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Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer.

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Affiliations

  • 1. From Sorbonne Université and Hôpital Saint Antoine, Paris (T.A.), Bordeaux University Hospital, Bordeaux (D.S.), and Léon Bérard Center, Lyon (C.F.) - all in France; University College Hospital, NHS Foundation Trust, London (K.-K.S.); Asan Medical Center, University of Ulsan, Seoul, South Korea (T.W.K.); Herlev and Gentofte Hospital, Herlev (B.V.J.), and University Hospital of Southern Denmark, Vejle (L.H.J.) - both in Denmark; Amsterdam University Medical Center, University of Amsterdam, Amsterdam (C.P.); Hospital Universitario 12 de Octubre, Imas12, Madrid (R.G.-C.), Hospital Regional Universitario, Malaga (M.B.), Hospital Universitario Marques de Valdecilla, Santander (F.R.), and Vall d'Hebron Institute of Oncology, Barcelona (E.E.) - all in Spain; Western Health, St. Albans, VIC, Australia (P.G.); Sarah Cannon Research Institute-Tennessee Oncology, Nashville (J.B.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (D.T.L.); National Cancer Center Hospital East, Kashiwa, Japan (T.Y.); University Hospital Gasthuisberg and KU Leuven, Leuven, Belgium (E.V.C.); MSD China, Beijing (P.Y.); Merck, Kenilworth, NJ (M.Z.H.F., P.M.); and Memorial Sloan Kettering Cancer Center, New York (L.A.D.).
      Authors
    • André T 1
    • Shiu KK 1
    • Kim TW 1
    • Jensen BV 1
    • Jensen LH 1
    • Punt C 1
    • Smith D 1
    • Garcia-Carbonero R 1
    • Benavides M 1
    • Gibbs P 1
    • de la Fouchardiere C 1
    • Rivera F 1
    • Elez E 1
    • Bendell J 1
    • Le DT 1
    • Yoshino T 1
    • Van Cutsem E 1
    • Yang P 1
    • Farooqui MZH 1
    • Marinello P 1
    • Diaz LA Jr 1
    (21 authors)

ORCIDs linked to this article

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The New England Journal of Medicine, 01 Dec 2020, 383(23):2207-2218
https://doi.org/10.1056/nejmoa2017699 PMID: 33264544 

A comment on this article appears in "The Evolving Personalized Landscape of Colorectal Cancer Therapies." Int J Radiat Oncol Biol Phys. 2021 Aug 1;110(5):1255-1262. A comment on this article appears in "Microsatellite-Instability-High Advanced Colorectal Cancer." N Engl J Med. 2021 Mar 11;384(10):971-972. A comment on this article appears in "Microsatellite-Instability-High Advanced Colorectal Cancer." N Engl J Med. 2021 Mar 11;384(10):972. Show all (5)

Abstract 

Background

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 efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown.

Methods

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. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival.

Results

At 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. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). 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). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. 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. 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. 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.

Conclusions

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. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).

Full text links 

Read article at publisher's site: https://doi.org/10.1056/nejmoa2017699

Read article for free, from open access legal sources, via Unpaywall: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2017699?articleTools=trueUnpaywall

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Funding 

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Merck (1)