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Cited by 59Colorectal Cancer Treatments and StudiesGenetic factors in colorectal cancerCancer Immunotherapy and Biomarkers

KEYNOTE-177: Phase III randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer

Shiu, Kai-Keen, Andre, Thierry, Kim, Tae Won, Jensen, Benny Vittrup, Jensen, Lars Henrik, Punt, Cornelis J. A., Smith, Denis Michel, Garcia-Carbonero, Rocio +12 more·2021·Journal of Clinical Oncology
DOI 10.1200/jco.2021.39.3_suppl.6
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Abstract

6 Background: KEYNOTE-177 (NCT02563002) evaluated the antitumor activity of pembrolizumab (pembro) vs chemotherapy ± bevacizumab or cetuximab (chemo) as first-line therapy for patients with microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). We present results of the final PFS analysis and analysis of PFS2. Methods: Patients with locally-determined MSI-H/dMMR mCRC and ECOG PS 0 or 1 were randomized 1:1 to first-line pembro 200 mg Q3W for up to 2 years or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab (chosen before randomization). Treatment continued until progression, unacceptable toxicity, patient/investigator decision to withdraw, or completion of 35 cycles (pembro only). Patients receiving chemo could crossover to pembro for up to 35 cycles after confirmed PD. Primary end points were PFS (RECIST v1.1, central review) and OS. Secondary end points included ORR (RECIST v1.1, central review) and safety. Exploratory endpoints included duration of response (DOR), PFS2 (time from randomization to progression on next line of therapy or any cause death), and health-related quality of life (HRQoL). Data cutoff was Feb 19, 2020. Results: At data cutoff a total of 307 patients were randomized (153 to pembro, 154 to chemo). Median (range) study follow-up was 32.4 mo (24.0-48.3). Pembro was superior to chemo for PFS (median 16.5 mo vs 8.2 mo; HR 0.60; 95% CI, 0.45-0.80; P= 0.0002). The 12- and 24-mo PFS rates were 55.3% and 48.3% with pembro vs 37.3% and 18.6% with chemo. Confirmed ORR was 43.8% vs 33.1%; median (range) DOR was not reached (2.3+ to 41.4+) with pembro vs 10.6 mo (2.8 to 37.5+) with chemo. PFS2 was longer with pembro vs chemo (median not reached vs 23.5 mo [HR 0.63; 95% CI, 0.45-0.88]). OS analysis is ongoing. Grade ≥3 treatment related adverse event (TRAE) rates were 22% vs 66% for pembro vs chemo. There were no grade 5 TRAEs in the pembro arm and 1 grade 5 intestinal perforation in the chemo arm. HRQoL scores were improved with pembro vs chemo. Conclusions: Pembro provided a statistically significant improvement in PFS vs chemo as first-line therapy for patients with MSI-H/dMMR mCRC, with fewer TRAEs observed. Furthermore, pembro provided a clinically meaningful improvement in PFS2 for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02563002.

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Crossref · 10.1200/jco.2021.39.3_suppl.6

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  • In the PFS subgroup analysis of Keynote 177, pembrolizumab monotherapy showed a benefit in RAS wild-type patients (HR: 0.44 (95% CI: 0.29-0.67)), whereas no PFS benefit was demonstrated in RAS mutant patients (HR: 1.19 (95% CI: 0.68-1.43)).

    “In the subgroup analysis presented for PFS, pembrolizumab monotherapy showed a benefit in RAS wild-type patients (HR: 0.44 (95% CI: 0.29–0.67)), whereas no PFS benefit was demonstrated with pembrolizumab monotherapy in RAS mutant patients (HR: 1.19 (95% CI: 0.68–1.43)).”

    From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [86]

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Authors
Shiu, K.-K., Andre, T., Kim, T. W., Jensen, B. V., Jensen, L. H., Punt, C. J. A., Smith, D. M., Garcia-Carbonero, R., Benavides, M., Gibbs, P., De La Fouchardiere, C., Rivera, F., Elez, E., Bendell, J. C., Le, D. T., Yoshino, T., Yang, P., Farooqui, M. Z. H., Marinello, P., & Diaz, L. A.
Affiliations
  • University College Hospital (GB)
  • Sorbonne Université and Hôpital Saint Antoine, Paris, France;
  • Asan Medical Center (KR)
  • Herlev Hospital (DK)
  • Vejle Sygehus (DK)
  • Amsterdam University Medical Centers (NL)
  • Centre Hospitalier Universitaire de Bordeaux (FR)
  • Hospital Universitario 12 de Octubre, Imas12, CNIO, UCM, Madrid, Spain;
  • Hospital Regional Universitario de Málaga (ES)
  • Western Health (AU)
  • Centre Léon Bérard, Lyon, France;
  • Marqués de Valdecilla University Hospital (ES)
  • Vall d'Hebron Institute of Oncology, Barcelona, Spain;
  • Sarah Cannon (US)
  • Johns Hopkins University (US)
  • National Cancer Center Hospital East (JP)
  • MSD (China) Investment Co., Ltd. (China) (CN)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • Memorial Sloan Kettering Cancer Center (US)
ORCID
Venue
Journal of Clinical Oncology
Publisher
American Society of Clinical Oncology (ASCO)
Published
2021-01-20
Volume
39
Issue
3_suppl
Pages
6-6
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
DOI
10.1200/jco.2021.39.3_suppl.6
OpenAlex
W3124887287
Cited by
59
References
0
Citations by year
2025: 5 · 2024: 5 · 2023: 11 · 2022: 23 · 2021: 15
Type
conference abstract
Language
en
Open access
closed
Locations
  • Journal of Clinical Oncology (publishedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
Funders
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USAh
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
pembrolizumab, microsatellite instability-high, mismatch repair deficiency, metastatic colorectal cancer, first-line therapy, immune checkpoint inhibitors, chemotherapy, bevacizumab, cetuximab, progression-free survival, overall survival, objective response rate, duration of response, health-related quality of life, mFOLFOX6, FOLFIRI

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