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Pembrolizumab improves OS in advanced urothelial carcinoma
Second-line pembrolizumab extended OS with a low rate of adverse events compared with chemotherapy in patients with platinum-refractory advanced urothelial carcinoma, according to a phase 3 study presented at the Genitourinary Cancers Symposium and published simultaneously in The New England Journal of Medicine.
“For the first time, after more than 30 years of clinical research, immunotherapy shows a survival advantage compared with chemotherapy in second-line metastatic urothelial cancer,” Joaquim Bellmunt, MD, PhD, associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center at Dana-Farber Cancer Institute, told HemOnc Today. “In Europe, vinflunine (Javlor, Pierre Fabre) was approved for second-line use, but with limited benefit.”
Urothelial carcinoma affects an estimated 76,000 people in the United States each year, resulting in about 1,600 deaths annually.
There are currently two FDA–approved checkpoint inhibitors for bladder cancer refractory to platinum chemotherapy. Atezolizumab (Tecentriq, Genentech) was approved in May 2016, and nivolumab (Opdivo, Bristol-Myers Squibb) was approved in February. Both were approved based on single-arm phase 2 studies — IMvigor 210 and CheckMate 275 — and on the observed response rates.
“The FDA granted approval of these two drugs due to the lack of any active agent in that space,” Bellmunt said.
In the open-label, international KEYNOTE-045 trial, Bellmunt and colleagues randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed following platinum-based chemotherapy to receive 200 mg pembrolizumab (Keytruda, Merck) every 3 weeks or researchers’ choice of chemotherapy with paclitaxel, docetaxel or vinflunine.
OS and PFS served as primary endpoints among all patients and among those who had a tumor PD-L1 combined positive score of 10% or more.
The median OS was 10.3 months (95% CI, 8-11.8) among all patients treated with pembrolizumab compared with 7.4 months (95% CI, 6.1-8.3) in the chemotherapy group (HR = 0.73; 95% CI, 0.59-0.91).
The median OS among patients who had a tumor PD-L1 combined positive score of 10% or more was 8 months (95% CI, 5.0-12.3) in the pembrolizumab group, compared with 5.2 months (95% CI, 4.0-7.4) in the chemotherapy group (HR = 0.57; 95% CI, 0.37-0.88).
“Although it is not scientifically correct due to the lack of head-to-head comparisons, the median survival and overall response rate, including complete responses, are among the highest seen using checkpoint inhibitors,” Bellmunt said.
There were no significant differences in the duration of PFS in the total population and PD-L1–positive patients.
Patients in the pembrolizumab group reported fewer treatment-related adverse events of any grade compared with the chemotherapy group (60.9% vs. 90.2%). There also were fewer adverse events of grade 3, 4 or 5 in the pembrolizumab group (15% vs. 49.4%).
“If this is the first agent to show a statistically significant survival in this setting, the rationale is that this will be an obvious addition to standard of care,” Bellmunt said. “Results of ongoing phase 3 trials in the same setting are eagerly awaited.”
The KEYNOTE-045 trial will have a “practice-changing effect” on the treatment of bladder cancer, but also provokes three questions, Guru Sonpavde, MD, associate professor of medicine at University of Alabama in Birmingham, noted in an accompanying editorial.
“First, is there a preferred agent among pembrolizumab, nivolumab, and atezolizumab?” he wrote. “Second, when should PD-1 or PD-L1 inhibitor therapy be discontinued? And third, can a biomarker inform the selection of patients?”
Sonpavde noted that, in the absence of a randomized trial comparing these three immunotherapies, it is not possible to choose from them objectively.
“As we celebrate that 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,” Sonpavde wrote. “Patients who require salvage therapy remain incurable. Studies have highlighted the extraordinary molecular heterogeneity of urothelial carcinoma. Therefore, clinical trials evaluating biologic agents for rationally selected patients who have an elevated level of the molecular target of the drug in the tumor, potentially in combination with PD-1 and PD-L1 inhibitors, may yield further increments and are being pursued.
“Moreover, PD-1 and PD-L1 inhibitors are active as first-line therapy,” Sonpavde added. “Indeed, they are being investigated in randomized phase 3 trials assessing their use as first-line therapy in combination with platinum-based chemotherapy and CTLA-4–inhibiting immune modulators and as adjuvant therapy after surgery for high-risk disease.” – by Chuck Gormley
For more information:
Joaquim Bellmunt, MD , PhD, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215; email: joaquim_bellmunt@dfci.harvard.edu.
Disclosure: Bellmunt reports personal fees from Merck and Genentech outside the submitted work. Please see the full study for a list of all other researchers’ relevant financial disclosures. Sonpavde reports grant support from Bayer, Biotheranostics, Boehringer-Ingelheim and Onyx-Amgen; grant support and personal fees from Merck; and personal fees from Agensys, Amgen, Argos, AstraZeneca, Bristol-Myers Squibb, Clinical Care Options, Eisai, Exelixis, Genentech, Janssen, the National Comprehensive Cancer Network, Novartis, Pfizer, Sanofi and UpToDate outside the submitted work.
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Elizabeth Plimack
This is the first randomized phase 3 trial of a PD-1 inhibitor in bladder cancer to report out. This study randomly assigned patients who had prior platinum-based chemotherapy to pembrolizumab (Keytruda, Merck) vs. either paclitaxel, docetaxel or vinflunine. The results show absolute OS improvement of 3 months in in the patients treated with pembrolizumab compared with chemotherapy. Although the incremental improvement may at first glance appear low, in a population where the median OS has historically been 6 to 9 months, this is meaningful. Interestingly, the PD-L1 biomarker did not enrich for responses to pembrolizumab, although it may be prognostic for better outcome. Importantly, the safety and tolerability profile was better with pembrolizumab compared with chemotherapy. Currently atezolizumab (Tecentriq, Genentech) and nivolumab (Opdivo, Bristol-Myers Squibb) are FDA–approved treatments in this setting. We anticipate, based on this report, that pembrolizumab is soon to follow.