Combining RAS(ON) inhibitors with ivonescimab for adults with RAS‑mutant advanced solid tumors

A Phase 1/2 Open-Label, Multicenter Study of RAS(ON) Inhibitors in Combination With Ivonescimab With or Without Other Anti-Cancer Agents in Patients With Solid Tumors

This trial will test whether combining RAS(ON) inhibitors with ivonescimab is safe and can shrink or control tumors in adults with advanced or metastatic solid tumors that have RAS mutations.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 370 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Revolution Medicines, Inc. (industry)
• Drugs / interventions: ivonescimab
• Locations: 5 sites (Norwich, Connecticut and 4 other locations)
• Trial ID: NCT07397338 on ClinicalTrials.gov

What this trial studies

This open‑label, multicenter Phase 1/2 trial tests three different RAS(ON) inhibitors (daraxonrasib, elironrasib, zoldonrasib) each given with the monoclonal antibody ivonescimab in adults with RAS‑mutant advanced or metastatic solid tumors. Each arm includes a Part 1 dose‑finding stage to explore safety, tolerability, and pharmacokinetics, followed by a Part 2 dose‑expansion stage to look for antitumor activity and further safety signals, with some expansions allowing additional anti‑cancer agents such as platinum/pemetrexed chemotherapy. Primary outcomes include safety, tolerability, and drug exposure, and secondary assessments include preliminary tumor responses measured by RECIST v1.1. Enrollment criteria and prior‑treatment limits differ by arm and cohort (for example, certain expansions enroll treatment‑naive non‑squamous NSCLC or colorectal/solid tumors after limited prior lines of therapy).

Who should consider this trial

Good fit: Adults (≥18) with measurable, locally advanced or metastatic solid tumors harboring documented KRAS, HRAS, or NRAS mutations, ECOG 0–1, adequate organ function, and who meet the prior‑therapy criteria for the relevant expansion cohort are the intended participants.

Not a fit: Patients without a RAS mutation, those with head and neck squamous cell carcinoma, poor performance status (ECOG >1), significant organ dysfunction, or who do not meet the protocol's prior‑treatment requirements are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, the combination could provide a new targeted option that controls or reduces RAS‑mutant tumors in patients who have limited effective treatments.

How similar studies have performed: Selective KRAS inhibitors (notably for G12C) have shown clinical benefit in prior trials, but combining RAS(ON) inhibitors with an antibody like ivonescimab is a newer strategy that has not yet been widely validated.

Eligibility criteria

Inclusion Criteria:

* At least 18 years old and has provided informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Histologically confirmed, locally advanced or metastatic solid tumor malignancy with documented RAS mutation in KRAS, HRAS, or NRAS.
* Received and progressed or been intolerant to prior standard therapy (Part 1 Dose Exploration).
* Non-squamous NSCLC without a treatable driver mutation in other oncogenes that has not received prior systemic treatment (Arms A \& B for Part 2 Dose Expansion).
* Solid tumor or CRC previously treated with no more than 2 prior lines of therapy for advanced disease and progressed or been intolerant to prior standard therapies (Arm C for Part 2 Dose Expansion).
* Measurable disease per RECIST v1.1
* Adequate organ function (bone marrow, liver, kidney, coagulation, endocrine).
* Able to take oral medications.

Exclusion Criteria:

* Head and neck squamous cell carcinoma.
* Any conditions that may affect the ability to take or absorb study drug.
* Major surgery within 4 weeks prior to receiving study drug(s).
* Patient is unable or unwilling to comply with protocol-required study visits or procedures.
* Other inclusion/exclusion criteria may apply.

Where this trial is running

Norwich, Connecticut and 4 other locations

• Eastern Connecticut Hematology and Oncology Associates — Norwich, Connecticut, United States (RECRUITING)
• Tennessee Oncology — Nashville, Tennessee, United States (RECRUITING)
• NEXT Dallas — Irving, Texas, United States (RECRUITING)
• NEXT Oncology — San Antonio, Texas, United States (RECRUITING)
• NEXT Virginia — Fairfax, Virginia, United States (RECRUITING)

Study contacts

• Study coordinator: Revolution Medicines Study Director

Conditions: Advanced Solid Tumors, Metastatic Solid Tumors, Non-small Cell Lung Cancer, NSCLC, Colorectal Cancer, CRC, RAS, NRAS