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    Immunotherapy found efficacious as second-line therapy

    Results of KEYNOTE-045, an international randomized phase III study, show that pembrolizumab (Keytruda) as second-line therapy for advanced urothelial carcinoma (UC) provided superior overall survival and a better safety profile compared with commonly used chemotherapy options.

    The findings were published online in the New England Journal of Medicine (Feb. 17, 2017). As reported at the Genitourinary Cancers Symposium in Orlando, FL, pembrolizumab was also associated with substantially better health-related quality of life relative to chemotherapy, said Joaquim Bellmunt, MD, PhD.

    Dr. Bellmunt, of Harvard Medical School and Dana-Farber Cancer Institute, Boston, is lead author of the New England Journal of Medicine study. He told Urology Times, “Pembrolizumab is the first and, at this point, the only checkpoint inhibitor to demonstrate an overall survival advantage over chemotherapy for advanced UC in a randomized phase III study. Pembrolizumab is also the only checkpoint inhibitor to demonstrate a substantial improvement in health-related quality of life in patients with advanced UC.”

    “Nivolumab (Opdivo), atezolizumab (Tecentriq), and durvalumab have demonstrated promising outcomes as second-line therapy for advanced UC in phase II studies, and data from phase III trials for some of these checkpoint inhibitors are eagerly awaited.”

    Patients enrolled in KEYNOTE-045 had advanced UC that recurred or progressed after platinum-based chemotherapy. A total of 542 patients were randomized to receive pembrolizumab, 200 mg every 3 weeks or the investigator’s choice of chemotherapy with paclitaxel (Taxol), docetaxel (Taxotere), or vinflunine.

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    After a median follow-up duration of 14.1 months, there were a total of 334 deaths. Median overall survival was approximately 3 months longer in patients treated with pembrolizumab compared with the control group (10.3 months vs. 7.4 months; hazard ratio for death 0.73, p=.002). Estimated survival rate at 12 months was 43.9% for pembrolizumab and 30.7% for chemotherapy.

    Subgroup analyses showed that the benefit of pembrolizumab for improving overall survival was consistent regardless of ECOG performance status, tumor programmed death-ligand 1 (PD-L1) expression level, primary tumor location (upper or lower tract), or receipt of one versus two prior therapies for advanced disease.

    Progression-free survival (PFS), which was analyzed as a coprimary endpoint, did not differ significantly between the pembrolizumab and chemotherapy groups (hazard ratio 0.98, p=.42). Pembrolizumab was associated with a significantly higher objective response rate compared with chemotherapy (21.1% vs 11.4%; p=.001).

    Dr. Bellmunt noted that results from several other phase III studies investigating checkpoint inhibitors as second-line therapy in patients with other types of cancer similarly showed no PFS advantage for the immunotherapy compared with chemotherapy or targeted therapy.

    “Improved overall survival benefit remains the gold standard for assessing the benefit of anticancer immunotherapies. The general lack of a PFS benefit for immunotherapy compared with chemotherapy and targeted therapy may reflect underlying differences in mechanism of action, but it is interesting to note that PFS curves do start to separate in favor of immunotherapy at 12 months,” Dr. Bellmunt said.

    Next: Lower rates of treatment-related adverse events, grade 3-5 treatment-related adverse events

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