Encorafenib Triplet Exhibits Early Efficacy in MSS BRAFV600E Metastatic CRC

Efficacy data from the trial revealed that among patients treated with the triplet combination, the objective response rate was 50%.

The triplet combination of encorafenib (Braftovi), cetuximab (Erbitux), and nivolumab (Opdivo) exhibited safety and early efficacy in patients with microsatellite stable (MSS) BRAF^V600E metastatic colorectal cancer (CRC), according to findings from a phase 1/2 study (NCT04017650) published in Cancer Cell.¹

Efficacy data from the trial revealed that among patients treated with the triplet combination (n = 24), the objective response rate (ORR) was 50% (95% CI, 29%-71%), and the confirmed ORR was 42% (95% CI, 22%-64%). Furthermore, in the intention-to-treat (ITT) population (n = 26), the ORR was 46% (95% CI, 27%-67%). The estimated median duration of response was 7.7 months (95% CI, 4.5-not available [NA]), and the disease control rate (DCR) was 96% (95% CI, 79%-100%).

After a median duration of follow-up of 18.1 months, the median progression-free survival (PFS) in the ITT population was 7.4 months (95% CI, 5.6-9.6), and the median overall survival (OS) was 22.0 months (95% CI, 11.2-25.8). A total of 13 patients remained on study for at least 6 months after the start of treatment, with 2 remaining on study for over 2 years, at 26.7 months and 33.6 months, respectively.

Of note, left-sided tumors were significantly associated with likelihood of response, with 58% of these patients experiencing a response vs 42% of those with right-sided tumors (OR, 0.24; 95% CI, 0.078-0.84; P = .04). Additionally, among 8 responders and 5 non-responders with available archival tumor specimens, on differences in tumor mutation burden was observed, with 18.0 mutations/megabase (Mb) DNA vs 26.3 mutations/Mb, respectively (P = .21). Furthermore, no association between co-occurrence of JAK1mutations (OR, 0.9; 95% CI, 0.9-9; P = .93) and RNF43 mutations (OR, 7; 95% CI, 0.29-170; P = .23) and response to treatment with the triplet combination were observed.

“The overall response rate in this phase 1/2 study was 50%, and the primary objective to show anti-tumor activity was satisfied. The median PFS was 7.4 months, and the median OS was 22 months for encorafenib, cetuximab, and nivolumab, which is significantly higher than historical prior studies evaluating BRAF plus EGFR combinations,” Van K. Morris, MD, associate professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, wrote in the publication with study coinvestigators. “Dynamic changes in evRNA signatures were associated with responses to treatment with encorafenib, cetuximab, and nivolumab. evRNA analyses correlated responders with deeper reductions in MAPK signatures and greater increases in interferon gamma signatures.”

Patients with unresectable and/or metastatic adenocarcinoma of the colon/rectum previously treated with 1 or 2 prior regimens in the phase 1/2 study were treated with the encorafenib-based triplet. Treatment consisted of 300 mg of daily oral encorafenib, 500 mg/m² of intravenous cetuximab every 14 days, and 480 mg of intravenous nivolumab every 28 days. A dose de-escalation design was employed for the phase 1 portion of the study.

Patients enrolled on the trial had a median age of 59 years (range, 32-85) and were mostly female (62%) and Caucasian (81%). Patients most commonly were treated with 1 line of previous therapy (62%), had right-sided tumors (58%), and had metastatic involvement in the liver (58%), peritoneum (58%), lymph nodes (38%), and lungs (35%).

The primary end point of the study was the safety and tolerability of the triplet in the phase 1 portion of the study and ORR in the phase 2 portion. Secondary end points included PFS, OS, and DOR.

Regarding safety, no dose-limiting toxicities (DLTs) were experienced by any patients treated on the trial. In total, 6 patients reported grade 3 or 4 treatment-related adverse effects (TRAEs), all occurring following at least 1 cycle of treatment. A single instance of grade 4 myositis/myocarditis requiring discontinuation of study treatment was observed.

The most common grade 3 or higher AEs were elevated serum lipase (n = 3) and elevated serum amylase (n = 2) levels, all of which were asymptomatic and associated with nivolumab treatment.

Reference

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;43:1-13. doi:10.1016/j.ccell.2025.08.002