Phase 1/2 Open‑Label Study of RAS(ON) Inhibitor RMC-6291 with ivonescimab ± combination therapy in patients with advanced RAS‑mutated solid tumors

The primary objective is to assess the safety and tolerability of RAS(ON) inhibitors combined with ivonescimab, with or without additional anticancer agents, and to define the recommended phase 2 dose (RP2D) for this regimen in patients with RAS‑mutated solid tumors, thereby informing dose selection and risk‑benefit evaluation for subsequent development. Secondary objectives include:

• characterization of the pharmacokinetic profile of RAS(ON) inhibitors when administered with ivonescimab, with or without other anticancer agents;
• evaluation of preliminary antitumor efficacy of the combination regimen;
• characterization of the pharmacokinetic profile of ivonescimab in the same context;
• assessment of ivonescimab immunogenicity.

The trial enrolled 118 participants diagnosed with advanced RAS‑mutated solid tumors. Both female and male adults were eligible, with an age range beginning at 18 years. Eligible individuals had metastatic or unresectable disease with at least one lesion measurable by imaging and demonstrated adequate organ function. Participants were selected based on documented RAS mutation status and the ability to undergo required assessments. General health status required sufficient performance status to tolerate investigational therapy. No specific dietary, exercise, or habit restrictions were stipulated in the protocol. Key inclusion criteria included age ≥ 18 years, measurable disease, and appropriate organ function; exclusion criteria were not emphasized in the provided summary.

The study is a Phase 1/2 open-label multicenter trial evaluating the safety, tolerability, and recommended phase‑2 dose of a RAS(ON) inhibitor in combination with ivonescimab administered with or without standard anti‑cancer agents in patients with solid tumors. After obtaining written informed consent, participants undergo a screening visit to confirm eligibility, including assessment of RAS mutation status, measurable disease by imaging, and organ function. Eligible subjects then enter the baseline visit where study drugs are initiated and baseline safety labs, vital signs, and pharmacokinetic samples are collected. Subsequent study visits occur every 3 weeks during the dose‑escalation and expansion phases to monitor adverse events, laboratory parameters, vital signs, and drug concentrations; imaging assessments for response are performed every 8 weeks per RECIST v1.1. The trial continues until disease progression, unacceptable toxicity, withdrawal of consent, or completion of the planned treatment period, after which an end‑of‑study visit documents final safety and efficacy outcomes. Participants are expected to remain in the study for up to approximately 12 months, with the overall trial enrollment period spanning from July 2026 to May 2029. Early termination of individual participation may occur if a dose‑limiting toxicity is observed, if the investigator determines that continued treatment is not in the patient’s best interest, or if protocol‑required assessments cannot be completed.

Ivonescimab is supplied as an injectable solution for intravenous infusion. It is administered by slow IV infusion according to the study schedule. Infusion dates and volumes are recorded to ensure compliance.

Erbitux 5 mg/mL solution for infusion contains cetuximab and is given as an intravenous infusion. The infusion is performed on designated study days, and administration details are captured in the infusion log.

Cisplatin Hikma 1 mg/mL concentrate for infusion is prepared as a solution for intravenous infusion. The drug is infused intravenously according to the chemotherapy schedule defined in the protocol, with dosing recorded in the treatment diary.

Carboplatin Kabi 10 mg/mL concentrate for infusion is also administered as an intravenous infusion. Dosing follows the protocol‑specified cycle, and infusion parameters are monitored for each administration.

Pemetrexed 25 mg/mL concentrate for solution for infusion is provided as a concentrate that is diluted and given by intravenous infusion. The infusion is scheduled per protocol and documented in the patient’s record.

RMC‑6291 is supplied as an oral tablet. The tablet is taken by mouth at the dose and frequency specified in the study protocol. Pill counts and patient diaries are used to assess adherence.

DARAXONRASIB (RMC‑6236) is provided as an oral tablet. Administration is oral, with dosing and schedule defined by the protocol. Compliance is monitored through returned tablet counts and electronic diaries.

RMC‑9805 is an oral tablet administered by mouth according to the protocol‑defined dose and schedule. Adherence is evaluated by pill count and patient‑reported intake.

Efficacy will be evaluated using radiographic response criteria and pharmacodynamic assessments. Tumor response will be quantified according to RECIST v1.1, providing the objective response rate (ORR), duration of response (DOR), disease control rate (DCR), time to response (TTR), and progression‑free survival (PFS). Imaging studies will be performed at baseline and at predefined assessment visits, with centralized independent review to ensure consistency.

Pharmacokinetic and immunogenicity evaluations will support efficacy interpretation. Serial blood samples will be analyzed for ivonescimab serum concentrations and for concentrations of the RAS(ON) inhibitor using validated bioanalytical methods. The presence of anti‑ivonescimab antibodies will be determined at baseline and during treatment using a validated immunoassay, reporting the proportion of patients with detectable antibodies.