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Keynote 1773/19/2023 The majority (approximately 80%) of cases of sporadic dMMR colorectal cancer are caused by methylation of the MLH1 gene promoter, whereas more than 70% of hereditary cases are associated with germline mutations in the MLH1 and MSH2 genes. One well-described genetic subset of colorectal cancer is tumors with mismatch-repair deficiency (dMMR), which are found in 15% of all patients with colorectal cancer (12% of whom have sporadic cases, and 3% hereditary cases). Patients with newly diagnosed metastatic colorectal cancer are treated with 5-fluorouracil (5-FU)–based regimens, such as FOLFOX (5-FU, oxaliplatin, and leucovorin) or FOLFIRI (5-FU, irinotecan, and leucovorin) alone or in combination with therapies that block epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) signaling. 1-3 Despite well-known genetic differences in the disease, chemotherapy treatment of colorectal cancer is largely uniform. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer KEYNOTE-177 number, NCT02563002.) IntroductionĬolorectal cancer is clinically defined by its tissue of origin in the colon or rectum, but it is a heterogeneous disease classified by its genetics. Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H–dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). ResultsĪt the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. The two primary end points were progression-free survival and overall survival. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. In this phase 3, open-label trial, 307 patients with metastatic MSI-H–dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil–based therapy with or without bevacizumab or cetuximab) every 2 weeks. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H–dMMR advanced or metastatic colorectal cancer is unknown. Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) tumors after previous therapy. The most trusted, influential source of new medical knowledge and clinical best practices in the world. Information and tools for librarians about site license offerings. Valuable tools for building a rewarding career in health care. The authorized source of trusted medical research and education for the Chinese-language medical community. The most advanced way to teach, practice, and assess clinical reasoning skills. Information, resources, and support needed to approach rotations - and life as a resident. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. NEW! Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery.Ĭoncise summaries and expert physician commentary that busy clinicians need to enhance patient care. NEW! A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making.
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