RMC6236: RAS-IN-2 (Compound A122) is a potent RAS(ON)MULTI inhibitor and can be used for the research of cancer[1].
RMC-6236 (RAS Duote Me)
RMC-6236 is an oral RAS (ON) inhibitor designed to treat cancer patients G12D, Krass G12V, and Krass G12R driven by multiple RAS mutations, including KRAS. Initially evaluated as monotherapy, it can also be used in combination with mutation selective RAS (ON) inhibitors as RAS concomitant inhibitors.
The ongoing Phase 1/1b monotherapy trial (NCT05379985) is a multicenter, open-label, dose-increasing, and dose-extending study for G12 mutations in advanced solid tumor patients carrying specific KRAS, including KRASG12D, Krass G12V, and Krass G12R
Early findings indicate that RMC-6236 has oral bioavailability in patients, exhibits pharmacokinetics consistent with our preclinical data, and provides a dose-dependent increase in plasma exposure during daily administration, and is generally well tolerated. The recommended dosage for Phase 2 has not been determined yet.
As of the data deadline of February 17, 2023, this study evaluated the initial safety and tolerability of 36 patients. All of these patients have previously received standard care and/or other treatment regimens, with an overall median of three previous treatments. As of the data cut-off, RMC-6236 was generally well tolerated in this group. Some patients exhibit predictable and controllable targeting of normal tissue effects.
As of the data deadline of February 17, 2023, 12 patients (3 patients with non-small cell lung cancer (NSCLC) and 9 patients with pancreatic cancer) were treated with RMC-6236 at a dose of 40 mg, 80 mg or 120 mg, and the efficacy could be evaluated. All 12 patients showed stable or better optimal response; Ten of them showed a decrease in tumor volume by the data deadline. Importantly, as of the data deadline, all patients are still in the study, with a total duration of approximately 1.5 to 4.5 months. A KRAS patient with NSCLC treated with 80mg of G12D achieved partial remission (PR) during the first re staging scan, which was subsequently confirmed through subsequent scans. One case of metastatic KRAS patient with G12D advanced pancreatic cancer after the third course of chemotherapy received RMC-6236 80 mg per day and was well tolerated. At baseline, the patient had three different lung lesions that required imaging examination. At six weeks, the size of all three tumor lesions decreased, with a 17% reduction reported according to the Solid Tumor Response Assessment Standard (RECIST). At 12 weeks, all three residual lesions were almost undetectable, and patients achieved a 70% reduction and PR through RECIST. The patient will continue the study on the data deadline and wait for subsequent scans to confirm their response
