Triplet Therapy Benefits Treatment-Resistant MSS BRAF V600E-Mutant CRC

A phase 1/2 clinical trial (NCT04017650) has demonstrated substantially enhanced efficacy for a triple combination therapy of encorafenib (Braftovi), cetuximab (Erbitux), and nivolumab (Opdivo) in patients with microsatellite stable (MSS) BRAF V600E-mutant metastatic colorectal cancer (mCRC), a subset of the disease historically associated with poor prognosis and limited treatment options.^1,2

The study, conducted by Van Morris, MD, and colleagues at MD Anderson Cancer Center, reported an overall response rate (ORR) of 50% (95% CI, 29%–71%) and a median progression-free survival (PFS) of 7.4 months (95% CI, 5.6–9.6) among 26 enrolled patients. Crucially, the median overall survival (OS) reached 22.0 months (95% CI, 11.2–25.8). These outcomes significantly surpass those observed with the current FDA-approved doublet therapy of encorafenib and cetuximab, which has shown limited duration of response.

“Previously, combination immunotherapy approaches have proven ineffective in patients with MSS metastatic CRC. However, most of these efforts did not prespecify unique subsets of this biologically diverse population of patients with CRC,” Morris et al wrote in the study, published in Cancer Cell.¹

The BRAF V600E gene mutation is present in approximately 8% to 10% of all colorectal cancers and is a known marker for aggressive disease and poorer survival rates. While some colorectal cancers with high microsatellite instability respond favorably to immunotherapy, the majority (approximately 80%) of BRAF V600E-mutant mCRCs are MSS and typically do not benefit from anti–PD-1 antibody treatments alone.

The combination of encorafenib and cetuximab, though FDA-approved for refractory BRAF V600E mCRC, demonstrated a median PFS of 4.2 months, an OS of 9.4 months, and an ORR of 20% in the phase 3 BEACON trial (NCT02928224). This underscored the urgent need for more effective therapeutic strategies for this challenging patient population.

Recognizing that MSS BRAF V600E tumors exhibit greater immune activation compared to their BRAF wild-type counterparts, researchers hypothesized that targeting mitogen-activated protein kinase (MAPK) signaling with encorafenib and cetuximab could prime these tumors for anti–PD-1 antibody nivolumab treatment.

The single-institution study enrolled 26 participants with MSS BRAF V600E mCRC. The median age of participants was 59 years (range, 32–85), with 62% having received only 1 prior line of systemic chemotherapy for metastatic disease. Patients received encorafenib 300 mg orally once daily, cetuximab 500 mg/m² intravenously every 14 days, and nivolumab 480 mg intravenously every 28 days. Prior exposure to BRAF/MEK/ERK inhibitors, anti-EGFR antibodies, or immune checkpoint therapies was not permitted.

Safety assessments revealed no dose-limiting toxicities (DLTs) or grade 5 adverse events (AEs) among the study participants. Six patients (23%) experienced grade 3 or 4 treatment-related adverse events, primarily elevated serum lipase (12%) and elevated serum amylase (8%), both asymptomatic and attributed to nivolumab. Common all-grade treatment-related AEs (occurring in >20% of cases) included headache (58%), nausea (42%), arthralgia (39%), anemia (31%), acneiform rash (31%), pruritus (27%), and infusion reaction (23%). Six patients developed encorafenib-related keratoacanthomas or squamous cell cancers of the skin that required dermatological evaluation and treatment.

Regarding efficacy, 24 participants were evaluable for radiographic response. The study observed 1 complete radiographic response and 11 partial responses, leading to a confirmed ORR of 42% (95% CI, 22%–64%). The disease control rate (DCR) was high at 96% (95% CI, 79%–100%), and the median duration of response was estimated at 7.7 months (95% CI, 4.5–not reached). A notable finding was the durable benefit observed in some patients, with 13 remaining on the study 6 months after treatment initiation and 2 patients (8%) continuing treatment for over 2 years (26.7 and 33.6+ months). These 2 patients also showed the highest increase in interferon gamma (IFNγ) response scores in extracellular vesicle RNA (evRNA) analyses.

Furthermore, a statistically significant association was found between left-sided primary tumors and a higher likelihood of response (58% vs 42% for right-sided tumors), a finding that warrants further investigation in larger validation studies. Responders in the study experienced more favorable median PFS (9.6 months vs 5.0 months) and OS (30.5 months vs 8.7 months) compared to nonresponders.

Exploratory biomarker analyses provided crucial insights into the mechanisms underlying treatment response. Transcriptomic profiling of pretreatment biopsies and evRNA from plasma identified distinct signatures between responders and non-responders. Responders exhibited enrichment of p38 MAPK and immune activation signatures, including inflammatory immune response pathways such as natural killer cell, B cell, T cell, neutrophil, and macrophage activation. They also showed higher proportions of cytotoxic T cells, activated T cells, and megakaryocytes within the tumor microenvironment. In contrast, nonresponders were characterized by higher complement pathway activation, as well as metabolic signatures related to fatty acid, amino acid, and drug metabolism, alongside classical RAF pathway enrichment.

Dynamic changes observed in serial evRNA profiling further corroborated these findings, with responders demonstrating deeper reductions in MAPK signatures and greater increases in IFNγ signatures following treatment initiation. Conversely, nonresponders maintained signatures of complement and coagulation cascade activation post-treatment. These molecular insights suggest that tumors with higher baseline inflammation may be more likely to benefit from combined MAPK and PD-1-targeted treatment.

The robustness of these molecular signatures was supported by independent validation using a dataset from a separate clinical trial (NCT03290621) evaluating dabrafenib (Tafinlar), trametinib (Mekinist), and spartalizumab (PDR001) in a comparable patient population. This external validation reinforces the utility of the identified molecular signatures in predicting response to MAPK and PD-1 inhibition.

Despite the promising results, the authors acknowledge several limitations, including the single-arm, single-institution design and the relatively small number of patients, which limit definitive conclusions. The findings are currently being validated in a larger, randomized phase 2 trial, SWOG S2107 (NCT05308446), to rigorously evaluate the efficacy and safety of this triple combination therapy. The objective of these ongoing efforts is to potentially offer this new combination to patients with this prognostically unfavorable subtype of mCRC.

REFERENCES:

1. Morris VK, Parseghian CM, Bahrambeigi V, et al. Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAFV600E metastatic colorectal cancer. Cancer Cell. 2025 Aug 21:S1535-6108(25)00340-X. doi: 10.1016/j.ccell.2025.08.002. Online ahead of print.

2. Triple combination therapy shows promise for treatment-resistant microsatellite stable BRAF V600E-mutant metastatic colorectal cancer. News release. MD Anderson Cancer Center. August 28, 2025. Accessed September 2, 2025. https://tinyurl.com/7h5jrbkk