Background
Phase III RCT of 307 treatment-naive patients with metastatic MSI-H/dMMR colorectal cancer.
Interventions and follow up
Arm A: Pembrolizumab 200 mg IV Q3W (up to 35 cycles)
Arm B: Investigator-choice chemotherapy (mFOLFOX6 or FOLFIRI) with or without bevacizumab or cetuximab
Primary endpoints: Progression-free survival (PFS) and overall survival (OS)
mFollow up: 32.4 mo (PFS analysis)
Arm B: Investigator-choice chemotherapy (mFOLFOX6 or FOLFIRI) with or without bevacizumab or cetuximab
Primary endpoints: Progression-free survival (PFS) and overall survival (OS)
mFollow up: 32.4 mo (PFS analysis)
Results
mPFS: 16.5 mo (Arm A) vs 8.2 mo (Arm B); HR 0.60, 95% CI 0.45–0.80; P=.0002
ORR: 43.8% vs 33.1%, with more durable responses in the pembrolizumab arm
OS (final analysis): mOS not reached vs 36.7 mo; HR 0.74, 95% CI 0.53–1.03; P=.036 (did not cross prespecified threshold, confounded by crossover)
ORR: 43.8% vs 33.1%, with more durable responses in the pembrolizumab arm
OS (final analysis): mOS not reached vs 36.7 mo; HR 0.74, 95% CI 0.53–1.03; P=.036 (did not cross prespecified threshold, confounded by crossover)
Adverse events
Treatment-related (grade ≥3, A vs B): 22% vs 66%
Immune-mediated (any grade, A vs B): 31% vs 13%; serious immune-mediated events were uncommon
Discontinuation: Lower with pembrolizumab
Immune-mediated (any grade, A vs B): 31% vs 13%; serious immune-mediated events were uncommon
Discontinuation: Lower with pembrolizumab
Conclusions
First-line pembrolizumab significantly improved PFS versus chemotherapy with a favorable safety profile in patients with MSI-H/dMMR metastatic colorectal cancer, establishing immunotherapy as a 1L standard in this molecular subset.
Key Limitations
OS interpretation confounded by ~60% crossover from chemotherapy to anti-PD-1; early progression in a subset of pembrolizumab patients (early crossing of survival curves); applies only to the MSI-H/dMMR subset (~5% of mCRC).
Clinical Context
KEYNOTE-177 led to FDA (2020) and EMA approval of first-line pembrolizumab for MSI-H/dMMR mCRC, making it the ESMO-preferred 1L option for this biomarker-selected group. It underscores the need for universal MMR/MSI testing at diagnosis; dual checkpoint blockade (nivolumab/ipilimumab, CheckMate 8HW) is an emerging alternative.
References
André et al, NEJM, 2020, PMID: 33264544
Diaz LA Jr et al, Lancet Oncol, 2022 (final OS), PMID: 35345594
Diaz LA Jr et al, Lancet Oncol, 2022 (final OS), PMID: 35345594