Abstract PR010: Preliminary safety and pharmacokinetic profiles of RMC-6236, a first-in-class, RAS-selective, tri-complex RASMULTI(ON) inhibitor in patients with KRAS mutant solid tumors on the Phase 1 trial RMC-6236-001

Abstract Background: RMC-6236 is an oral RASMULTI(ON) tri-complex inhibitor that is selective for the active, GTP-bound state of both mutant and wild-type variants of the canonical RAS isoforms. RMC-6236 binds to cyclophilin A, which is abundantly expressed in normal tissues and tumors, resulting in a binary complex that potently binds to RAS(ON) to form a tri-complex, blocking downstream signaling. Preclinical studies with RMC-6236 demonstrated deep and sustained regressions across multiple RASMUT tumor types at well tolerated doses, particularly tumors harboring KRAS glycine-12 substitutions (KRASG12X). Methods: Patients with previously treated, advanced KRASG12X mutant solid tumors were enrolled at escalating doses of single agent RMC-6236 administered once daily (QD). Results: As of May 11, 2023, 54 patients received RMC-6236 at dose levels from 10 to 220 mg QD. The majority of patients had pancreatic cancer (26 [48%]), non-small cell lung cancer (13 [24%]), or colorectal cancer (10 [19%]). The most common (≥10% of patients) treatment-related adverse events (TRAEs) were rash and gastrointestinal (GI)-related toxicities that were all Grade 1 or 2 in severity. Most rashes were acneiform (35%) or maculopapular (13%), consistent with known on-target rash presentation from other RAS pathway inhibitors. Rash frequency, but not severity, was dose-dependent. One patient required a dose reduction due to Grade 2 acneiform rash. The most common GI-related toxicities were nausea (32%), diarrhea (19%), and vomiting (15%) that were manageable with standard supportive care. There were two Grade ≥3 TRAEs in patients with pancreatic cancer: Grade 4 large intestine perforation at the site of an invasive tumor that reduced in size on treatment, and Grade 3 pancreatitis reported at the time of disease progression. Thirty-one patients (57%) remain on treatment, and 23 (43%) discontinued, including 17 (31%) due to progressive disease (PD) per RECIST v1.1, 2 (4%) due to clinical progression, and other reasons due to adverse event (Grade 4 large intestine perforation), death (due to PD), investigator’s decision, or patient withdrawal (1 patient each). RMC-6236 exhibited dose-dependent increases in exposure in patients with no apparent accumulation in the blood following repeated daily dosing. At 220 mg QD, exposure to RMC-6236 was within range of the preclinical exposures in mice that demonstrated significant tumor regressions. Preliminary evidence of anti-tumor activity, including partial responses per RECIST v1.1, was observed in patients across several tumor types and dose levels. Molecular responses were observed with reduction in circulating tumor DNA of the KRAS-mutated allele and other somatic mutations consistent with inhibition of mutant RAS by RMC-6236. Conclusions: RMC-6236 is safe and well tolerated at doses that induce anti-tumor activity in patients with tumors harboring KRASG12X mutations and has favorable pharmacokinetics with oral dosing. A recommended phase 2 dose has not yet been determined and dose escalation is ongoing. Citation Format: Alexander I Spira, Alexander N Starodub, Kathryn C Arbour, David Sommerhalder, Brian M Wolpin, Minal Barve, Ignacio Garrido-Laguna, Salman Punekar, Meredith Pelster, Sumit Kar, Jamie Wong, Tong Lin, Rakesh Raman, Lin Tao, Zeena Salman, Xiaolin Wang, W. Clay Gustafson, David S Hong. Preliminary safety and pharmacokinetic profiles of RMC-6236, a first-in-class, RAS-selective, tri-complex RASMULTI(ON) inhibitor in patients with KRAS mutant solid tumors on the Phase 1 trial RMC-6236-001 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR010.