Combination Study of RMC-4630 and Sotorasib for NSCLC Subjects With KRASG12C Mutation After Failure of Prior Standard Therapies

A Phase 2, Open-Label, Multicenter Study of the Combination of RMC-4630 and Sotorasib for Non-Small Cell Lung Cancer Subjects With KRASG12C Mutation After Failure of Prior Standard Therapies

The purpose of this study is to evaluate the antitumor effects of sotorasib and RMC-4630 in subjects with KRASG12C mutant NSCLC

Study Overview

• Status: Completed
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: RMC-4630; Drug: Sotorasib

Detailed Description

This is a phase 2 multicenter, open-label study evaluating the efficacy, safety, tolerability, and pharmacokinetics (PK) of RMC-4630 in combination with sotorasib in subjects with KRASG12C mutant NSCLC after failure of prior standard therapies.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Blacktown, Australia, 2148
    • Blacktown Hospital
  • Shepparton, Australia, 3630
    • Goulburn Valley Health
  • Victoria
    • Warrnambool, Victoria, Australia, 3280
      • South West Oncology
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • Ontario
    • Mississauga, Ontario, Canada, L5N 5M8
      • William Osler Health System
• France
  • Marseille, France, 13015
    • APHM Hopital Nord, Service d'Oncologie Multidisciplinaire et innovations therapeutics
  • Toulouse, France, 31059
    • Hospital Larrey Universite Paul Sabatier
• Germany
  • Berlin, Germany, 12200
    • Charite Benjamin Franklin Comprehensive Cancer center
  • Berlin, Germany, 13125
    • Evangelische Lung Clinic
  • Hamburg, Germany, 20251
    • Hamato-Onkologie Hamburg
  • Baden-Wurttemberg
    • Esslingen am Neckar, Baden-Wurttemberg, Germany, 73730
      • Klinikum Esslingen GmbH
  • Bavaria
    • Gauting, Bavaria, Germany, 82131
      • Asklepios Fachkliniken Munchen
  • North Rhine-Westphalia
    • Hemer, North Rhine-Westphalia, Germany, 58675
      • Lungenklinik Hemer
    • Moers, North Rhine-Westphalia, Germany, 47441
      • Bethanien Hospital Moers
  • Saarland
    • Homburg, Saarland, Germany, 66421
      • Comprehensive Cancer Center Mainfranken, University Wuerzburg
    • Homburg, Saarland, Germany, 66421
      • Lung Cancer Center, University of Saarland
  • Saxony
    • Leipzig, Saxony, Germany, 04347
      • POIS Sachsen GmbH
• Italy
  • Milan, Italy, 20141
    • Istituto Europeo di Oncologia
  • Campania
    • Napoli, Campania, Italy, 80131
      • Azienda Ospedaliera dei Colli
  • Piedmont
    • Orbassano, Piedmont, Italy, 10043
      • Azienda Sanitaria Ospedaliera S Luigi Gonzaga
• South Korea
  • Cheongju-si, South Korea, 28644
    • Chungbuk National University Hospital
  • Seoul, South Korea, 03080
    • Seoul National University Hospital
  • Seoul, South Korea, 05505
    • Asan Medical Center
  • Seoul, South Korea, 06351
    • Samsung Medical Center
• Spain
  • Madrid, Spain, 28027
    • Clinica Universidad de Navarra
  • Valencia, Spain, 46026
    • Hospital Universitario y Politécnico La FE
  • Andalusia
    • Seville, Andalusia, Spain, 41009
      • Hospital Universitario Virgen Macarena
  • Catalonia
    • Barcelona, Catalonia, Spain, 08036
      • Hospital Clinic De Barcelona
  • Galicia
    • A Coruña, Galicia, Spain, 15006
      • Complejo Hospitalario Universitario A Coruña
  • Navarre
    • Pamplona, Navarre, Spain, 31008
      • Clinica Universidad de Navarra
• Taiwan
  • Kaohsiung City, Taiwan, 824
    • E-DA Hospital
  • Kaohsiung City, Taiwan, 807
    • Kaohsiung Medical University Chung Ho Memorial Hospital
  • Taichung, Taiwan, 40705
    • Taichung Veterans General Hospital
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
• United Kingdom
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M20 4BX
      • The Christie NHS Foundation Trust
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • The Royal Marsden NHS Foundation Trust
• United States
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
    • Plantation, Florida, United States, 33322
      • BRCR Medical Center Inc.
    • Saint Augustine, Florida, United States, 32086
      • Cancer Specialists of North Florida
  • Illinois
    • Evergreen Park, Illinois, United States, 60805
      • GenHarp Clinical Solutions
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Hematology Oncology Clinic
  • Maine
    • Scarborough, Maine, United States, 04074
      • New England Cancer Specialists
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • American Oncology Partners of Maryland, PA
    • Columbia, Maryland, United States, 21044
      • Maryland Oncology Hematology, P.A.
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Minnesota Oncology Hematology, P.A.
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Nebraska Cancer Specialists
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada
  • New Jersey
    • Brick, New Jersey, United States, 08724
      • New Jersey Center for Cancer Research
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Comprehensive Cancer Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10021
      • Clinical Research Alliance, Inc.
  • Ohio
    • Columbus, Ohio, United States, 43219
      • Zangmeister Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • Charleston Oncology
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Tennessee Oncology
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Texarkana, Texas, United States, 75503
      • CHRISTUS St. Michael-Colom and Carney Clinic P.A
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates
  • Washington
    • Vancouver, Washington, United States, 98684
      • Northwest Cancer Specialists, P.C.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject must be ≥18 years of age.
• Subject must have pathologically documented, locally advanced or metastatic KRASG12C NSCLC (not amenable to curative surgery) that has progressed on prior standard therapies (no more than 3 prior lines of therapies are allowed)

Exclusion Criteria

• Primary central nervous system (CNS) tumors
• Known or suspected leptomeningeal or brain metastases or spinal cord compression
• Clinically significant cardiac disease
• Known impairment of GI function that would alter the absorption
• Active autoimmune disease requiring systemic treatment within past 2 years
• History of severe allergic reactions to any of the study intervention components
• Major surgical procedures within 28 days or non-study-related minor procedures within 7 days of treatment.
• Prior therapy with KRASG12C inhibitor and/or SHP2 inhibitor

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RMC-4630 and sotorasib, Safety Run-in; Safety Run-In: RMC-4630 and sotorasib	Drug: RMC-4630; RMC-4630 administered orally as a capsule; Other Names: SAR442720; Drug: Sotorasib; Sotorasib administered orally as a tablet; Other Names: AMG 510; Lumakras
Experimental: RMC-4630 and sotorasib, Expansion; Dose Expansion: RMC-4630 and sotorasib	Drug: RMC-4630; RMC-4630 administered orally as a capsule; Other Names: SAR442720; Drug: Sotorasib; Sotorasib administered orally as a tablet; Other Names: AMG 510; Lumakras

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) as Assessed Per RECIST v1.1	Evaluation of the antitumor effects of RMC-4630 and sotorasib in locally advanced or metastatic NSCLC patients with KRASG12C mutation with and without co-existing genetic aberrations in specific genes such as STK11/LKB1, KEAP1, and PIK3CA after failure of prior standard therapy. Objective Response Rate (%) is defined as the proportion of patients with Best Overall Response of confirmed CR, or PR. Response was confirmed by a repeat assessment no less than 28 days.	31 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinically Significant Changes in Vital Signs	Characterization of the safety, tolerability of RMC-4630 in combination with sotorasib for subjects with KRASG12C mutant NSCLC after failure of prior standard therapy	31 months
Clinically Significant Changes in Laboratory Tests	Characterization of the safety, tolerability of RMC-4630 in combination with sotorasib for subjects with KRASG12C mutant NSCLC after failure of prior standard therapy	31 months
Clinically Significant Changes in ECGs	Characterization of the safety, tolerability of RMC-4630 in combination with sotorasib for subjects with KRASG12C mutant NSCLC after failure of prior standard therapy	31 months
Trough and Approximate Peak Concentrations of RMC-4630	Characterization of PK of RMC-4630 in combination with sotorasib for subjects with KRASG12C mutant NSCLC.	31 months
Trough and Approximate Peak Concentrations of Sotorasib	Characterization of PK of RMC-4630 in combination with Sotorasib for subjects with KRASG12C mutant NSCLC	31 months
Duration of Response (DOR) as Assessed Per RECIST v1.1	Characterization of efficacy or RMC-4630 in combination with Sotorasib as assessed by DOR, DCR, PFS, and OS in patients with KRAS G12C-mutant locally advanced or metastatic NSCLC after failure of prior standard therapy	31 months
Disease Control Rate (DCR) as Assessed Per RECIST v.1.1	Characterization of efficacy or RMC-4630 in combination with Sotorasib as assessed by DOR, DCR, PFS, and OS in patients with KRAS G12C-mutant locally advanced or metastatic NSCLC after failure of prior standard therapy	31 months
Progression-free Survival (PFS) as Assessed Per RECIST v1.1	Characterization of efficacy or RMC-4630 in combination with Sotorasib as assessed by DOR, DCR, PFS, and OS in patients with KRAS G12C-mutant locally advanced or metastatic NSCLC after failure of prior standard therapy	31 months
Overall Survival (OS)	Characterization of efficacy or RMC-4630 in combination with Sotorasib as assessed by DOR, DCR, PFS, and OS in patients with KRAS G12C-mutant locally advanced or metastatic NSCLC after failure of prior standard therapy	31 months
Incidence, Nature and Severity of TEAEs, SAEs	Characterization of the safety, tolerability of RMC-4630 in combination with sotorasib for patients with KRASG12C-mutant NSCLC after failure of prior standard therapy. The specifics of the incidence, nature and severity data can be found under the Adverse Events section.	31 months

Collaborators and Investigators

• Sponsor: Revolution Medicines, Inc.
• Collaborators: Sanofi; Amgen
• Investigators: Study Director: Revolution Medicines, Inc., Revolution Medicines, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 30, 2021
• Primary Completion (Actual): July 3, 2024
• Study Completion (Actual): August 29, 2024

Study Registration Dates

• First Submitted: September 14, 2021
• First Submitted That Met QC Criteria: September 14, 2021
• First Posted (Actual): September 23, 2021

Study Record Updates

• Last Update Posted (Estimated): January 6, 2026
• Last Update Submitted That Met QC Criteria: December 29, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: NSCLC; SHP2; KRAS G12C; BRAF Class 1/2/unclassified; KRAS amplification; KRAS mutation; STK11/LKB1; KEAP1; PIK3CA; ATRX; BRCA2; carcinoma, non-small lung cancer; bronchial neoplasms; lung neoplasms; respiratory tract neoplasms; neoplasms by site; neoplasms; lung diseases; respiratory tract diseases
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Neoplasms by Histologic Type; Bronchial Diseases; Neurodegenerative Diseases; Neoplasms, Glandular and Epithelial; Thoracic Neoplasms; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Carcinoma, Bronchogenic; Nervous System Malformations; Polyneuropathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neoplasms; Lung Diseases; Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Diseases; Respiratory Tract Neoplasms; Neoplasms by Site; Bronchial Neoplasms; Hereditary Sensory and Autonomic Neuropathies; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; sotorasib
• Other Study ID Numbers: RMC-4630-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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