemotherapy group, there were two treatment-related deaths from sepsis, one from septic shock, and one unspecified.
The most common adverse events with chemotherapy were alopecia, fatigue, and anemia, while in the pembrolizumab group the most common side effects were pruritis, fatigue, and nausea.
The study was supported by Merck. Sixteen authors declared personal fees, grants, honoraria, consultancies, and advisory board positions with pharmaceutical companies including Merck, three authors were employees of Merck with stock options, and one had nothing to declare.
In the context of cancer therapy, PD-L1 and PD-1 inhibitors may be aptly described as the metaphorical rising tide that lifts all boats. These monoclonal antibodies have yielded major advances across multiple malignant conditions by unleashing the antitumor activity of T-lymphocytes by targeting this T-cell inhibitory pathway.
The KEYNOTE-045 trial will have a practice-changing effect. The longer survival and lower rate of toxic adverse effects with pembrolizumab than with chemotherapy confer an improved therapeutic index in these generally elderly patients with coexisting conditions. As we celebrate the major advance that is provided by pembrolizumab, it is important to remember that this remains an incremental advance overall, although the responses were remarkably durable.
Guru Sonpavde, MD, is from the University of Alabama at Birmingham Comprehensive Cancer Center. These comments are taken from an accompanying editorial (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMe1701182). Dr. Sonpavde reported a range of grants and personal fees from the pharmaceutical industry, including from Merck.
In the context of cancer therapy, PD-L1 and PD-1 inhibitors may be aptly described as the metaphorical rising tide that lifts all boats. These monoclonal antibodies have yielded major advances across multiple malignant conditions by unleashing the antitumor activity of T-lymphocytes by targeting this T-cell inhibitory pathway.
The KEYNOTE-045 trial will have a practice-changing effect. The longer survival and lower rate of toxic adverse effects with pembrolizumab than with chemotherapy confer an improved therapeutic index in these generally elderly patients with coexisting conditions. As we celebrate the major advance that is provided by pembrolizumab, it is important to remember that this remains an incremental advance overall, although the responses were remarkably durable.
Guru Sonpavde, MD, is from the University of Alabama at Birmingham Comprehensive Cancer Center. These comments are taken from an accompanying editorial (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMe1701182). Dr. Sonpavde reported a range of grants and personal fees from the pharmaceutical industry, including from Merck.
In the context of cancer therapy, PD-L1 and PD-1 inhibitors may be aptly described as the metaphorical rising tide that lifts all boats. These monoclonal antibodies have yielded major advances across multiple malignant conditions by unleashing the antitumor activity of T-lymphocytes by targeting this T-cell inhibitory pathway.
The KEYNOTE-045 trial will have a practice-changing effect. The longer survival and lower rate of toxic adverse effects with pembrolizumab than with chemotherapy confer an improved therapeutic index in these generally elderly patients with coexisting conditions. As we celebrate the major advance that is provided by pembrolizumab, it is important to remember that this remains an incremental advance overall, although the responses were remarkably durable.
Guru Sonpavde, MD, is from the University of Alabama at Birmingham Comprehensive Cancer Center. These comments are taken from an accompanying editorial (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMe1701182). Dr. Sonpavde reported a range of grants and personal fees from the pharmaceutical industry, including from Merck.
Treatment with checkpoint inhibitor pembrolizumab is associated with significant gains in overall survival among patients with treatment-refractory advanced urothelial carcinoma, according to new research.
Data from the KEYNOTE-045 trial was presented simultaneously at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, and published in the New England Journal of Medicine.
The open-label, international phase III trial involved 542 patients with advanced urothelial carcinoma that had recurred or progressed after platinum-based chemotherapy. Participants were randomized either to 200 mg pembrolizumab every 3 weeks, or the investigator’s choice of paclitaxel, docetaxel, or vinflunine chemotherapy.
After a median follow-up of 14.1 months, researchers saw a 27% lower hazard ratio for death among the pembrolizumab group, compared with the chemotherapy group (P = .002), with a median overall survival of 10.3 months with pembrolizumab, compared with 7.4 months with chemotherapy (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMoa1613683).
The estimated overall survival rate at 1 year was 43.9% among those treated with pembrolizumab and 30.7% in the chemotherapy group. The authors also saw no significant differences when each chemotherapy regimen was examined separately.
Patients treated with pembrolizumab also showed a significant higher objective response rate, compared with those treated with chemotherapy (21.1% vs. 11.4%, P = .001). At the time of data cut-off, 72% of patients in the pembrolizumab group showed a continued response, compared with 35% of the chemotherapy group.
“Most responses in patients in the pembrolizumab group occurred quickly and were reported at the first scheduled imaging assessment,” wrote Joaquim Bellmunt, MD, PhD, from the Dana-Farber Cancer Institute, Boston and his coauthors. “Continued disease regression over time in some patients resulted in radiologically confirmed responses that were reported as long as 6.3 months after the start of therapy.”
They also looked at how the level of programmed death 1 ligand (PD-L1) expression in the tumor influenced response by examining outcomes in a subgroup of patients whose tumor PD-L1 combined positive score – the percentage of PD-L1 expressing tumor and infiltrating immune cells relative to the total number of tumor cells – exceeded 10%.
In this group, median overall survival was 8 months with pembrolizumab, compared with 5.2 months with chemotherapy, representing a significant 43% reduction in mortality with immunotherapy.
There was an interaction between smoking status and response, with current smokers showing a significantly greater response that favored pembrolizumab. The authors pointed out that this effect has also been observed in other advanced cancers, and may reflect the impact of a greater mutational load in the cancers of smokers.
The study did not find any difference in the duration of progression-free survival between the two groups, nor among participants with a PD-L1 combined positive score of 10% of more. Median progression-free survival was 2.1 months in the pembrolizumab group and 3.3 months in the chemotherapy group.
Researchers also noted a lower rate of adverse events among patients treated with pembrolizumab, compared with chemotherapy. Treatment-related adverse events of grade 3-5 occurred in 49.4% of patients on chemotherapy, compared with 15% of those on pembrolizumab.
There was one death from treatment-related pneumonitis in the pembrolizumab group, and three deaths attributed to the study treatment; one urinary tract obstruction, one malignant neoplasm, and one unspecified cause. In the chemotherapy group, there were two treatment-related deaths from sepsis, one from septic shock, and one unspecified.
The most common adverse events with chemotherapy were alopecia, fatigue, and anemia, while in the pembrolizumab group the most common side effects were pruritis, fatigue, and nausea.
The study was supported by Merck. Sixteen authors declared personal fees, grants, honoraria, consultancies, and advisory board positions with pharmaceutical companies including Merck, three authors were employees of Merck with stock options, and one had nothing to declare.
Treatment with checkpoint inhibitor pembrolizumab is associated with significant gains in overall survival among patients with treatment-refractory advanced urothelial carcinoma, according to new research.
Data from the KEYNOTE-045 trial was presented simultaneously at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, and published in the New England Journal of Medicine.
The open-label, international phase III trial involved 542 patients with advanced urothelial carcinoma that had recurred or progressed after platinum-based chemotherapy. Participants were randomized either to 200 mg pembrolizumab every 3 weeks, or the investigator’s choice of paclitaxel, docetaxel, or vinflunine chemotherapy.
After a median follow-up of 14.1 months, researchers saw a 27% lower hazard ratio for death among the pembrolizumab group, compared with the chemotherapy group (P = .002), with a median overall survival of 10.3 months with pembrolizumab, compared with 7.4 months with chemotherapy (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMoa1613683).
The estimated overall survival rate at 1 year was 43.9% among those treated with pembrolizumab and 30.7% in the chemotherapy group. The authors also saw no significant differences when each chemotherapy regimen was examined separately.
Patients treated with pembrolizumab also showed a significant higher objective response rate, compared with those treated with chemotherapy (21.1% vs. 11.4%, P = .001). At the time of data cut-off, 72% of patients in the pembrolizumab group showed a continued response, compared with 35% of the chemotherapy group.
“Most responses in patients in the pembrolizumab group occurred quickly and were reported at the first scheduled imaging assessment,” wrote Joaquim Bellmunt, MD, PhD, from the Dana-Farber Cancer Institute, Boston and his coauthors. “Continued disease regression over time in some patients resulted in radiologically confirmed responses that were reported as long as 6.3 months after the start of therapy.”
They also looked at how the level of programmed death 1 ligand (PD-L1) expression in the tumor influenced response by examining outcomes in a subgroup of patients whose tumor PD-L1 combined positive score – the percentage of PD-L1 expressing tumor and infiltrating immune cells relative to the total number of tumor cells – exceeded 10%.
In this group, median overall survival was 8 months with pembrolizumab, compared with 5.2 months with chemotherapy, representing a significant 43% reduction in mortality with immunotherapy.
There was an interaction between smoking status and response, with current smokers showing a significantly greater response that favored pembrolizumab. The authors pointed out that this effect has also been observed in other advanced cancers, and may reflect the impact of a greater mutational load in the cancers of smokers.
The study did not find any difference in the duration of progression-free survival between the two groups, nor among participants with a PD-L1 combined positive score of 10% of more. Median progression-free survival was 2.1 months in the pembrolizumab group and 3.3 months in the chemotherapy group.
Researchers also noted a lower rate of adverse events among patients treated with pembrolizumab, compared with chemotherapy. Treatment-related adverse events of grade 3-5 occurred in 49.4% of patients on chemotherapy, compared with 15% of those on pembrolizumab.
There was one death from treatment-related pneumonitis in the pembrolizumab group, and three deaths attributed to the study treatment; one urinary tract obstruction, one malignant neoplasm, and one unspecified cause. In the chemotherapy group, there were two treatment-related deaths from sepsis, one from septic shock, and one unspecified.
The most common adverse events with chemotherapy were alopecia, fatigue, and anemia, while in the pembrolizumab group the most common side effects were pruritis, fatigue, and nausea.
The study was supported by Merck. Sixteen authors declared personal fees, grants, honoraria, consultancies, and advisory board positions with pharmaceutical companies including Merck, three authors were employees of Merck with stock options, and one had nothing to declare.
FROM THE GENITOURINARY CANCERS SYMPOSIUM
Key clinical point: Pembrolizumab is associated with significant gains in overall survival among patients with treatment-refractory advanced urothelial carcinoma.
Major finding: Patients treated with pembrolizumab had a 27% lower mortality, compared with those treated with chemotherapy.
Data source: The KEYNOTE-045 open-label, international phase III trial in 542 patients with advanced urothelial carcinoma.
Disclosures: The study was supported by Merck. Sixteen authors declared personal fees, grants, honoraria, consultancies, and advisory board positions with pharmaceutical companies including Merck, three authors were employees of Merck with stock options, and one had nothing to declare.