A newer report of this study has been published: 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 (2022)
A small share of metastatic bowel (colorectal) cancers have a kind of “fault in the DNA repair system” (MSI-H or dMMR), which is found with a test on the tumour sample. This study showed that in these patients the immunotherapy drug pembrolizumab (Keytruda), given as the first treatment, kept the disease under control on average about twice as long as chemotherapy (median 16.5 versus 8.2 months), with far fewer severe side effects. In many patients the responses lasted a long time. This is why MSI/MMR testing is now recommended for all patients with bowel cancer.
MSI-H/dMMR metastatic colorectal cancer; first-line (in ESMO 2026, when dual therapy is not possible)
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pembrolizumab | 200 mg every 3 weeks or 400 mg every 6 weeks | IV | Day 1 |
Dose from the FDA label for pembrolizumab; in KEYNOTE-177, 200 mg every 3 weeks for up to 35 doses.
On the page “Colorectal cancer” · MSI-H/dMMR metastatic colorectal cancer: first-line
First-line; cetuximab or panitumumab only for RAS wild-type disease (especially left-sided tumours); bevacizumab for RAS-mutant or right-sided tumours
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Oxaliplatin | 85 mg/m² | IV over 2 h | Day 1 |
| Leucovorin | 400 mg/m² | IV over 2 h | Day 1 |
| Fluorouracil (bolus) | 400 mg/m² | IV bolus | Day 1 |
| Fluorouracil (infusion) | 2400 mg/m² | IV, continuous 46-h infusion | Starting day 1 |
| Plus one of these drugs | |||
| Bevacizumab | 5 mg/kg | IV | Day 1 |
| Cetuximab | 500 mg/m² over 120 min (or 400 mg/m², then 250 mg/m² weekly) | IV | Day 1 |
| Panitumumab | 6 mg/kg over 60 min (doses above 1000 mg: 90 min) | IV | Day 1 |
Doses of mFOLFOX6 with bevacizumab 5 mg/kg or with cetuximab from KEYNOTE-177; per the European SmPC, the bevacizumab dose in metastatic colorectal cancer is 5 or 10 mg/kg every 2 weeks or 7.5 or 15 mg/kg every 3 weeks; cetuximab; panitumumab with FOLFOX in the first line for RAS wild-type disease.
On the page “Colorectal cancer” · pMMR/MSS metastatic colorectal cancer: first-line
First- or second-line metastatic disease; cetuximab only for RAS wild-type disease
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Irinotecan | 180 mg/m² | IV over 90 min | Day 1 |
| Leucovorin | 400 mg/m² | IV | Day 1 |
| Fluorouracil (bolus) | 400 mg/m² | IV bolus | Day 1 |
| Fluorouracil (infusion) | 1200 mg/m² per day for 2 days (2400 mg/m²) | IV, continuous infusion | Days 1 and 2 |
| Plus one of these drugs | |||
| Bevacizumab | 5 mg/kg | IV | Day 1 |
| Cetuximab | 500 mg/m² every 2 weeks, or 400 then 250 mg/m² weekly | IV | Day 1 |
Doses of FOLFIRI and bevacizumab from KEYNOTE-177; cetuximab with FOLFIRI per the FDA label; after progression on a bevacizumab-containing regimen, bevacizumab 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks can be continued with irinotecan- or oxaliplatin-based backbone chemotherapy.
On the page “Colorectal cancer” · pMMR/MSS metastatic colorectal cancer: first-line
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Pembrolizumab 200 mg IV on day 1 of each 21-day cycle (every 3 weeks), up to 35 cycles (about 2 years) or until disease progression or unacceptable toxicity.
One of these regimens every 2 weeks: mFOLFOX6 (oxaliplatin 85 mg/m² day 1, leucovorin 400 mg/m² day 1, fluorouracil 400 mg/m² bolus day 1, then continuous infusion 1200 mg/m² per day for 2 days) or FOLFIRI (irinotecan 180 mg/m² day 1 with the same leucovorin and fluorouracil doses); all IV.
With or without bevacizumab 5 mg/kg IV every 2 weeks, or cetuximab weekly IV (first dose 400 mg/m², then 250 mg/m²).
Crossover to pembrolizumab for up to 35 cycles was allowed after disease progression.
Source of the regimen details: Pembrolizumab dose and treatment duration from ClinicalTrials.gov NCT02563002 and the abstract; doses of the chemotherapy regimens and targeted agents from the abstract of the final analysis (Diaz LA et al., Lancet Oncol 2022;23:659-670, DOI 10.1016/S1470-2045(22)00197-8) and ClinicalTrials.gov
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Adults (18 years or older) with microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer with no previous treatment for metastatic disease and ECOG performance status 0 or 1. Patients were enrolled from 193 centres in 23 countries.
Dual primary endpoints: progression-free survival (PFS) and overall survival (OS).
Secondary endpoints: overall response rate per RECIST version 1.1, duration of response and safety.
Treatment-related grade 3 or higher adverse events occurred in 22% of the pembrolizumab group versus 66% of the chemotherapy group. In the final analysis, the most common grade 3 or higher events attributed to pembrolizumab were increased ALT, colitis, diarrhoea and fatigue (3 patients each, 2%), and for chemotherapy decreased neutrophil count (17%), neutropenia (15%), diarrhoea (10%) and fatigue (9%). Serious treatment-related adverse events: 16% versus 29%. No deaths were attributed to pembrolizumab.
On the basis of this trial, the US Food and Drug Administration (FDA) approved pembrolizumab for adults with unresectable or metastatic MSI-H or dMMR colorectal cancer (current Keytruda label). First-line pembrolizumab became one of the standard treatments for this subgroup. In the final overall survival analysis (Lancet Oncol 2022), statistical superiority in overall survival was not demonstrated (HR 0.74; p=0.036 versus a threshold of 0.025), which is partly attributed to extensive crossover of control-group patients to immunotherapy.
Open-label design (no blinding); extensive crossover of chemotherapy-group patients to immunotherapy, which complicates interpretation of overall survival; the progression-free survival curves crossed in the first months and a proportion of patients progressed rapidly on pembrolizumab at first; no comparison with a combination of two immunotherapies.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.
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