A phase III, randomized, open-label study of tunlametinib plus vemurafenib versus investigator's choice of therapy in patients with previously treated <i>BRAF</i> ^V600E -mutant metastatic colorectal cancer.

Abstract

LBA3509 Background: The BRAF V600E mutation present in approximately 10% of metastatic colorectal cancer (mCRC) cases, confers a poor prognosis with limited response to chemotherapy. Tunlametinib is a novel, oral, high-potent MEK1/2 inhibitor. Synergistic effect of tunlametinib with vemurafenib was seen in BRAF mutant non-small cell lung cancer and mCRC in the previously published phase I trial (NCT03781219.). Based on promising Phase I/II data, we have this BRAF/MEK inhibitor dual-target regimen to advance to a Phase III randomized controlled trial in this population, addressing a significant unmet need. Methods: This randomized, open-label, phase III trial (NCT06008119) enrolled patients. with BRAF V600E–mutant mCRC after ≥1 prior line of systemic therapy. Patients were randomized 2:1 to tunlametinib (12 mg BID) + vemurafenib (720 mg BID) (T+V) or investigator's choice of therapy (control). A prespecified crossover from the control to the experimental arm is allowed upon IRC-confirmed disease progression. The primary endpoint is progression-free survival (PFS) assessed by a blinded Independent Review Committee per RECIST v1.1. Secondary endpoints include overall survival (OS), objective response rate (ORR), and safety. The primary endpoint PFS analysis will use a stratified log-rank test, with the hazard ratio (HR) and its 95% confidence interval estimated using a Cox proportional hazards model. Results: As of the data cutoff date for this analysis (March 5, 2026), the full analysis set included 157 patients (105 T+V, 52 control). Based on investigator assessment (IRC assessment ongoing), median PFS was significantly prolonged with T+V versus control (4.2 months vs. 1.5 months; HR 0.374; 95% CI 0.252–0.555; P &lt; 0.001). The ORR was 37.1% (95% CI 27.9–47.1) in the T+V group versus 7.7% (95% CI 2.1–18.5) in the control group. P＜0.0001. DCR was 81.9% versus 38.5% (P &lt; 0.0001), respectively. OS data was immature. Treatment-related grade≥3 adverse events (TRAEs) occurred in 62.0% vs 44.2% of patients, Permanent treatment discontinuation due to TRAEs occurred in 0.9% and 3.8%, respectively. Safety was consistent with that known for each agent. Conclusions: This is the first phase III randomized controlled trial to demonstrate that a BRAF/MEK inhibitor combination (tunlametinib plus vemurafenib) significantly improves PFS and ORR compared with conventional chemotherapy-based regimens in previously treated BRAF V600E–mutant mCRC, with a manageable safety profile and the added benefit of a convenient all-oral regimen. Clinical trial information: NCT06008119 .