Elsevier

The Lancet Oncology

Volume 23, Issue 5, May 2022, Pages 659-670
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(22)00197-8Get rights and content

Summary

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.

Introduction

Mismatch repair deficiency occurs in approximately 4–5% of all metastatic colorectal cancers.1, 2 Mismatch repair-deficient tumours are unable to repair certain classes of mutations, resulting in tumours with a high mutational burden and microsatellite instability.3, 4

PD-1 blockade with the antibodies pembrolizumab or nivolumab in individuals with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer has provided an efficacious treatment option for chemotherapy-resistant tumours.5, 6 Treatment with the anti-PD-1 therapies pembrolizumab or nivolumab provided durable antitumour responses in patients with previously treated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, leading to US Food and Drug Administration (FDA) approval of these therapies for this patient population in 2017.5, 6 Initial data from the randomised, phase 3 KEYNOTE-177 study of pembrolizumab versus standard-of-care chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer showed that pembrolizumab improved progression-free survival as a first-line therapy and improved health-related quality of life (QOL).7, 8 These data supported the FDA (June, 2020) and European Medicines Agency (EMA; January, 2021) approval of pembrolizumab for first-line treatment of patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.9, 10 Current guidelines recommend testing for high microsatellite instability or mismatch-repair deficiency status in patients diagnosed with metastatic colorectal cancer.11, 12 Immunotherapy-based regimens have not yet shown definitive evidence of clinical efficacy in patients with mismatch repair-proficient or microsatellite-stable metastatic colorectal cancers.13, 14

To our knowledge, the KEYNOTE-177 study was the first randomised study to have shown the clinical benefit of PD-1 blockade in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the first-line setting.7 Before the results of KEYNOTE-177 were released, chemotherapy was the standard of care for patients with newly diagnosed metastatic colorectal cancer, regardless of the molecular genotype, with our without targeted therapy. This standard approach has included chemotherapy with fluorouracil-based regimens, such as FOLFOX (fluorouracil, oxaliplatin, and leucovorin), FOLFIRI (fluorouracil, irinotecan, and leucovorin) with or without anti-EGFR or anti-VEGF therapies, and FOLFOXIRI (fluorouracil, oxaliplatin, and irinotecan) with or without anti-VEGF therapies.15

We herein report the overall survival observed at the final analysis of the phase 3 KEYNOTE-177 study of first-line pembrolizumab versus chemotherapy (with or without the VEGF inhibitor bevacizumab or EGFR inhibitor cetuximab) in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.

Research in context

Evidence before the study

We searched PubMed for studies published from inception to Dec 9, 2021, using the terms (“PD-1” OR “PD-L1” OR “pembrolizumab” OR “Keytruda” OR “nivolumab” OR “Opdivo” OR “atezolizumab” OR “Tecentriq” OR “durvalumab” OR “Imfinzi” OR “avelumab” OR “Bavencio” AND “MSI-H/dMMR metastatic colorectal cancer”). No exclusion criteria were applied to the search. We also searched the 2020 and 2021 abstract records of the American Society of Clinical Oncology, American Society of Clinical Oncology Gastrointestinal Cancers Symposium, the World Congress on Gastrointestinal Cancer, and the European Society for Medical Oncology Congress using the same search terms to identify results of clinical studies that were not yet published in the peer-reviewed literature. We identified three published clinical studies of anti-PD-1 or anti-PD-L1 therapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer: the phase 3, open-label KEYNOTE-177 interim analysis of first-line pembrolizumab versus chemotherapy; the phase 2, open-label KEYNOTE-164 study of pembrolizumab as second-line or later therapy; and the phase 2, open-label CheckMate 142 study of nivolumab as second-line or later therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.

Added value of this study

Data from the final analysis of KEYNOTE-177 support the results observed in the previously published interim analysis, which were the first from a phase 3 randomised study of an anti-PD-1 inhibitor as a first-line treatment for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer versus an active comparator. These data show that progression-free survival improved with pembrolizumab versus chemotherapy. However, we found no significant difference in overall survival. The overall survival analysis might have been affected by the high proportion of patients who crossed over from chemotherapy to second-line anti-PD-1 or anti-PD-L1 therapy. Responses were durable and continued to improve with pembrolizumab versus chemotherapy. The safety profile was favourable at final analysis, with fewer high-grade treatment-related adverse events observed with pembrolizumab than with chemotherapy.

Implications of the available evidence

These data show that pembrolizumab results in a durable antitumour response and fewer treatment-related adverse events in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the first-line setting compared with chemotherapy, and support pembrolizumab as a standard first-line treatment in this population.

Section snippets

Study design and participants

KEYNOTE-177 is an international, randomised, open-label, phase 3 study of pembrolizumab versus investigator-choice of chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. The study was done in 193 academic medical centres and hospitals in 23 countries (appendix pp 2–6). Eligible patients were aged at least 18 years, with locally confirmed microsatellite instability-high or mismatch repair-deficient stage IV

Results

852 patients were screened for the study, of whom 545 (64%) did not meet the inclusion criteria or met exclusion criteria and were therefore ineligible for enrolment (figure 1). Between Feb 11, 2016, and Feb 19, 2018, 307 patients were randomly assigned to receive pembrolizumab (n=153) or chemotherapy (n=154). Demographics and participant baseline characteristics were previously reported7 and were generally well balanced between treatment groups. Briefly, patients had a median age of 63 years

Discussion

At the final analysis of the randomised, phase 3 KEYNOTE-177 study, first-line treatment with pembrolizumab versus chemotherapy did not result in a significant difference in overall survival in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.

The progression-free survival benefit of pembrolizumab versus chemotherapy that was observed at the second interim analysis7 was also found at final analysis, with a greater proportion of patients

Data sharing

Merck Sharp & Dohme, a subsidiary of Merck, Merck Sharp & Dohmeis committed to providing qualified scientific researchers access to anonymised data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. Merck Sharp & Dohme is also obligated to protect the rights and privacy of trial patients and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified

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

References (25)

  • S Venderbosch et al.

    Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies

    Clin Cancer Res

    (2014)
  • M Koopman et al.

    Deficient mismatch repair system in patients with sporadic advanced colorectal cancer

    Br J Cancer

    (2009)
  • Cited by (0)

    *

    A complete list of KEYNOTE-177 Investigators is given in the appendix (pp 2–6)

    View full text