Abstract 76TiP
Background
Sotorasib is a selective, irreversible, oral small molecule covalent inhibitor of KRASG12C (OFF) recently approved in the U.S. for previously treated patients with KRASG12C NSCLC. RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a protein tyrosine phosphatase functioning downstream of multiple RTKs as a convergent node in RAS signaling. RMC-4630 has demonstrated acceptable tolerability with an intermittent dosing schedule (Day 1 and Day 2 of each week) and single agent activity in KRASG12C NSCLC tumors in a phase 1b study. Combination treatment with RMC-4630 and a KRASG12C(OFF) inhibitor enhances antitumor activity in preclinical models. In these models SHP2 inhibition can abrogate residual or bypass upstream RTK activity and reduce RAS signaling, thereby promoting deeper and more durable responses. This combination is also being tested in diverse KRASG12C mutant solid tumors in an ongoing phase 1b study sponsored by Amgen (CodebreaK 101).
Trial design
This phase 2 multicenter, open-label study (RMC-4630-03; NCT05054725) will further characterize the efficacy, safety/ tolerability and PK of the RMC-4630 and sotorasib combination for previously treated subjects with KRASG12C NSCLC. Adult subjects (n=46) with locally advanced or metastatic KRASG12C NSCLC who have progressed on no more than 3 prior standard therapies are eligible. Emerging clinical data from sotorasib and adagrasib monotherapy studies in KRASG12C NSCLC reveal heterogeneity in the response of subpopulations defined by co-mutations in associated targets such as KEAP1 and STK11. Based on these learnings, the present study is designed to prospectively evaluate the antitumor effects of RMC-4630 and sotorasib in KRASG12C NSCLC subjects with and without co-existing genetic aberrations in specific genes such as STK11, KEAP1, and PIK3CA. The primary endpoint is ORR per RECIST v1.1. Secondary endpoints include DOR, DCR, PFS, OS, safety/tolerability, and PK of RMC-4630 in combination with sotorasib. This trial is currently enrolling in the United States and will also be open at sites in Europe, UK, Australia, and Asia.
Clinical trial identification
RMC-4630-03; NCT05054725.
Legal entity responsible for the study
Revolution Medicines.
Funding
Revolution Medicines.
Disclosure
M.L. Johnson: Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Acerta; Financial Interests, Institutional, Research Grant: Adaptimmune; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Apexigen; Financial Interests, Institutional, Research Grant: Arcus Biosciences; Financial Interests, Institutional, Research Grant: Array BioPharma; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Atreca; Financial Interests, Institutional, Research Grant: BeiGene; Financial Interests, Institutional, Research Grant: BerGenBio; Financial Interests, Institutional, Research Grant: BioAtla; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Calithera Biosciences; Financial Interests, Institutional, Research Grant: Checkpoint Therapeutics; Financial Interests, Institutional, Research Grant: Corvus Pharmaceuticals; Financial Interests, Institutional, Research Grant: Curis; Financial Interests, Institutional, Research Grant: CytomX; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Dracen Pharmaceuticals; Financial Interests, Institutional, Research Grant: Dynavax; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Elicio Therapeutics; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Erasca; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: Genmab; Financial Interests, Institutional, Research Grant: Genocea Biosciences; Financial Interests, Institutional, Research Grant: GlaxoSmithKlein; Financial Interests, Institutional, Research Grant: Gritstone Oncology; Financial Interests, Institutional, Research Grant: Guardant Health; Financial Interests, Institutional, Research Grant: Harpoon; Financial Interests, Institutional, Research Grant: Helsinn Healthcare; Financial Interests, Institutional, Research Grant: Hengrui Therapeutics; Financial Interests, Institutional, Research Grant: Hutchinson MediPharma; Financial Interests, Institutional, Research Grant: IDEAYA Biosciences; Financial Interests, Institutional, Research Grant: IGM Biosciences; Financial Interests, Institutional, Research Grant: Immunocore; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Jounce Therapeutics; Financial Interests, Institutional, Research Grant: Kadmon Pharmaceuticals; Financial Interests, Institutional, Research Grant: Loxo Oncology; Financial Interests, Institutional, Research Grant: Lycera; Financial Interests, Institutional, Research Grant: Memorial-Sloan Kettering; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Mirati Therapeutics; Financial Interests, Institutional, Research Grant: NeoImmune Tech; Financial Interests, Institutional, Research Grant: Neovia Oncology; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Numab Therapeutic; Financial Interests, Institutional, Research Grant: Nuvalnt OncoMed Pharmaceuticals; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: PMV Pharmaceuticals; Financial Interests, Institutional, Research Grant: Rain Therapeutics; Financial Interests, Institutional, Research Grant: RasCal Therapeutics; Financial Interests, Institutional, Research Grant: Regeneron Pharmaceuticals; Financial Interests, Institutional, Research Grant: Relay Therapeutics; Financial Interests, Institutional, Research Grant: Revolution Medicines; Financial Interests, Institutional, Research Grant: Ribon Therapeutics; Financial Interests, Institutional, Research Grant: Rubius Therapeutics; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Seven and Eight Biopharmaceuticals; Financial Interests, Institutional, Research Grant: Shattuck Labs; Financial Interests, Institutional, Research Grant: Silicon Therapeutics; Financial Interests, Institutional, Research Grant: StemCentRx; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Tarveda; Financial Interests, Institutional, Research Grant: TCR2 Therapeutics; Financial Interests, Institutional, Research Grant: Tempest Therapeutics; Financial Interests, Institutional, Research Grant: Tizona Therapeutics; Financial Interests, Institutional, Research Grant: TMUNITY Therapeutics; Financial Interests, Institutional, Research Grant: Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: University of Michigan; Financial Interests, Institutional, Research Grant: Vyriad; Financial Interests, Institutional, Research Grant: WindMIL; Financial Interests, Institutional, Research Grant: Y-mAbs Therapeutics; Financial Interests, Institutional, Other, Consulting: AbbVie; Financial Interests, Institutional, Other, Consulting: Amgen; Financial Interests, Institutional, Other, Consulting: Astellas; Financial Interests, Institutional, Other, Consulting: AstraZeneca; Financial Interests, Institutional, Other, Consulting: Axelia Oncology; Financial Interests, Institutional, Other, Consulting: Black Diamond; Financial Interests, Institutional, Other, Consulting: Boehringer Ingelheim; Financial Interests, Institutional, Other, Consulting: Bristol Myers Squibb; Financial Interests, Institutional, Other, Consulting: Calithera; Financial Interests, Institutional, Other, Consulting: CytomX; Financial Interests, Institutional, Other, Consulting: Daiichi Sankyo; Financial Interests, Institutional, Other, Consulting: EcoR1; Financial Interests, Institutional, Other, Consulting: Editas Medicine; Financial Interests, Institutional, Other, Consulting: Eisai; Financial Interests, Institutional, Other, Consulting: EMD Serono; Financial Interests, Institutional, Other, Consulting: G1 Therapeutics; Financial Interests, Institutional, Other, Consulting: Genentech/Roche; Financial Interests, Institutional, Other, Consulting: Genmab; Financial Interests, Institutional, Other, Consulting: GlaxoSmithKlein; Financial Interests, Institutional, Other, Consulting: Gritstone Oncology; Financial Interests, Institutional, Other, Consulting: Ideaya Biosciences; Financial Interests, Institutional, Other, Consulting: iTeos; Financial Interests, Institutional: Janssen. A. Spira: Financial Interests, Institutional, Leadership Role: NEXT Oncology Virginia; Financial Interests, Personal, Other, Stock and Other Ownership Interests: Eli Lilly; Financial Interests, Personal, Other: CytomX Therapeutics; Financial Interests, Personal, Other, Honoraria: AstraZeneca/MedImmune; Financial Interests, Personal, Other, Honoraria: Merck; Financial Interests, Personal, Other, Honoraria: Takeda; Financial Interests, Personal, Other, Honoraria: Amgen; Financial Interests, Personal, Other, Honoraria: Janssen Oncology; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: Bayer; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Mirati Therapeutics; Financial Interests, Personal, Advisory Role: Gritstone Oncology; Financial Interests, Personal, Advisory Role: Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: Janssen Research & Development; Financial Interests, Institutional, Advisory Role: Array BioPharma; Financial Interests, Institutional, Advisory Role: AstraZeneca/MedImmune; Financial Interests, Institutional, Advisory Role: Merck; Financial Interests, Institutional, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Other, Research Funding: LAM Therapeutics; Financial Interests, Institutional, Other, Research Funding: Roche; Financial Interests, Institutional, Other, Research Funding: AstraZeneca; Financial Interests, Institutional, Other, Research Funding: Boehringer Ingelheim; Financial Interests, Institutional, Other, Research Funding: Astellas Pharma; Financial Interests, Institutional, Other, Research Funding: MedImmune; Financial Interests, Institutional, Other, Research Funding: Novartis; Financial Interests, Institutional, Other, Research Funding: Newlink Genetics; Financial Interests, Institutional, Other, Research Funding: Incyte; Financial Interests, Institutional, Other, Research Funding: AbbVie; Financial Interests, Institutional, Other, Research Funding: Ignyta; Financial Interests, Institutional, Other, Research Funding: LAM Therapeutics; Financial Interests, Institutional, Other, Research Funding: Trovagene; Financial Interests, Institutional, Other, Research Funding: Takeda; Financial Interests, Institutional, Other, Research Funding: Macrogenics; Financial Interests, Institutional, Other, Research Funding: CytomX Therapeutics; Financial Interests, Institutional, Other, Research Funding: Astex Pharmaceuticals; Financial Interests, Institutional, Other, Research Funding: Bristol Myers Squibb; Financial Interests, Institutional, Other, Research Funding: Loxo; Financial Interests, Institutional, Other, Research Funding: Arch Therapeutics; Financial Interests, Institutional, Other, Research Funding: Gritstone; Financial Interests, Institutional, Other, Research Funding: Plexxikon; Financial Interests, Institutional, Other, Research Funding: Amgen; Financial Interests, Institutional, Other, Research Funding: Loxo; Financial Interests, Institutional, Other, Research Funding: Daiichi Sankyo; Financial Interests, Institutional, Other, Research Funding: ADCT; Financial Interests, Institutional, Other, Research Funding: Janssen Oncology; Financial Interests, Institutional, Other, Research Funding: Mirati Therapeutics; Financial Interests, Institutional, Other, Research Funding: Rubius; Financial Interests, Institutional, Other, Research Funding: Synthekine. S. Sohoni: Financial Interests, Personal, Stocks/Shares: Revolution Medicines. Y. Chen: Financial Interests, Personal, Stocks/Shares: Revolution Medicines. J. Hayes: Financial Interests, Personal, Stocks/Shares: Revolution Medicines. Y. Mu: Financial Interests, Personal, Stocks/Shares: Revolution Medicines. X. Wang: Financial Interests, Personal, Stocks/Shares: Revolution Medicines. All other authors have declared no conflicts of interest.