Revolution Medicines is advancing its pipeline of RAS(ON) inhibitors, RMC-6236 and RMC-6291, demonstrating promising clinical activity in non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). The company is preparing for a pivotal Phase 3 trial of RMC-6236 in NSCLC and is evaluating options for late-stage development in PDAC.
RMC-6236: A RASMULTI Inhibitor
RMC-6236, a RASMULTI inhibitor, has shown objective anti-tumor activity against KRAS G12D, G12V, and G12R mutations, which collectively drive a significant portion of RAS-driven solid tumors. Data from an ongoing clinical trial indicates that RMC-6236 is well-tolerated at clinically active doses, enabling continuous dosing, which is crucial for treating RAS-addicted cancers.
In NSCLC, RMC-6236 achieved a 38% objective response rate (ORR). The company anticipates this number settling out in the 40% to 50% range at the recommended Phase 2 dose. Based on these findings, Revolution Medicines plans to initiate a pivotal Phase 3 trial in second-line RAS-mutant NSCLC in 2024, with a potential accelerated approval opportunity.
For PDAC, the blended ORR was 20%. While ORR is not the key clinical endpoint for PDAC, the disease control rate was 87%, significantly higher than reports for salvage chemotherapy. Median progression-free survival (PFS) for standard second-line PDAC treatment is approximately three months. Encouragingly, many patients on the RMC-6236 study have already crossed this threshold and remain on treatment, with some continuing as far out as 48 weeks. The company expects to establish RMC-6236's durability profile via median PFS and identify a recommended Phase 2 dose in 2024, with plans to initiate a pivotal monotherapy trial in pancreatic cancer.
RMC-6291: Targeting KRAS G12C Cancers
RMC-6291, another investigational drug, targets KRAS G12C cancers. Clinical data shows that RMC-6291 is well-tolerated across a wide range of clinically active doses. In NSCLC patients who had recently progressed on prior treatment with an approved KRAS G12C(OFF) inhibitor, RMC-6291 demonstrated a 50% ORR, compared to a 7% ORR with G12C(OFF) inhibitors in similar patients. In colorectal cancer patients who had not yet experienced a RAS inhibitor, the ORR for single-agent RMC-6291 was 43%, similar to reported data from G12C(OFF) inhibitors when used in combination with anti-EGFR antibodies.
Revolution Medicines is conducting monotherapy dose optimization with the goal of selecting a single-agent recommended Phase II dose. The company is also committed to evaluating combination options, including the pairing of RMC-6236 plus RMC-6291.
Acquisition of EQRx
Revolution Medicines expects to acquire EQRx in an all-stock transaction, gaining an estimated $1.1 billion in additional net capital. This strengthened balance sheet will support the late-stage development of its RAS(ON) inhibitor pipeline, initially focused on RMC-6236, 6291, and 980.
