‘Switch maintenance’ pembrolizumab may benefit patients with metastatic urothelial cancer
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Maintenance pembrolizumab immediately following first-line platinum-based chemotherapy prolonged PFS and led to additional objective responses among a cohort of patients with metastatic urothelial cancer, according to results of a randomized phase 2 study published in Journal of Clinical Oncology.
“Platinum-based chemotherapy has been the standard first-line treatment for metastatic urothelial cancer for decades,” Matthew D. Galsky, MD, director of genitourinary medical oncology and professor of urology, medicine and medical oncology at Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai, told Healio. “Unfortunately, virtually all patients with metastatic urothelial cancer will experience disease progression after stopping chemotherapy. However, we know that if we continue the same platinum-based chemotherapy until progression of cancer, the side effects continue to accumulate but the benefits plateau.”
Five PD-1/PD-L1 inhibitors have been FDA-approved for the treatment of metastatic urothelial cancer that progressed despite prior platinum-based chemotherapy, Galsky added.
“Given that these drugs are noncross-resistant with chemotherapy in at least a subset of patients and because they are well-tolerated by a large proportion of patients, a logical question is, rather than waiting until cancer progresses after stopping first-line chemotherapy, what if we started pembrolizumab [Keytruda, Merck] immediately?” Galsky told Healio.
The double-blind phase 2 study by Galsky and colleagues included 107 patients with metastatic urothelial cancer who achieved at least stable disease during first-line platinum-based chemotherapy. The researchers randomly assigned patients to “switch maintenance” 200 mg IV pembrolizumab (n = 55; median age, 68 years; range, 41-83) once every 3 weeks for a median eight cycles (interquartile range [IQR], 4-15) or placebo (n = 52; median age, 65 years; range, 44-87) for a median six cycles (IQR, 4-9).
PFS served as the primary endpoint. Secondary outcomes included OS and treatment outcomes according to PD-L1 combined positive score.
Median follow-up was 12.9 months (range, 0.9-34.5).
Results showed significantly longer PFS with pembrolizumab compared with placebo (5.4 months vs. 3 months; HR = 0.65; maximum efficacy robust test P = .039).
Median OS was 22 months (95% CI, 12.9 to not reached) with pembrolizumab vs. 18.7 months (95% CI, 11.4 to not reached) with placebo.
Patients demonstrated an ORR of 23% with pembrolizumab, with a 9% complete response rate, vs. 10% with placebo, with no complete responses.
Researchers observed no significant associations for OS or PFS between treatment group and PD-L1 combined positive score of 10 or greater.
More than half of patients (59%) in the pembrolizumab group and 38% of patients in the placebo group experienced grade 3 or grade 4 treatment-associated adverse events. Twenty percent of patients in the pembrolizumab group experienced immune-related adverse events that required systemic steroid treatment. One treatment-related death, due to hepatitis, occurred in the pembrolizumab group.
The 27 patients in the placebo group who crossed over to the pembrolizumab group demonstrated an ORR of 22%. Median PFS from crossover was 2.7 months (95% CI, 2.5-9.3) and median OS was 15.8 months (95% CI, 8 to not reached), according to the study.
“Changing standard of care should be based on larger trials that demonstrate patients live longer with this approach,” Galsky told Healio. “However, [although] our study was the first to test this approach and the first to report the results demonstrating a potential benefit, in January 2020, a press release indicated that a trial with the PD-L1 inhibitor avelumab, rather than the PD-1 inhibitor pembrolizumab we tested, demonstrated an improvement in survival with the switch maintenance approach.”
Avelumab (Bavencio; EMD Serono, Pfizer) received FDA breakthrough therapy designation earlier this month for first-line maintenance treatment of locally advanced or metastatic urothelial carcinoma. The agency based the designation on results of an interim analysis of the randomized phase 3 JAVELIN Bladder 100 trial, which showed statistically significant improvement in OS with first-line avelumab maintenance plus best supportive care vs. best supportive care alone.
“The avelumab study has not yet been presented or published, so we need to wait for final results, but we now have two randomized studies supporting this approach, and once the results of the other study are published, depending on the degree of benefit, it is highly likely that this will become a standard treatment approach,” he added. “Physicians should await the results of the latter study, so that we can interpret the results of the two studies in total, before changing their current approach.” – by Jennifer Southall
For more information:
Matthew D. Galsky, MD, can be reached at Mount Sinai School of Medicine Tisch Cancer Institute, 1 Gustave L Levy Place, New York, NY 10029; email: matthew.galsky@mssm.edu.
Disclosures: Galsky reports advisory roles with AstraZeneca, Bristol-Myers Squibb, Genentech, Merck and Pfizer; grants from Dendreon, Genentech and Merck; personal fees from Aileron, Astellas, AstraZeneca, Bristol-Myers Squibb, Dracen, Dragonfly Therapeutics, EMD Serono, GlaxoSmithKline, Incyte, Inovio, Janssen, Lilly, Novartis, NuMab, Pfizer and Seattle Genetics; and research funding from Bristol-Myers Squibb and Merck. Please see the study for all other authors’ relevant financial disclosures.
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