Results of a study of dabrefenib, trametinib, and spartalizumab showed efficacy for the combination of a BRAF inhibitor, a MEK inhibitor, and an anti–PD-1 agent in patients with BRAF V600-mutated colorectal cancer.
Patients with BRAF V600-mutated metastatic colorectal cancers (CRCs) experienced synergistic antitumor response with long duration of response (DOR) when receiving a combination of immunotherapy and targeted therapy, according to a paper published in Nature Medicine.1
In the single-arm phase 2 trial (NCT03668431), there was an overall response rate (ORR) of 24.3% (95% CI, 11.9%-41.2%) in patients receiving dabrafenib (Tafinlar), trametinib (Mekinist), and spartalizumab (PDR001). Additionally, 57% of patients remained on treatment for at least 6 months, and a portion continued the combination for over a year.
“Immunotherapy and targeted therapy represent 2 of the biggest breakthroughs in cancer treatment in the last decade,” Ryan Corcoran, MD, PhD, co-corresponding author of the paper and director of the Gastrointestinal Cancer Center Program and physician-investigator at the Massachusetts General Cancer Center, stated in a press release.2 “By combining these 2 approaches, we saw a dramatic increase in patients who responded to treatment and unprecedented durability, with 18% of patients staying in the trial for a year or more.”
BRAF inhibitors alone have low efficacy in patients with BRAF V600-mutated CRC, and the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib only had a confirmed ORR of 7% (95% CI, 1.5%-19.1%) and a median progression-free survival (PFS) of 3.5 months in this setting.1,3 Investigators theorized that the inhibition of the MAPK pathway with a BRAF and MEK inhibitor would improve immune response, leading to preclinical research that showed the efficacy of combining targeted therapy with PD-1 immune checkpoint blockade.
The study treated 37 patients with the combination of dabrafenib, trametinib, and the anti–PD-1 agent spartalizumab.1 Patients must have had confirmed metastatic CRC and a documented BRAF V600 mutation, and must have been negative for KRAS and NRAS mutations. Patients who received prior chemotherapy, immunotherapy, or BRAF/MEK inhibitor were permitted.
The primary end points were ORR and the rate of grade 3 or higher adverse events (AEs), and secondary end points included PFS, disease control rate (DCR), DOR, and overall survival (OS). Of the 37 patients enrolled, 32 had microsatellite-stable (MSS) tumors and 5 had microsatellite instability-high tumors, the latter of which respond better to immunotherapy.
Nine out of 37 patients achieved a confirmed response, with 1 additional unconfirmed response. There were 2 complete responses. The DCR was 70.3% (95% CI 53.0%-84.1%). At the median follow-up of 995 days, the median PFS was 4.3 months (95% CI, 3.7-7.3) and the median OS was 13.6 months (95% CI, 8.2-16.5). The median duration of treatment was 7.4 months (95% CI, 4.2-7.9).
In patients with MSS, confirmed ORR was 25% (95% CI, 10.7%-44.9%) and DCR was 75% (95% CI, 55.1%-89.3%), suggesting that the triplet combination’s efficacy was synergistic considering that MSS patients respond poorly to immunotherapy alone and a similar population responded poorly to the BRAF/MEK combination without immunotherapy.
In terms of safety, the combination was well tolerated. The most common any-grade AEs were fever in 17 patients (45.9%) and fatigue in 15 (40.5%). Increased lipase and increased serum amylase, each occurring in 3 patients (8.1%) were the most common grade 3 or higher AEs.
Single-cell RNA analysis of patients showed an increase in tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients who responded, demonstrating a potential association between greater MAPK inhibition and the efficacy of immunotherapy.
“For almost every type of cancer, a large percentage of tumors will harbor mutations in the MAPK pathway,” Corcoran said in the press release.2 “Our work suggests that combining other treatments that target this pathway with an immunotherapy could lead to a cooperative, enhanced immune response that may improve outcomes for patients.”
1. Tian J, Chen JH, Chao SX, et al. Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial. Nat Med. 2023. doi:10.1038/s41591-022-02181-8
2. Immunotherapy combined with targeted therapy for colorectal cancer yields promising outcomes for patients. Massachusetts General Hospital. News release. January 26, 2023. Accessed February 7, 2023. https://bit.ly/40AthF4
3. Corcoran RB, Atreya CE, Falchook GS, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol. 2015;33(34):4023-4031. doi:10.1200/JCO.2015.63.2471