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

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