Avutometinib plus cetuximab after chemotherapy in patients with KRAS -mutated metastatic colorectal cancer: Results of phase 1 dose escalation.

• DOI: 10.1200/jco.2025.43.4_suppl.199
• Publication Date: 2025-01-27T14:28:59Z
• Authors: Rushabh Gujarathi; Blase N. Polite; John Cursio; Aurelie Desgardin; Ryan El-Naggar; Cindy Savaiano; Katherine Wherity; Afnan Shaik; Chetan Nambiar; Nicole Arndt; Lianna Serbas; Anu Radha Neerukonda; Chih-Yi Liao; Ardaman Shergill

199 Background: Anti-EGFR antibodies like cetuximab are ineffective in KRAS mutated (mt) colorectal cancer (CRC) due to constitutive activation of downstream pathways. Avutometinib is a first class, oral, novel, dual RAF/MEK inhibitor. In patient-derived xenograft models mt CRC, the combination an anti-EGFR antibody with avutometinib conferred stronger tumor growth inhibition than either agent alone. We present results from dose escalation phase (1b) ongoing 1b/2 trial evaluating plus metastatic (m) CRC. Methods: This single-center, open-label, study safety and combined tolerability cetuximab. Patients received 2.4mg (at DL0) or 3.2mg DL1) orally twice week for 3 weeks out 4-week cycle + 500mg/m 2 intravenously q2week. disease progression on, intolerance 5-FU, oxaliplatin, irinotecan, measurable per RECIST v1.1 were enrolled. The primary endpoint 1b was establish maximum tolerated (MTD) hence determine recommended (RP2D). Dose limiting toxicity (DLT) period 28 days. A 3+3 design used level (DLs) 0 (2.4mg avutometinib) as starting one DL+1 (3.2mg avutometinib). Results: report 1b. 10 patients, 7 at DL0 DL+1, Median age 52.5 yrs (range 41 – 75). Any grade (G) treatment related adverse events (TRAEs) seen all patients. Most common TRAEs acneiform rash (100%), chills (30%), diarrhea fatigue (30%). G3 4/7 (57.1%) patients 2/3 (66.7%) No G4 seen. noted table. One patient initial three enrolled not evaluable underdosing. Another later found meet eligibility criteria, but they did clear DLT period. Hence, 6/7 evaluated AE assessment, which 1 had DLT. additional DL+1. toxicities (both DLTs) rash. Hence established MTD/RP2D. Conclusions: mCRC. RP2D when q2week Enrollment continues currently expansion efficacy assessment. Clinical information: NCT05200442 . attributed both drugs unless specified. TRAE # Acneiform 3/7 (42.9%) Hand-Foot syndrome 1/7 (14.3%) Extremity edema Cellulitis Sepsis Anemia Creatine phosphokinase elevation (14.3% only)