Phase 1 dose escalation results of the WEE1 inhibitor, azenosertib (A), in combination with encorafenib (E) and cetuximab (C) in patients (pts) with previously treated <i>BRAF V600E</i> mutantmetastatic colorectal cancer (mCRC).
Authors: Jeanne Tie, Marcos Melian, Ana Ruiz-Casado, Lucjan Wyrwicz, Piotr Jan Wysocki, Patrick Stuebs, Enrique Aranda, Nuria Salas, Elena Elez, Giuseppe Curigliano, Barbara Radecka, Christine Parseghian, Istvan Takacs, Volker Heinemann, Grace Vandal, Nidal Huniti, Joana Vidal Barrul
Journal: Journal of Clinical Oncology (2025)

3551 Background: Encorafenib + cetuximab was approved for treating pts with BRAF V600E mutant mCRC after prior systemic therapy based on the Phase 3 BEACON study (observed response rate 20%; Kopetz et al. 2019). Azenosertib is a highly selective WEE1 inhibitor that causes mitotic catastrophe and cell death. Combining BRAF targeting treatment (E+C) with orthogonal pathway inhibitors may allow for an additive or synergistic combination effect of A. This study aimed to evaluate safety and tolerability, determine the maximum tolerated dose (MTD), and assess anti-tumor activity in pts with BRAF V600E mutant mCRC receiving A+E+C. Methods: This phase 1 dose escalation, open-label, multicenter study (NCT05743036) evaluated safety, tolerability, and activity of A administered in combination with E+C in adult pts with BRAF V600E -mutant mCRC who received 1-3 prior regimens for metastatic disease. Azenosertib is a CYP3A4 substrate and is predicted to moderately inhibit CYP3A4 while weakly inhibiting CYP2C19. Encorafenib is primarily metabolized by CYP3A4 and CYP2C19, and acts as a CYP3A4 inducer. To allow for exposures to optimize treatment benefits and minimize toxicity, the recommended starting dose of E is 150 mg once a week. The primary endpoint was dose-limiting toxicities (DLTs) in cycle 1. Pts were treated across 5 dose-finding cohorts, receiving A (dose range: 100 mg-400 mg once a day [QD] oral [PO] on a continuous schedule) and E (dose range: 75 mg or 150 mg QD PO), and C (500 mg/m 2 intravenous twice a week) until disease progression or unacceptable toxicity. Results: As of Nov 25, 2024, 44 pts were enrolled and treated with a median age of 64 years. 52.3% of pts received ≥2 prior lines of therapy, 34 pts were BRAF inhibitor (BRAFi)-naïve. The most frequent treatment-related Grade ≥3 adverse events were asthenia (11.4%) and fatigue (6.8%). DLTs were observed at the dose levels of A300+E150 and A400+E75 and included dose-limiting fatigue, atrial fibrillation, recurring elevated bilirubin (all Grade 3), and Grade 4 neutropenia. The MTD was determined to be A300+E75 and C. Twelve of 34 (35.3%) BRAFi-naïve pts achieved confirmed response per RECIST v1.1 (2 complete response, 10 partial response [PR]) while none of the BRAFi-pretreated pts responded. Seven of 17 (41.2%) BRAFi-naïve pts treated at A300+75 or A300+150 achieved confirmed PR. The median duration of response and the median progression-free survival in the BRAFi-naïve pts were 5.6 and 5.4 months, respectively. Conclusions: The combination of A+E+C was well tolerated at the MTD and yielded response rates in BRAFi-naïve mCRC pts which exceeded the historical data from the E+C doublet. Clinical trial information: NCT05743036 .