4219 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a notoriously difficult-to-treat malignancy, with limited therapy options for patients with advanced disease. While KRAS mutations are the dominant oncogenic driver in PDAC, next-generation sequencing has enabled the identification of rare, targetable alterations such as the BRAF V600E mutation, which occurs in approximately 2-3% of cases. BRAF mutant cell lines are responsive to MEK and RAF inhibitors. This study evaluates the efficacy of the combination of encorafenib and binimetinib as ≥ 2nd line therapy in this specific molecular subgroup of pancreatic cancer patients. Methods: This study used a planned two-stage design. Seven patients were pre-registered; one did not meet eligibility criteria and was excluded. Six patients were enrolled in Stage 1, which required an objective response (OR) in 40% of patients to proceed to Stage 2. Stage 2 was planned to enroll an additional 16 patients, contingent on meeting this efficacy threshold. Enrolled patients received treatment in 28-day cycles until disease progression or for a maximum of 36 cycles. Patients self-administered encorafenib (450 mg orally once daily) and binimetinib (45 mg orally twice daily) starting on Day 1 of each cycle. Objective responses were assessed using RECIST version 1.1 over 24 weeks. Results: The median number of cycles was 8. The objective response rate at 24 weeks was 33.33%. The overall objective response rate was 50%. The median time to response for progression-free survival, overall survival, duration of response, and time to response was 7.1, 15.0, 9.9, and 3.9 months respectively, with 95% CI in all categories. 50% of patients experienced at least one Grade ≥3 adverse event, including anemia, thromboembolic events, and acute kidney injury. Conclusions: The six BRAF-V600E-mutated PDAC patients in our cohort demonstrated meaningful antitumor activity with a manageable safety profile after treatment with encorafenib and binimetinib. Although the study was prematurely terminated due to limited accrual, observed objective responses and survival outcomes suggest that dual RAF/MEK inhibition may represent a feasible therapeutic strategy in this rare molecular subgroup. Larger studies are warranted to further define the efficacy and safety of this treatment combination in BRAF-V600E-mutated pancreatic cancer. Clinical trial information: NCI-2020-02972 .
Arouchian et al. (Wed,) studied this question.