Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study

Abstract

Background: Pembrolizumab has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. However, the treatment's effect on overall survival in this cohort of patients was unknown. Here, we present the final overall survival analysis of the KEYNOTE-177 study.

Methods: This randomised, open-label, phase 3 study was done in 193 academic medical centres and hospitals in 23 countries. We recruited patients aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Patients were randomly assigned (1:1) in blocks of four using an interactive voice response system or integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous mFOLFOX6 (oxaliplatin 85 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2) or intravenous FOLFIRI (irinotecan 180 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2), every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous weekly cetuximab (first dose 400 mg/m2, then 250 mg/m2 for every subsequent dose). Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 treatment cycles after progression. The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov, NCT02563002, and is no longer enrolling patients.

Findings: Between Feb 11, 2016, and Feb 19, 2018, 852 patients were screened, of whom 307 (36%) were randomly assigned to pembrolizumab (n=153) or chemotherapy (n=154). 93 (60%) patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy (56 patients to on-study pembrolizumab and 37 patients to off-study therapy). At final analysis (median follow-up of 44·5 months [IQR 39·7-49·8]), median overall survival was not reached (NR; 95% CI 49·2-NR) with pembrolizumab vs 36·7 months (27·6-NR) with chemotherapy (hazard ratio [HR] 0·74; 95% CI 0·53-1·03; p=0·036). Superiority of pembrolizumab versus chemotherapy for overall survival was not demonstrated because the prespecified α of 0·025 needed for statistical significance was not achieved. At this updated analysis, median progression-free survival was 16·5 months (95% CI 5·4-38·1) with pembrolizumab versus 8·2 months (6·1-10·2) with chemotherapy (HR 0·59, 95% CI 0·45-0·79). Treatment-related adverse events of grade 3 or worse occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) of 143 patients in the chemotherapy group. Common adverse events of grade 3 or worse that were attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy were decreased neutrophil count (in 24 [17%] patients), neutropenia (22 [15%]), diarrhoea (14 [10%]), and fatigue (13 [9%]). Serious adverse events attributed to study treatment occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients in the chemotherapy group. No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy.

Interpretation: In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.

Funding: MSD.

Conflict of interest statement

Declaration of Interests LAD Jr reports membership on the board of directors of Personal Genome Diagnostics and Jounce Therapeutics; honoraria for consulting and advisory role to Personal Genome Diagnostics, 4Paws, and Neophore; uncompensated advisory and consulting role for Merck Sharp & Dohme; clinical trial funding paid to institution from Merck Sharp & Dohme; and patents for circulating tumour DNA analyses and mismatch repair deficiency for diagnosis and therapy with checkpoint blockade from Johns Hopkins University, the latter licensed to Personal Genome Diagnostics and Qiagen (some licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and LAD Jr); and equity in 4Paws, Personal Genome Diagnostics, Jounce Therapeutics, Thrive Earlier Detection and Neophore; his spouse holds equity in Amgen. The terms of all these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. K-KS reports honoraria including compensation for travel, accommodation, and expenses from Bayer, Bristol Myers Squibb, Guardant Health, Daiichi-Sankyo, Innovent Biologics, Merck KGaA, Merck Sharp & Dohme, Mirati Therapeutics, Roche, and Servier; and Institutional Funding for Research from Adaptimmune Therapeutics, AstraZeneca, Merck KGaA, Merck Sharp & Dohme, and Roche. T-WK reports clinical trial funding paid to institution from Merck Sharp & Dohme and Merck Serono. BVJ, DS, MB, and PG report clinical trial funding paid to institution funding paid to institution from Merck Sharp & Dohme. LHJ reports research funding to the institution from Merck Sharp & Dohme, 2cureX, Incyte, and Bristol Myers Squibb. CP reports research funding to the institution from Merck Sharp & Dohme; and a consulting and advisory role to Bayer, Nordic Pharma, and Servier. RG-C reports clinical trial funding paid to institution from Merck Sharp & Dohme, Bristol Myers Squibb, Ipsen, Roche, Servier, Novartis, Pfizer, Merck, Bayer, and Pharma Mar; and honoraria from Roche, Sanofi Aventis, Servier, Novartis, Pfizer, Merck, Bayer, Pharma Mar, AAA, Advandz Pharma, Midatech Pharma, and Pierre Fabre. CdlF reports clinical trial funding paid to institution funding paid to institution from Merck Sharp & Dohme; a consulting and advisory role for Merck Sharp & Dohme (ESMO 2019). FR reports clinical trial funding paid to institution funding paid to institution from Merck Sharp & Dohme, Roche, Merck-Serono, Amgen, Pierre-Fabre, Sanofi-Aventis, Bayer, Servier, and Lilly; a consulting and advisory role for Roche, Merck-Serono, Amgen, Pierre Fabre, Sanofi-Aventis, Bayer, Servier, Lilly, AstraZeneca, and Bristol Myers Squibb; honoraria from Merck Sharp & Dohme, Roche, Merck-Serono, Amgen, Pierre-Fabre, Sanofi-Aventis, Bayer, Servier, Lilly, AstraZeneca, Pfizer, and Bristol Myers Squibb; and non-financial support from Merck Sharp & Dohme, Roche, Merck-Serono, Amgen, Pierre-Fabre, Sanofi-Aventis, Bayer, and Servier. Exrts clinical trial funding paid to institution from Merck Sharp & Dohme and Sanofi; honoraria from Amgen, Sanofi, Servier, Merck Sharp & Dohme, Pierre Fabre, and Hoffman La Roche; and non-financial support from Amgen, Sanofi, Merck Sharp & Dohme, and Hoffman La Roche. DTL serves on advisory boards for Merck, Bristol Myers Squibb, and Janssen; has received research funding from Merck, Bristol Myers Squibb, Aduro Biotech, Curegenix, Medivir, Nouscom, and AbbVie; has received speaking honoraria from Merck; and is an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. The terms of these arrangements are being managed by Johns Hopkins. TY reports grants from Merck Sharp & Dohme for the submitted work; and grants from Ono, Sanofi, Daiichi Sankyo, Chugai, Parexel International, Taiho, Amgen, and Sumitomo Dainippon, outside the submitted work; WYZ, DF, and PM are employees of Merck Sharp & Dohme, a subsidiary of Merck, and hold stock in Merck. TA reports honoraria from Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Chugai, Clovis, Gritstone Oncology, GSK, Haliodx, Kaleido Biosciences, Merck, Pierre Fabre, Roche/Ventana, Sanofi, Transgene, Seagen, and Servier; and compensation for travel, accommodation, and expenses from Roche/Genentech, Merck Sharp & Dohme, and Bristol Myers Squibb.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Figures

Figure 1.

Study profile. Summary of patients who were screened for enrollment and randomized to pembrolizumab or chemotherapy.a11 patients randomized to the chemotherapy group subsequently withdrew consent and did not receive treatment.

Figure 2.

Kaplan-Meier estimates of overall survival in patients with MSI-H/dMMR mCRC

Figure 3.

Overall survival in key subgroups of patients with MSI-H/dMMR mCRC. All subgroups were prespecified except for sex, ECOG performance status, and KRAS mutation. Prespecified categories were age, geographic region, recurrent versus new-diagnosed, BRAF wildtype vs BRAF V600E, site of primary tumor. The hazard ratios for death for the comparison of pembrolizumab versus standard-of-care therapy in all subgroups was calculated based on a Cox proportional regression model with Efron’s method of tie handling with treatment as a covariate. Two-sided interaction p-values are provided based on a multivariate Cox regression model with treatment, age, sex, ECOG performance status, geographic region, recurrent versus new-diagnosed, BRAF/KRAS/NRAS all wild type versus BRAF V600E, BRAF/KRAS/NRAS all wildtype versus KRAS or NRAS mutant, site of primary tumor and their interactions with treatment as covariates. The joint testing was done as a post-hoc exploratory analysis and P values are not adjusted for multiplicity and are nominal only. The dashed line indicates the overall OS HR for the study.

Figure 4.

Kaplan-Meier estimate of (A) time from randomization to progression on next line of therapy or any cause death in patients with MSI-H/dMMR mCRC. (B) Median duration of response in patients with MSI-H/dMMR mCRC