SO-26 Clinical efficacy of combined BRAF, MEK, and PD-1 inhibition in BRAFV600E colorectal cancer patients

Abstract

While combinations of BRAF inhibitors with EGFR and/or MEK inhibitors have improved efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and durability is limited. Preclinical and correlative studies suggest that targeting BRAF signaling in combination with immune checkpoint inhibition could enhance activity. BRAFV600E CRC patients recruited from the Massachusetts General Hospital Cancer Center or the Dana-Farber Cancer Institute were treated with the PD-1 inhibitor spartalizumab (PDR001) 400mg IV q28d, dabrafenib 150mg PO BID, and trametinib 2mg PO daily. Single-cell RNAseq was performed on paired baseline and day 15 tumor biopsies, patient-derived organoids were established from baseline biopsies, and serial ctDNA was analyzed. To date, 21 BRAFV600E CRC patients have been enrolled (4 MSI, 17 MSS). 5 had prior therapy with BRAF inhibitors and/or immunotherapy. Median age was 64 (range 35-86) and 12 (57%) were female. Regimen was well-tolerated with rash, fever, and diarrhea as the most common AEs. Of 20 patients with at least one restaging scan, ORR was 35% (7/20) and disease control rate of 75%, which compares favorably to the historical 12% ORR of dabrafenib plus trametinib alone in BRAFV600E CRC. 45% (9/20) patients remained on therapy for >6 months, and one MSS patient remains on therapy >16 months with -100% reduction by RECIST. Among 12 MSS patients with no prior BRAF inhibitor or immunotherapy, response rate was 42% (5/12), and all 12 patients exhibited a reduction in tumor size. Response rate in MSI patients was 25% (1/4) with two remaining on therapy >6 months. Serial ctDNA analysis showed profound and sustained reduction in BRAFV600E ctDNA levels in responders and emergence of MAPK pathway alterations upon acquired resistance. Single-cell RNAseq of paired pre-treatment and day 15 on-treatment biopsies revealed increased infiltration by T-cells and other immune populations with therapy, as well as increased expression of cytotoxic genes specifically in the T-cell compartment. Single-cell RNAseq also confirmed inhibition of MAPK signature genes specifically in the tumor cell compartment, as well as induction of antigen presentation genes and other immune-modulatory programs within tumor cells. Patient-derived organoids treated with dabrafenib and trametinib exhibited gene expression changes that mirrored the changes observed in single-cell RNAseq of tumor cells in paired biopsies from the same trial patient from which they were derived. Spartalizumab, dabrafenib, and trametinib was well-tolerated and produced favorable response rates and durability relative to historical controls in BRAFV600E CRC patients. Correlative studies, including single-cell RNAseq of paired pre-treatment and on-treatment tumor biopsies and analysis of patient-derived organoids suggest potential mechanistic links that could underlie cooperativity between BRAF targeting and immune checkpoint inhibition. Updated data will be presented.