Combined PDCD1, BRAF and MAP2K7 Inhibition in BRAFV600E Colorectal Cancer: A Phase 2 Trial

In this study, we evaluated the clinical efficacy of combined PDCD1, BRAF, and MAP2K7 inhibition in metastatic BRAFV600E Colorectal Cancer (CRC) patients (NCT03668431). We performed bulk whole exome sequencing (WXS) and bulk RNA sequencing (RNA-Seq) in 35 pre-treatment tumor biopsies and matching germline for tumor mutational burden (TMB), BM1/BM2 transcriptional subtypes, and consensus molecular subtypes (CMS) analysis, which were previously reported to affect prognosis and response to therapy (PMIDs: 32047001, 27354468, and 26457756). Analysis of bulk data showed that TMB, BM1/BM2 subtypes, and CMS did not correlate with clinical response in this study. Analysis of single cell RNA sequencing (scRNA-Seq) data of tumor epithelial cells from 23 paired day 0 and day 15 tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome.]]>
Eligible patients must have had histologically or cytologically confirmed metastatic CRC, a documented BRAF V600E mutation by a CLIA-certified laboratory test, and be wild type for KRAS and NRAS. Patients were required to be aged ≥18 years, have measurable disease according to RECIST v.1.1, have an Eastern Cooperative Oncology Group performance status of less than or equal to two, and have adequate baseline organ function (as determined by laboratory parameters). Patients must not have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or any serious or unstable preexisting medical condition.]]>