Patients in the SOC arm who have PD and meet crossover criteria may be eligible to receive pembrolizumab for up to 17 treatment cycles. Eligible patients may continue pembrolizumab beyond initial RECIST-defined progression. Response is to be assessed every 9 weeks per RECIST v1.1 by central imaging vendor review and per RECIST adapted for immunotherapy response patterns. Treatment is to continue until progressive disease (PD), unacceptable toxicity, patient/investigator decision, or completion of 35 cycles (pembrolizumab only). ~270 patients will be randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 weeks or investigator's choice of SOC chemotherapy (mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab, chosen before randomization). Methods: Key eligibility criteria include age ≥18 years, confirmed MSI-high or MMR-deficient metastatic CRC, ECOG PS 0-1, no active autoimmune disease or brain metastases, and no prior therapy for metastatic disease. KEYNOTE-177 (, NCT02563002) is an international, randomized, open-label, phase 3 study of pembrolizumab versus standard-of-care (SOC) chemotherapy in first-line MMR-deficient or MSI-high metastatic CRC. In the phase 2 KEYNOTE-016 study, the anti–PD-1 antibody pembrolizumab demonstrated antitumor activity against MMR-deficient tumors in patients with treatment-refractory metastatic CRC. MSI-high tumors contain high levels of lymphocyte infiltrates and express the PD-1 immune checkpoint receptor and its ligand, PD-L1. No deaths attributed to pembrolizumab occurred one deathĭue to intestinal perforation was attributed to chemotherapy.Background: A subset of colorectal carcinomas (CRCs) are characterized by mismatch repair (MMR) deficiency resulting in microsatellite instability (MSI). Occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients Serious adverse events attributed to study treatment Were decreased neutrophil count (in 24 patients), neutropenia (22 ), diarrhoea That were attributed to pembrolizumab were increased alanine aminotransferase, colitis,ĭiarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy Common adverse events of grade 3 or worse Occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) ofġ43 patients in the chemotherapy group. Treatment-related adverse events of grade 3 or worse Months (95% CI 5♴–38♱) with pembrolizumab versus 8♲ months (6♱–10♲) with chemotherapy At this updated analysis, median progression-free survival was 16♵ Not demonstrated because the prespecified α of 0♰25 needed for statistical significance Superiority of pembrolizumab versus chemotherapy for overall survival was Reached (NR 95% CI 49♲–NR) with pembrolizumab vs 36♷ months (27♶–NR) with chemotherapy (hazard ratio 0♷4 95% CI 0♵3–1♰3 (median follow-up of 44♵ months ), median overall survival was not To on-study pembrolizumab and 37 patients to off-study therapy). Patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy (56 patients Were randomly assigned to pembrolizumab (n=153) or chemotherapy (n=154). Is registered at, NCT02563002, and is no longer enrolling patients. Survival and progression-free survival in the intention-to-treat population. Patients receiving chemotherapy could cross over to pembrolizumabįor up to 35 treatment cycles after progression. MFOLFOX6 (oxaliplatin 85 mg/m 2 on day 1, leucovorin 400 mg/m 2 on day 1, and fluorouracil 400 mg/m 2 bolus on day 1 followed by a continuous infusion of 1200 mg/m 2 per day for 2 days on days 1–2) or intravenous FOLFIRI (irinotecan 180 mg/m 2 on day 1, leucovorin 400 mg/m 2 on day 1, and fluorouracil 400 mg/m 2 bolus on day 1 followed by a continuous infusion of 1200 mg/m 2 per day for 2 days on days 1–2), every 2 weeks with or without intravenous bevacizumabĥ mg/kg every 2 weeks or intravenous weekly cetuximab (first dose 400 mg/m 2, then 250 mg/m 2 for every subsequent dose). Pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous Interactive voice response system or integrated web response system to intravenous Patients were randomly assigned (1:1) in blocks of four using an Untreated microsatellite instability-high or mismatch repair-deficient metastaticĬolorectal cancer. We recruited patients aged at least 18 years, withĪn Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously This randomised, open-label, phase 3 study was done in 193 academic medical centresĪnd hospitals in 23 countries. The Lancet Regional Health – Western Pacific.The Lancet Regional Health – Southeast Asia.The Lancet Gastroenterology & Hepatology.
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