Pembrolizumab and encorafenib + cetuximab are associated with meaningful survival benefits in BRAF-mutant metastatic CRC.A real-world study presented at ESMO GI 2026 shows that pembrolizumab immunotherapy and a combination regimen of encorafenib and cetuximab are associated with meaningful survival benefits in BRAF-mutant metastatic colorectal cancer (CRC).
In 2020, two studies introduced practice-changing treatments for CRC: KEYNOTE-177 (pembrolizumab for microsatellite instability [MSI]-high tumours) and BEACON CRC (encorafenib + cetuximab). [N Engl J Med 2020;383:2207-2218; N Engl J Med 2019;381:1632-1643]
“[We sought] to evaluate if this therapeutic shift resulted in improved overall survival (OS) in a real-world population,” noted the investigators, led by Olivia Daisley, a medical student from the School of Medicine, Dentistry and Nursing, University of Glasgow, UK, at ESMO GI 2026.
The study showed a longer median OS in 2020–2023 than in 2015–2019 (9 vs 7 months; hazard ratio [HR], 0.70, 95 percent confidence interval [CI], 0.54–0.92; p=0.008). [ESMO GI 2026, abstract 142P]
According to Daisley and colleagues, the strongest prognostic features in the multivariate analysis were MSI status and receipt of systemic anticancer therapy (SACT).
Among participants with known MSI disease receiving SACT, the use of first-line immunotherapy increased from 5 percent prior to 2020 to 78 percent after 2020. This increase correlated with a significant median OS benefit (8 months vs not estimable; HR, 0.28, 95 percent CI, 0.09–0.87; p=0.019).
Among non-MSI participants who received SACT, the use of second-line encorafenib + cetuximab increased markedly from 6 percent before 2020 to 87 percent after 2020. Multivariate analysis showed exposure to encorafenib + cetuximab as the strongest predictor of survival (median OS 11 vs 23 months; HR, 032, 95 percent CI, 0.20–0.51; p<0.001).
Tailored Tx approach warranted
“BRAF V600E-mutant metastatic CRC is a distinct clinical subgroup with poor OS,” the investigators noted. This CRC type is more frequently observed in women and has a unique metastatic pattern, with a predilection for peritoneal dissemination, thus warranting tailored approaches for disease monitoring and management. [Cancer Treat Rev 2025:134:102905; Cancer Cell Int 2020 29:20:30]
Daisley and colleagues retrospectively evaluated 238 individuals diagnosed with BRAF-mutant metastatic CRC in NHS Greater Glasgow and Clyde between January 1, 2015 and December 31, 2023. Of these, 104 participants (60 percent women) were diagnosed in 2015–2019 and 134 (51 percent women) in 2020–2023. Fifty-three percent of the participants were aged <70 years (median age at diagnosis 69 years).
Among participants diagnosed in 2015–2019, 35 percent had peritoneal metastasis, a majority (72 percent) had unknown MSI status, and 64 percent received SACT. Among those diagnosed in 2020–2023, 42 percent had peritoneal metastasis, most (68 percent) had proficient mismatch repair and microsatellite stable disease, and 60 percent received SACT.
More than half of the participants had high levels of systemic inflammation (neutrophil-lymphocyte ratio, ≥4), and one-third did not produce carcinoembryonic antigen.
Compared with participants diagnosed before 2019, those diagnosed after had greater exposure to immunotherapy (18 percent vs 1 percent; p<0.01) or encorafenib + cetuximab (29 percent vs 5 percent; p<0.01).
“In this 8-year real-world cohort, the introduction of pembrolizumab immunotherapy and encorafenib + cetuximab in 2020 was associated with clinically meaningful improvements in survival in BRAF-mutant metastatic CRC, supporting the real-world effectiveness of these therapies,” Daisley and colleagues concluded.