Durable Response Seen With PD-1 Plus BRAF/MEK Inhibitor Combo in CRC

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.”

_References:

_{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}