Prolonged response to pembrolizumab in BRAFV600E microsatellite stable metastatic colorectal cancer following an increase in tumor mutational burden.

BRAFV600E-mutant metastatic colorectal cancer (mCRC) is an aggressive molecular subtype associated with poor prognosis and relative chemoresistance. Outcomes following progression on chemotherapy and MAPK-targeted therapy with encorafenib plus cetuximab remain poor, highlighting an unmet need for effective later-line treatments. Immune checkpoint inhibitors have limited activity in microsatellite-stable (MSS) mCRC, and predictive biomarkers beyond mismatch repair deficiency remain poorly defined. We report a patient with BRAFV600E-mutant MSS mCRC who achieved a prolonged response to PD-1 blockade with pembrolizumab following a dynamic increase in tumor mutational burden (TMB). A 58-year-old woman initially responded to first-line chemotherapy but subsequently progressed on multiple treatment lines, including encorafenib plus cetuximab. Longitudinal genomic profiling using tumor tissue and circulating tumor DNA (ctDNA) revealed persistent BRAFV600E signaling with molecular evolution, including acquisition of a PIK3R1 variant associated with resistance to MAPK inhibition and emergence of TMB-high status. Fifth-line pembrolizumab produced a dramatic radiological response, with ongoing disease control more than 2 years later. We discuss the mechanistic framework by which a subset of BRAFV600E-mutant MSS mCRC may respond to immune checkpoint inhibition through an inflamed immune microenvironment driven by constitutive MAPK signaling. This case illustrates the interplay between tumor-agnostic biomarkers such as TMB-high and tumor-specific context, and highlights the value of longitudinal genomic profiling, including ctDNA, to identify resistance mechanisms and guide treatment selection.