Merck & Co. on Monday said it is voluntarily withdrawing the US indication for Keytruda (pembrolizumab) for the treatment of patients with metastatic small-cell lung cancer (SCLC) who experience disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. The decision comes after Merck released data in January last year from the confirmatory Phase III KEYNOTE-604 trial showing that while the anti-PD-1 therapy significantly improved progression-free survival (PFS), it missed the study's other dual primary endpoint of overall survival (OS).
Keytruda's accelerated approval in SCLC was granted in 2019 based on tumour response rate and durability of response data from specific cohorts of the KEYNOTE-158 and KEYNOTE-028 studies, with continued approval hinging on post-marketing data demonstrating superiority with respect to OS. KEYNOTE-604 involved 453 patients with previously untreated extensive-stage SCLC who were randomised to receive Keytruda or placebo, both in addition to standard chemotherapy.
At the time of the second interim analysis, which was the pre-specified final analysis for PFS, and was conducted at a median follow-up of 13.5 months, median PFS was 4.5 months for the Keytruda group, compared with 4.3 months for placebo. By the final analysis, at 21.6 months of median follow-up, Keytruda plus chemotherapy prolonged OS compared to placebo, with survival times of 10.8 months versus 9.7 months, respectively, but the significance threshold was not met.
According to Merck, its consultation with the FDA on this withdrawal is part of "an industry-wide evaluation of indications based on accelerated approvals that have not yet met their post-marketing requirements." The withdrawal follows a similar move in December when Bristol Myers Squibb pulled the SCLC indication for the PD-1 inhibitor Opdivo (nivolumab) in the US after confirmatory studies, including the Phase III CheckMate -331 trial, failed to meet their primary endpoints.
Other treatments currently approved by the FDA for SCLC include AstraZeneca's PD-L1 immunotherapy Imfinzi (durvalumab), which showed a significant survival benefit in the Phase III CASPIAN study when administered along with chemotherapy, but not when the anti-CTLA4 antibody tremelimumab was added to the regimen. Meanwhile, Roche's Tecentriq (atezolizumab), in combination with chemotherapy, was approved in 2019 for the first-line treatment of adults with extensive-stage SCLC based on the Phase III IMpower133 study, which showed that the PD-L1 inhibitor plus chemotherapy helped people live significantly longer compared to chemotherapy alone.
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