Study of RAS(ON) Inhibitors in Patients With Advanced RAS-mutated NSCLC

June 25, 2026 updated by: Revolution Medicines, Inc.

A Platform Study of RAS(ON) Inhibitors in Patients With RAS-Mutated Non-Small Cell Lung Cancer (NSCLC)

The purpose of this platform study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors as a monotherapy or combined with Standard(s) of Care (SOC) or with each other.

The first four subprotocols include the following:

Subprotocol A: RMC-6291 +/- RMC-6236 + SOC Subprotocol B: RMC-6236 + SOC Subprotocol C: RMC-9805 +/- RMC-6236 + SOC Subprotocol D: RMC-9805

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The platform study design allows combinations of RAS(ON) inhibitors with other anticancer agents or as a monotherapy to be evaluated in patients with RAS-mutated solid tumors with a focus on NSCLC.

This is an open-label platform Phase 1b/2 study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors combined with Standard of Care (SOC), or as a monotherapy and to define the Recommended Phase 2 Dose and Schedule (RP2DS). Enrollment of patients with KRAS or RAS mutations will be specified in each subprotocol.

Subprotocol A is an open-label, multicenter, Phase 1b/2 study of RMC-6291, with or without RMC-6236, in combination with pembrolizumab, with or without chemotherapy, in patients with KRAS G12C-mutated advanced solid tumors.

Subprotocol B is an open-label, multicenter, Phase1b/2 study of RMC-6236 in combination with pembrolizumab, with or without chemotherapy, in patients with RAS-mutated non-small cell lung cancer (NSCLC)

Subprotocol C is an open-label, multicenter, Phase1b/2 study of RMC-9805 with or without RMC-6236, in combination with other anticancer agents, in patients with RAS G12D-mutated non-small cell lung cancer (NSCLC)

Subprotocol D is a Phase 2, Open-label, Multicenter Study of Zoldonrasib (RMC-9805) in Previously Treated Patients with RAS G12D-Mutant Non-Small Cell Lung Cancer (NSCLC)

Subprotocols A, B, and C consist of two parts: Part 1 - Dose Exploration and Part 2 - Dose Expansion. Subprotocol D consists of only one part.

Study Type

Interventional

Enrollment (Estimated)

616

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Australia
    • New South Wales
      • Camperdown, New South Wales, Australia, 2050
        • Recruiting
        • Chris O'Brien Lifehouse Hosptial
      • Liverpool, New South Wales, Australia, 2170
        • Recruiting
        • Liverpool Hospital
      • St Leonards, New South Wales, Australia, 2065
        • Recruiting
        • Royal North Shore Hospital
    • Victoria
      • Clayton, Victoria, Australia, 3168
        • Recruiting
        • Monash Health
    • Western Australia
      • Nedlands, Western Australia, Australia, 6009
        • Recruiting
        • Linear Clinical Research
  • Austria
    • Austria
      • Sankt Pölten, Austria, Austria, 3100
        • Recruiting
        • Universitätsklinikum St. Pölten
  • Czechia
    • Czech Republic
      • Nový Jičín, Czech Republic, Czechia, 741 01
        • Recruiting
        • Nemocnice AGEL Novy Jicin a.s
  • Denmark
      • Copenhagen, Denmark, 2100
        • Recruiting
        • Rigshospitalet
      • Odense, Denmark, 5000
        • Recruiting
        • Odense University Hospital, Department of Oncology
  • France
      • Angers, France, 49055
        • Recruiting
        • Institut de Cancerologie de Ouest (ICO) - Angers
      • Boulogne, France, 92104
        • Recruiting
        • Ambroise-Paré Hospital
      • Caen, France, 14076
      • Paris, France, 75014
        • Recruiting
        • Hopital Cochin
      • Paris, France, 75020
        • Recruiting
        • Hopital Tenon - AP-HP
      • Suresnes, France, 92150
      • Toulouse, France, 31059
      • Villejuif, France, 94805
    • Auvergne-Rhône-Alpes
      • Bron, Auvergne-Rhône-Alpes, France, 69500
        • Recruiting
        • Hospices Civils de Lyon - Hôpital Louis Pradel
        • Contact:
    • Bourgogne-Franche-Comté
      • Dijon, Bourgogne-Franche-Comté, France, 21079
        • Recruiting
        • Centre Georges Francois Leclerc
        • Contact:
    • Hauts-de-France
      • Lille, Hauts-de-France, France, 59037
      • Nantes, Hauts-de-France, France, 44093
    • New Aquitaine
      • Bordeaux, New Aquitaine, France, 33000
    • Île-de-France Region
      • Paris, Île-de-France Region, France, 75005
  • Germany
      • Berlin, Germany, 12203
        • Recruiting
        • Charite-Universitaetsmedizin Berlin - Campus Charite Mitte
        • Contact:
      • Cologne, Germany, 50937
      • Dresden, Germany, 01307
        • Recruiting
        • Universitätsklinikum Carl Gustav Carus an der TU Dresden
        • Contact:
          • Max Langner
          • Phone Number: +49 351 458 7566
          • Email: ectu@ukdd.de
      • Frankfurt am Main, Germany, 60590
      • Heidelberg, Germany, 69126
      • Immenhausen, Germany, 34376
      • Moers, Germany, 47441
  • Greece
      • Athens, Greece, 115 26
        • Recruiting
        • Henry Dunant Hospital Center
      • Athens, Greece, 11527
        • Recruiting
        • Thoracic General Hospital of Athens "I Sotiria"
  • Italy
      • Milan, Italy, 20133
        • Recruiting
        • Fondazione IRCCS Istituto Nazionale dei Tumori
      • Milan, Italy, 20162
      • Orbassano, Italy, 10043
        • Recruiting
        • A.O.U. San Luigi Gonzaga-Orbassano - SCDU Oncologia Medica
      • Ravenna, Italy, 48121
      • Rome, Italy, 00168
      • Rome, Italy, 00144
    • Emilia-Romagna
      • Meldola, Emilia-Romagna, Italy, 47014
        • Recruiting
        • Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST S.r.l
        • Contact:
  • Netherlands
      • Amsterdam, Netherlands, 1066
        • Recruiting
        • The Netherlands Cancer Institute (NKI)
        • Contact:
      • Groningen, Netherlands, 9713
        • Recruiting
        • University Medical Centre Groningen
      • Leiden, Netherlands, 2333 ZA
        • Recruiting
        • Leiden University Medical Center
      • Utrecht, Netherlands, 3584
  • South Korea
    • Gangnam-gu
      • Seoul, Gangnam-gu, South Korea, 06351
        • Recruiting
        • Samsung Medical Center
    • Gyeonggi-do
      • Goyang-si, Gyeonggi-do, South Korea, 10408
        • Recruiting
        • National Cancer Center
    • Gyeonggido
      • Seongnam-si, Gyeonggido, South Korea, 13620
        • Recruiting
        • Seoul National University Bundang Hospital
    • Seocho-gu
      • Seoul, Seocho-gu, South Korea, 06591
        • Recruiting
        • Seoul St. Mary's Hospital, The Catholic University of Korea
    • Seodaemun-Gu
      • Seoul, Seodaemun-Gu, South Korea, 03722
        • Recruiting
        • Severance Hospital
  • Spain
      • A Coruña, Spain, 15006
      • Barcelona, Spain, 08035
        • Recruiting
        • Hospital Universitari Vall d' Hebrón
      • Barcelona, Spain, 08916
        • Recruiting
        • ICO Badalona - H.U. Germans Trias i Pujol
      • Madrid, Spain, 28034
        • Recruiting
        • Hospital Universitario Ramon Y Cajal
        • Contact:
          • Maria Eugenia Olmedo
          • Phone Number: 34-913-369-159
      • Madrid, Spain, 28040
        • Recruiting
        • Hospital Universitario Fundacion Jimenez Diaz
        • Contact:
      • Málaga, Spain, 29011
        • Recruiting
        • Hospital Regional Universitario de Malaga - Hospital Civil
        • Contact:
      • Seville, Spain, 41014
        • Recruiting
        • Hospital Universitario Virgen del Rocio - PPDS
        • Contact:
      • Valencia, Spain, 46009
        • Recruiting
        • Fundación Instituto Valenciano de Oncología
        • Contact:
    • Madrid
      • Madrid, Madrid, Spain, 28040
        • Recruiting
        • Hospital Clinico San Carlos
        • Contact:
      • Madrid, Madrid, Spain, 28041
    • Navarre
      • Pamplona, Navarre, Spain, 31008
        • Recruiting
        • Clinica Universidad de Navarra
        • Contact:
          • Mariano Ponz Sarvise
          • Phone Number: +34 91 353 19 20
          • Email: eecc@unav.es
    • Valencia
      • Valencia, Valencia, Spain, 46026
        • Recruiting
        • Hospital Universitari i Politecnic La Fe de Valencia
  • Taiwan
      • Kaohsiung City, Taiwan, 807
        • Recruiting
        • Kaohsiung Medical University Chung-Ho Memorial Hospital
      • Taichung, Taiwan, 40705
        • Recruiting
        • Taichung Veterans General Hospital
      • Tainan, Taiwan, 73657
        • Recruiting
        • Chi Mei Hospital, Liouying
      • Taipei, Taiwan, 11217
        • Recruiting
        • Taipei Veterans General Hospital
    • Wenshan Dist
      • Taipei, Wenshan Dist, Taiwan, 116
        • Recruiting
        • Taipei Municipal Wanfang Hospital
  • United States
    • Arizona
      • Gilbert, Arizona, United States, 85234
        • Recruiting
        • Banner MD Anderson Cancer Center
    • California
      • Duarte, California, United States, 91010
        • Recruiting
        • City of Hope - Duarte
        • Contact:
      • Irvine, California, United States, 92618
        • Recruiting
        • City of Hope - Lennar
        • Contact:
      • Sacramento, California, United States, 95817
        • Recruiting
        • UC Davis, Davis Comprehensive Cancer Center
        • Contact:
      • San Diego, California, United States, 92037
        • Recruiting
        • University of California, San Diego Moores Cancer Center
        • Contact:
      • San Francisco, California, United States, 94158
        • Recruiting
        • UCSF Medical Center - Mission Bay
        • Contact:
      • Stanford, California, United States, 94305
    • Colorado
      • Colorado Springs, Colorado, United States, 80909
        • Recruiting
        • Colorado Health Medical Group - Medical Oncology & Hematology
    • District of Columbia
      • Washington D.C., District of Columbia, United States, 20007
        • Recruiting
        • Georgetown University Medical Center
        • Contact:
    • Florida
      • Plantation, Florida, United States, 33322
        • Recruiting
        • Boca Raton Clinical Research Associates
        • Contact:
      • Saint Augustine, Florida, United States, 32086
        • Recruiting
        • Cancer Specialists of North Florida
        • Contact:
      • Tampa, Florida, United States, 33612
        • Recruiting
        • H Lee Moffitt Cancer Center and Research Institute
        • Contact:
    • Massachusetts
    • Michigan
      • Detroit, Michigan, United States, 48202
        • Recruiting
        • Henry Ford Cancer - Detroit (Brigitte Harris Cancer Pavilion)
        • Contact:
    • Montana
      • Billings, Montana, United States, 59102
        • Recruiting
        • Intermountain Health - St. Vincent Frontier Cancer Center
        • Contact:
    • Nebraska
      • Grand Island, Nebraska, United States, 68803
        • Recruiting
        • Nebraska Cancer Specialist
    • New York
      • New York, New York, United States, 10029
        • Recruiting
        • Icahn School of Medicine at Mount Sinai
        • Contact:
      • New York, New York, United States, 10032
      • New York, New York, United States, 10016
      • Westbury, New York, United States, 11590
        • Recruiting
        • Clinical Research Alliance
        • Contact:
          • Phone Number: 516-488-2918
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • Recruiting
        • University Hospitals Cleveland Medical Center
        • Contact:
          • Phone Number: 216-844-3951
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15232
    • Tennessee
      • Memphis, Tennessee, United States, 38120
        • Recruiting
        • Baptist Medical Center
      • Nashville, Tennessee, United States, 37203
        • Recruiting
        • Tennessee Oncology
    • Texas
      • Houston, Texas, United States, 77030
        • Recruiting
        • The University of Texas MD Anderson Cancer Center
        • Contact:
      • Irving, Texas, United States, 75039
    • Virginia
      • Fairfax, Virginia, United States, 22031
    • Washington
      • Seattle, Washington, United States, 98109
        • Recruiting
        • Fred Hutchinson Cancer Research Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion criteria:

All Patients (unless otherwise noted):

  • ≥ 18 years of age
  • ECOG PS is 0 to 1
  • Adequate organ function as outlined by the study
  • Received prior standard therapy appropriate for tumor type and stage
  • Must have pathologically documented, locally advanced or metastatic KRAS G12C-mutated solid tumor malignancy (not amenable to curative surgery) (Subprotocol A)
  • Must have pathologically documented, locally advanced or metastatic RAS-mutated NSCLC (Subprotocol B)
  • Must have pathologically documented, locally advanced or metastatic RAS G12D-mutated NSCLC (Subprotocol C and Subprotocol D)

Exclusion criteria:

All Patients:

  • Primary central nervous system (CNS) tumors
  • Impaired gastrointestinal (GI) function that may significantly alter the absorption of RMC drugs
  • Major surgery < 28 days of first dose
  • Active or history of interstitial lung disease (ILD) or pneumonitis requiring steroids

Other inclusion/exclusion criteria may apply.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Subprotocol C: RAS G12D-mutated NSCLC
RMC-9805 (QD or BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W).
Drug: Pemetrexed
IV infusion
Drug: Carboplatin
IV Infusion
Drug: Pembrolizumab
IV Infusion
Drug: Cisplatin
IV Infusion
Drug: RMC-6236
Oral tablet
Drug: RMC-9805
Oral Tablet
Experimental: Subprotocol A: KRAS G12C-Mutated Solid Tumors
RMC-6291 (BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W)
Drug: Pemetrexed
IV infusion
Drug: Carboplatin
IV Infusion
Drug: Pembrolizumab
IV Infusion
Drug: Cisplatin
IV Infusion
Drug: RMC-6291
Oral tablet
Drug: RMC-6236
Oral tablet
Experimental: Subprotocol B: RAS-mutated NSCLC
RMC-6236 (QD) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W)
Drug: Pemetrexed
IV infusion
Drug: Carboplatin
IV Infusion
Drug: Pembrolizumab
IV Infusion
Drug: Cisplatin
IV Infusion
Drug: RMC-6236
Oral tablet
Experimental: Subprotocol D: RAS G12D-mutated NSCLC
RMC-9805 (QD)
Drug: RMC-9805
Oral Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse events
Time Frame: Up to 5 years
Incidence and severity of treatment-emergent Adverse Events (AEs) and serious AEs and clinically significant changes in laboratory values, ECGs and vital signs
Up to 5 years
Dose limiting toxicities
Time Frame: 21 days
Number of participants with dose limiting toxicities
21 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
DOR
Time Frame: Up to 5 years
Duration of Response per RECIST v1.1
Up to 5 years
ORR
Time Frame: Up to 5 years
Objective Response Rate per RECIST v1.1
Up to 5 years
Cmax
Time Frame: Up to 21 weeks
Maximum observed blood concentration of each drug as applicable per subprotocol
Up to 21 weeks
Tmax
Time Frame: Up to 21 weeks
Time to reach maximum blood concentration of each drug as applicable per subprotocol
Up to 21 weeks
AUC
Time Frame: Up to 21 weeks
Area under the concentration-time curve of each drug as applicable per subprotocol
Up to 21 weeks
Drug concentrations over time
Time Frame: Up to 21 weeks
Observed blood concentration of each drug as applicable per subprotocol
Up to 21 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Revolution Medicines, Inc.

Investigators

  • Study Director: Revolution Medicines, Revolution Medicines

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 18, 2024

Primary Completion (Estimated)

June 1, 2027

Study Completion (Estimated)

December 1, 2028

Study Registration Dates

First Submitted

November 30, 2023

First Submitted That Met QC Criteria

November 30, 2023

First Posted (Actual)

December 8, 2023

Study Record Updates

Last Update Posted (Actual)

June 30, 2026

Last Update Submitted That Met QC Criteria

June 25, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RMC-LUNG-101

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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