A phase 1/2 study of revumenib in patients (pts) with advanced colorectal cancer (CRC) and other solid tumors.

130 Background: Aberrant activation of the Wnt/β-catenin signaling pathway contributes to solid tumor development, particularly CRC. Oncogenic Wnt/β-catenin signaling is dependent on menin-histone lysine methyltransferase 2A (KMT2A) interactions; disrupting this interaction impairs tumor growth. Revumenib, a first-in-class, oral, potent, and selective inhibitor of the menin-KMT2A interaction approved for relapsed/refractory acute leukemia harboring a KMT2A gene translocation in adult and pediatric pts (≥1 yr), has shown potential therapeutic benefit in preclinical studies of solid tumors driven by dysregulated Wnt/β-catenin activity, including CRC. We report phase 1 results of a phase 1/2 study evaluating safety and tolerability of revumenib in adult pts with solid tumors in whom standard of care (SOC) has failed and in pts with CRC in whom ≥1 prior line of therapy failed (NCT05731947). Methods: Phase 1 included dose-escalation (phase 1a; solid tumors) and signal-seeking expansion (phase 1b; CRC). Eligible pts were ≥18 yrs, had an ECOG performance status score of 0-1, and solid tumors with locally recurrent or metastatic disease or microsatellite stable/proficient mismatch repair metastatic CRC. CRC pts received ≥1 line of SOC with progression on, intolerance to, or an inability to receive oxaliplatin, irinotecan, and bevacizumab in advanced disease. Phase 1a used a rolling 6 design, with a revumenib starting dose of 160 mg (tablet) 3 times daily (TID) in 28-day cycles, with escalation to 220 mg and 270 mg. The recommended phase 2 dose (RP2D) was used for the phase 1b portion. Primary objectives were safety, tolerability, maximum tolerated dose, and RP2D of revumenib, frequency, duration, and severity of treatment-emergent adverse events (TEAEs), treatment-related AEs (TRAEs), and serious AEs (SAEs), and anti-tumor effects measured by overall response rate and disease control rate (DCR). Results: Based on phase 1a (n=20), the 270-mg dose of revumenib was chosen as the RP2D for phase 1b. In phase 1b (n=21), 100% of pts had ≥1 TEAE (grade ≥3: 52.4%); 90.5% had ≥1 TRAE; and 28.6% had ≥1 SAE. TEAEs leading to study drug discontinuation occurred in 23.8% of pts. No deaths due to TEAEs occurred. The most common TEAEs were nausea (42.9%), vomiting (38.1%), and prolonged QT (38.1%). The most common TRAEs were prolonged QT (38.1%), dysgeusia, nausea, and vomiting (each 23.8%). The most common SAEs were abdominal pain (14.3%) and back pain (9.5%). Overall, no pts in the response-evaluable population (n=19) achieved a clinical response and the DCR was 10.5%. Conclusions: This phase 1 study met its primary endpoint, demonstrating revumenib TID is safe and well tolerated at a high dose (270 mg) in a heavily pretreated solid tumor and CRC population. Although limited anti-tumor efficacy was observed, safety results align with findings in acute leukemia, supporting the safe use of revumenib in solid tumors. Clinical trial information: NCT05731947 .