KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer
For the roughly 5% of metastatic bowel cancers with defective DNA mismatch repair, pembrolizumab alone doubled the time without progression compared with chemotherapy, with far fewer side effects and many long-lasting remissions.
Open-label phase 3 trial of 307 patients with untreated microsatellite-instability-high or mismatch-repair-deficient metastatic colorectal cancer randomised to pembrolizumab or investigator's choice chemotherapy (FOLFOX or FOLFIRI with or without bevacizumab or cetuximab). Primary endpoints were PFS and OS.
Median PFS was 16.5 vs 8.2 months (HR 0.60), with 43.8% vs 33.1% responding and 83% vs 35% of responses lasting two years or more. Overall survival was not significantly different (HR 0.74) because 60% of chemotherapy patients crossed over to immunotherapy. It made first-line pembrolizumab the standard for dMMR metastatic colorectal cancer and cemented mismatch repair testing for every colorectal cancer.
- Median PFS 16.5 vs 8.2 months; HR 0.60 (95% CI 0.45-0.80); 24-month PFS 48.3% vs 18.6%.
- Objective response 43.8% vs 33.1%; complete response 11% vs 4%.
- Grade 3 or higher treatment-related adverse events 22% vs 66%.
- Overall survival (Lancet Oncology 2022): HR 0.74 (95% CI 0.53-1.03), not significant; median 77.5 vs 36.7 months; 60% of chemotherapy patients received subsequent anti-PD-1 therapy.
- PFS curves crossed early: about 29% of pembrolizumab patients progressed by 4 months, suggesting a subgroup of primary resistance.
Every colorectal cancer should be tested for mismatch repair deficiency, because patients whose metastatic tumour is dMMR should receive pembrolizumab rather than chemotherapy as first treatment, gaining a much better chance of durable remission with fewer side effects. About a third of dMMR tumours do not respond initially, so early scans are essential and chemotherapy remains available. The trial does not apply to the 95% of colorectal cancers that are mismatch-repair proficient.
- OS was not significantly improved, mostly because of crossover; the design makes an OS benefit unprovable.
- Early crossing of the PFS curves indicates a group with rapid progression on immunotherapy who might be better served by combinations (nivolumab plus ipilimumab in CheckMate 8HW).
- Open-label design and a heterogeneous chemotherapy control arm.
- Immunohistochemistry and PCR for mismatch repair can disagree; misclassification of pMMR tumours as dMMR leads to ineffective treatment.
Pages like this
not linked directly; found by shared links- Key paperLe 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ
Shares Dung T. Le, Luis A. Diaz Jr., Tumour mutational burden (TMB), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
- Key paperRUBY: dostarlimab with chemotherapy for advanced or recurrent endometrial cancer
Shares Lines of therapy, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Histopathology & immunohistochemistry, Overall survival (OS).
- Key paperLe 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval
Shares Dung T. Le, Luis A. Diaz Jr., Tumour mutational burden (TMB), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
- Key paperKEYNOTE-189: pembrolizumab plus chemotherapy as first treatment for non-squamous lung cancer without a driver mutation
Shares Lines of therapy, Merck & Co. (MSD), Overall survival (OS), Progression-free survival (PFS).
- Key paperKEYNOTE-048: pembrolizumab, alone or with chemotherapy, as first treatment for recurrent or metastatic head and neck cancer
Shares Lines of therapy, Merck & Co. (MSD), Overall survival (OS), Progression-free survival (PFS).
- Key paperBREAKWATER: encorafenib plus cetuximab with chemotherapy as first treatment for BRAF V600E-mutated colorectal cancer
Shares Elena Élez, Tae Won Kim, Takayuki Yoshino, Lines of therapy.
- Key paperHARMONi-2: ivonescimab, a PD-1 x VEGF bispecific, beats pembrolizumab head-to-head in PD-L1-positive lung cancer
Shares Lines of therapy, Merck & Co. (MSD), Overall survival (OS), Progression-free survival (PFS).
- TrialKEYNOTE-177
Shares Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), No one can predict who responds to immunotherapy, PD-1, Pembrolizumab.