Triple combination therapy shows promise for treatment-resistant microsatellite stable BRAF V600E-mutant metastatic colorectal cancer
MD Anderson Research Highlight August 28, 2025
The BRAF V600E gene mutation makes colorectal cancers (CRCs) more aggressive, leading to poorer survival rates. While some CRCs with high microsatellite instability respond well to immunotherapy, most BRAF V600E-mutant metastatic CRCs are microsatellite stable (MSS) and do not benefit from these treatments. The combination of encorafenib and cetuximab is Food and Drug Administration (FDA)-approved but has limited duration of response in these patients, which led , and colleagues at MD Anderson to examine the safety and efficacy of adding the anti-PD-1 antibody nivolumab to this combination in patients with MSS BRAF V600E-mutant metastatic CRC. This Phase I/II trial enrolled 26 patients and showed an overall response rate of 50%, with a median progression-free survival of over seven months. RNA analysis from liquid biopsies identified distinct patterns of response among patients who did or did not benefit from the triple combination. The positive outcomes of this study led to the launch of SWOG S2107, a nationwide Phase II trial in the same patient population, also led by Morris. Learn more in .
Importantly, some of the patients responding to this treatment maintained durable benefit, which we have not historically seen with encorafenib and cetuximab alone. Further analysis showed that RNA signatures of MAPK activity and interferon gamma activation were associated with responses to treatment, and that signatures of complement activation and cellular metabolism were associated with lack of response to this triple combination therapy.