RMC-6236, Revolution Medicines' RAS^MULTI (ON) inhibitor, is designed as a first-in-class, potent, oral, RAS-selective tri-complex inhibitor of multiple RAS(ON) variants including cancer drivers at all three of the major mutation hotspot positions, G12, G13, and Q61. The drug inhibits all three major RAS isoforms, suppressing the mutant cancer driver and cooperating wild-type RAS proteins.

The RMC-6236-001 Phase I/IB trial is a multicenter, open-label, dose-escalation and dose-expansion study designed to evaluate RMC-6236 as monotherapy in patients with advanced solid tumors harboring KRAS G12X mutations.  As of October 12, 2023, a total of 111 patients with NSCLC (n=46) or PDAC (n=65) were treated at dose levels administered once daily (QD) ranging from 80 mg to 400 mg. Common KRAS mutations in patients evaluated included G12D, G12V, G12R, G12A, and G12S; patients with KRAS G12C mutations were excluded from the study due to the availability of currently approved KRAS G12C(OFF) inhibitors. All patients had previously been treated with a standard of care appropriate for tumor type and stage. Patients with NSCLC had received a median of two prior lines of therapy while patients with PDAC had received a median of three prior lines of therapy. 

RMC-6236 demonstrated preliminary evidence of clinical activity and an acceptable safety profile that was generally well tolerated across the dose levels analyzed. Clinical activity was evaluated in patients who had received the first dose of RMC-6236 at least eight weeks before the data extraction date (n=86). Among the 40 efficacy evaluable NSCLC patients, the objective response rate was 38%, with one patient achieving a complete response (CR) as a best response and 14 patients achieving a partial response (PR) (including three unconfirmed PRs).  The disease control rate (DCR) in this NSCLC population was 85%. Among the 46 efficacy evaluable PDAC patients, the objective response rate was 20%, with nine patients achieving a PR (including four unconfirmed PRs) as a best response. The DCR in this PDAC population was 87%. Confirmed objective responses included tumors harboring KRAS mutations G12D, G12V, or G12R, and disease control was observed across all KRAS mutations, including G12A and G12S. 

The most common treatment-related adverse events (TRAEs) were rash and GI-related toxicities that were primarily Grade 1 or 2 in severity. The reported Grade 3 TRAEs were rash, stomatitis, and diarrhea. One previously reported Grade 4 TRAE occurred in a patient with PDAC at the 80 mg QD dose level who had a large intestine perforation at the site of an invasive tumor that reduced in size while on treatment, which resulted in treatment discontinuation. No safety signals were observed that indicated an elevated risk of hepatotoxicity, which has been reported for some KRAS G12C(OFF) inhibitors. 

RMC-6236 demonstrated notable efficacy in combating tumor growth among patients afflicted with KRAS G12X mutations in both PDAC and NSCLC, while maintaining a high level of tolerability at the administered doses.

KOL insights

“RMC-6236, a new RAS inhibitor, showed promising activity in PDAC and NSCLC with KRAS G12X mutations. Good safety profile and PK profile showed a decrease in ctDNA associated with the response.” - Medical Oncologist, Gustave Roussy Cancer Center, France

Conclusion

DelveInsight estimated that the United States had the highest number of KRAS mutation cases in NSCLC among the 7MM. Approximately 45-50% of all KRAS mutation cases in NSCLC in the 7MM were reported in the United States.

RMC-6236 has shown favorable tolerability at effective clinical doses. It has demonstrated promising anti-tumor effects in patients with previously treated NSCLC and PDAC, irrespective of their KRAS G12X genotypes, including common mutants like G12D, G12V, and G12R. Moreover, a correlation has been observed between the reduction in KRAS VAF in ctDNA and positive clinical responses, spanning different types of tumors. The preliminary safety and clinical activity data strongly support the continued development of RMC-6236 as a standalone treatment. Additionally, there are plans to explore its potential in combination with RMC-6291, immunotherapy, and other anti-cancer therapies, highlighting its versatility in cancer treatment strategies.

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the KRAS Inhibitors Market Forecast and Non-Small Cell Lung Cancer Market Forecast Report

Note: The therapeutics segment is experiencing significant NSCLC clinical trial activity, which is further expected to drive Non-Small Cell Lung Caner market growth in the coming years.