Revolution Medicines has begun treating patients in RASolve 308, a global Phase 3 trial evaluating whether adding zoldonrasib to pembrolizumab and chemotherapy can improve outcomes in previously untreated metastatic RAS G12D non-squamous non-small cell lung cancer (NSCLC).
The company announced the milestone on October 20, 2026. Zoldonrasib is an investigational oral RAS(ON) G12D-selective inhibitor.
Addressing an Underserved Lung Cancer Population
According to Revolution Medicines, RAS G12D mutations occur in approximately 4% of NSCLC cases, representing a population without an approved mutation-specific targeted treatment.
Alan Sandler, MD, Chief Development Officer of Revolution Medicines, said:
“Patients with metastatic RAS G12D non-squamous NSCLC, occurring in approximately 4% of cases, represent an underserved population, with no approved targeted treatment options.”
Sandler noted that initial clinical data for zoldonrasib combined with standard-of-care pembrolizumab and platinum doublet chemotherapy showed encouraging preliminary antitumor activity and a favorable safety profile in previously untreated metastatic RAS G12D non-squamous NSCLC. He said these findings provided a strong clinical rationale for the Phase 3 RASolve 308 trial.
He added that RASolve 308, together with other registrational trials evaluating the company’s RAS(ON) inhibitors across multiple tumor types, reflects Revolution Medicines’ commitment to establishing RAS(ON) inhibition as a new standard of care and a treatment backbone for patients with RAS-driven cancers.
RASolve 308: Adding Zoldonrasib to Chemoimmunotherapy
RASolve 308 (NCT07777822) is a randomized, double-blind study comparing zoldonrasib with placebo, each administered alongside pembrolizumab and platinum-based doublet chemotherapy. The trial’s formal title specifies pemetrexed as part of the chemotherapy regimen.
The study evaluates the efficacy of adding an investigational RAS(ON) inhibitor to the same chemoimmunotherapy backbone used in the control group.
The primary endpoint is progression-free survival. Key secondary endpoints include overall survival, objective response rate, duration of response, safety and tolerability, and patient-reported outcomes.
Which Patients Are Eligible?
According to the trial listing, key eligibility requirements include:
- Age 18 years or older.
- Previously untreated, histologically or cytologically confirmed metastatic non-squamous NSCLC.
- A documented RAS G12D mutation and known PD-L1 status.
- An Eastern Cooperative Oncology Group performance status of 0 or 1.
- Measurable disease according to RECIST version 1.1.
- Adequate organ function and the ability to take oral medication.
Listed exclusions include prior systemic anticancer treatment for metastatic NSCLC, previous RAS-directed therapy, and untreated central nervous system metastases. Additional protocol requirements apply.
Earlier Combination Data Supporting Phase 3 Evaluation
In its August 2026 clinical update, Revolution Medicines reported preliminary findings for zoldonrasib combined with pembrolizumab and platinum-based doublet chemotherapy in first-line RAS G12D NSCLC.
The analysis included 38 patients, with efficacy evaluable in 28 patients who had at least eight weeks of follow-up. At the May 11, 2026, data cutoff, median follow-up was 3.4 months.
The company reported:
- An objective response rate of 82%, including confirmed responses and responses pending confirmation.
- A disease control rate of 100%.
Response rates, including confirmed and pending responses, ranging from 60% to 100% across PD-L1 tumor proportion score subgroups.
Revolution Medicines described the combination’s safety profile as manageable, with treatment-related adverse events generally consistent with those associated with the chemoimmunotherapy backbone, minimal added toxicity, and a favorable liver safety profile.
These findings were preliminary results from the earlier combination evaluation; they were not outcomes from RASolve 308.
How Zoldonrasib Targets RAS G12D
Zoldonrasib, also known as RMC-9805, uses a tri-complex approach. It binds to cyclophilin A, forming a complex that selectively recognizes and inhibits the active, cancer-driving form of RAS G12D.
Revolution Medicines is developing zoldonrasib both as monotherapy and in combinations across different tumor types and treatment settings.
Earlier FDA Recognition in Previously Treated NSCLC
In January 2026, the company announced FDA Breakthrough Therapy Designation for zoldonrasib for adults with KRAS G12D-mutated locally advanced or metastatic NSCLC previously treated with anti-PD-1/PD-L1 therapy and platinum-based chemotherapy.
That designation was based on the monotherapy cohort of the Phase 1 RMC-9805-001 trial. It concerns a previously treated population, whereas RASolve 308 evaluates a combination regimen in the first-line metastatic setting.
Breakthrough Therapy Designation is intended to expedite the development and review of investigational medicines for serious conditions when preliminary clinical evidence indicates potential improvement over available treatment. Zoldonrasib remains investigational.
Read further on OncoDaily: Zoldonrasib Shows Early Strength in Previously Treated KRAS G12D NSCLC
