Revolution Medicines has reported encouraging clinical data for its investigational drug zoldonrasib (RMC-9805) in patients with KRAS G12D mutant non-small cell lung cancer (NSCLC), expanding the potential applications of this targeted therapy beyond pancreatic cancer.
The data, presented at the American Association for Cancer Research (AACR) Annual Meeting, showed that zoldonrasib achieved an objective response rate of 61% in NSCLC patients, with 11 out of 18 efficacy-evaluable patients demonstrating confirmed or pending confirmation of response. The disease control rate reached 89%, with 16 patients showing clinical benefit.
"These data reinforce the clinical potential of zoldonrasib following the initial tolerability and antitumor activity reported late last year in patients with pancreatic ductal adenocarcinoma," said Mark A. Goldsmith, CEO and Chairman of Revolution Medicines. "Together these results support further evaluation of zoldonrasib as monotherapy and in combination as we continue efforts to advance innovative targeted medicines for patients living with these hard-to-treat cancers."
Study Design and Safety Profile
The RMC-9805-001 trial is a multicenter, open-label, dose-escalation and dose-expansion Phase 1 study evaluating zoldonrasib in patients with advanced solid tumors harboring a KRAS G12D mutation. As of the December 2, 2024 data cutoff, 90 solid tumor patients had been treated with the recommended Phase 2 dose of 1200 mg once daily.
Zoldonrasib demonstrated an acceptable safety profile that was generally consistent with previously reported data in pancreatic cancer patients. The treatment was well-tolerated with most adverse events being Grade 1 or 2 in severity. Only two patients (2%) experienced Grade 3 events, which resolved following dose interruption. Notably, the drug maintained a favorable mean dose intensity of 98%, and no dose-limiting toxicities were observed.
Previous Success in Pancreatic Cancer
The new lung cancer data builds on Revolution Medicines' October 2024 announcement of promising results in pancreatic ductal adenocarcinoma (PDAC), a notoriously difficult-to-treat cancer with limited therapeutic options.
In that study, patients with previously treated PDAC who received zoldonrasib at the recommended Phase 2 dose (either 1200 mg once daily or 600 mg twice daily) achieved a 30% objective response rate and an 80% disease control rate. These results were considered significant given the historically poor outcomes for patients with KRAS-mutated pancreatic cancer.
Targeting the "Undruggable" KRAS
Zoldonrasib represents an important advancement in precision oncology as it selectively targets KRAS G12D mutations, which have long been considered "undruggable." KRAS mutations are among the most common oncogenic drivers in human cancers, with the G12D variant particularly prevalent in pancreatic, colorectal, and lung cancers.
The drug works by selectively inhibiting the active, GTP-bound form of KRAS G12D (RAS(ON)), a novel approach that differs from earlier KRAS inhibitors that target other variants such as G12C.
Market Impact and Future Directions
News of the positive clinical data had an immediate impact on Revolution Medicines' stock, which rose significantly following the announcement. The company's shares closed at $41.91 on May 8, up $4.25 or 11%.
During the company's first-quarter update, CEO Mark Goldsmith referred to the pipeline progress as "an embarrassment of riches," suggesting confidence in the broader development program.
The company plans to continue evaluating zoldonrasib both as a monotherapy and in combination with other agents. Given the significant unmet need in KRAS-mutated cancers and the promising early results, zoldonrasib could potentially address a substantial market opportunity if approved.
Clinical Implications
For oncologists treating patients with KRAS G12D-mutated cancers, these results offer hope for a new targeted approach. Currently, patients with these mutations have limited treatment options, particularly after progression on standard therapies.
The consistent activity observed across both lung and pancreatic cancers suggests that zoldonrasib's mechanism of action effectively targets the fundamental biology of KRAS G12D-driven tumors regardless of tissue origin. This could potentially lead to basket trial approaches that select patients based on mutation status rather than cancer type.
As Revolution Medicines continues to advance zoldonrasib through clinical development, the medical community will be watching closely to see if these early promising results translate into durable responses and meaningful survival benefits for patients with these challenging malignancies.
