652O - Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC)

Background

RMC-6236 is a novel, oral RAS^MULTI(ON) inhibitor that is selective for the active, GTP-bound state of both mutant and wild-type variants of the canonical RAS isoforms. Preclinical studies have demonstrated deep and sustained regressions across multiple RAS^MUT tumor types, particularly PDAC and NSCLC harboring KRAS glycine-12 substitutions (KRAS^G12X).

Methods

Patients with previously treated, advanced KRAS^G12X mutant solid tumors were enrolled at escalating doses (10mg to 160mg once daily (QD)) of single agent RMC-6236. Additional patients with PDAC or NSCLC were enrolled at dose levels that cleared dose-limiting toxicity evaluation.

Results

As of April 24, 2023, 22 patients with KRAS^G12X PDAC (13 G12D, 7 G12V, 2 G12R) and 11 with KRAS^G12X NSCLC (5 G12D, 4 G12V, 2 G12A) were enrolled, and 14 patients with PDAC and 9 patients with NSCLC continue treatment with RMC-6236. Median prior therapies was 3 (range, 1-7). Treatment-related adverse events (TRAEs) occurring in ≥10% of patients were rash (52%), diarrhea (21%), nausea (21%), and vomiting (15%). The only Grade ≥3 TRAE was in a patient with PDAC who had a Grade 4 large intestine perforation at the site of an invasive tumor that reduced in size on treatment. Preclinical modeling predicts tumor regressions at 80mg QD or higher in humans. Preliminary clinical activity in PDAC and NSCLC was assessed at 80mg and 120mg QD. Among 14 patients (10 PDAC, 4 NSCLC) dosed at least 8 weeks prior to the data cut-off date, the objective response rate was 36% (2 confirmed and 3 unconfirmed; 2/10 PDAC and 3/4 NSCLC). Median time to onset of initial response was 6 weeks (range, 5-11). Disease control rate was 86% (12/14; 8/10 PDAC and 4/4 NSCLC). Tumor reduction was observed in 4 patients with stable disease (range, -2% to -21% by RECIST v1.1). Of the 12 patients with partial response or stable disease, 11 continue on treatment.

Conclusions

RMC-6236 exhibits promising anti-tumor activity in patients with KRAS^G12X PDAC and NSCLC at doses that are well tolerated. Dose escalation is ongoing and data from additional patients will be available at the time of the meeting.

Clinical trial identification

NCT05379985.

Editorial acknowledgement

Legal entity responsible for the study

Revolution Medicines, Inc.

Funding

Revolution Medicines, Inc.

Disclosure

K.C. Arbour: Financial Interests, Personal, Advisory Board: G1 Therapeutics, Novartis, Sanofi-Genzyme; Financial Interests, Institutional, Local PI: Revolution Medicines, Mirati, Genentech. S. Punekar: Financial Interests, Institutional, Local PI, Clinical Trial PI: Revolution Medicine, Simcere Pharmaceuticals, Astellas Pharmaceuticals, Constellation, A2Bio, Vitrac; Non-Financial Interests, Principal Investigator, Clinical Trial PI: Revolution Medicine, A2Bio, Simcere, Constellation, Vitrac, Astellas Pharmaceuticals. I. Garrido-Laguna: Financial Interests, Personal, Other, Consulting: Kanaph, OncoXerna; Financial Interests, Personal, Other, DSMC: SOTIO; Financial Interests, Personal, Advisory Board: Jazz Pharmaceuticals; Financial Interests, Institutional, Local PI: Revolution Medicine, Yingli, BridgeBio Pharma, Repare Therapeutics, Sumitomo, Pfizer, Genentech, Amgen. D.S. Hong: Financial Interests, Personal, Other, Travel, accommodations, expenses: AACR, ASCO, Bayer, Genmab, Gilead, SITC, Telperian; Financial Interests, Personal, Other, Consulting, Speaker, or Advisory Role: AbbVie, Adaptimmune, Alpha Insights, Acuta, Alkermes, Amgen, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, COR2ed, COG, Cowen, Ecor1, Gennao Bio, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, MedaCorp, Medscape, Numab, Oncologia Brazil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, RAIN, Seagen, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point Therapeutics, WebMD, YingLing Pharma, Ziopharm; Financial Interests, Personal, Advisory Board: 28Bio, Affini-T, Astellas, Fate Therapeutics, CARSgen, InduPro, Projects in Knowledge, Quanta, Ridgeline, Stanford; Financial Interests, Personal, Ownership Interest, Advisor: Molecular Match; Financial Interests, Personal, Ownership Interest, Founder, Advisor: OncoResponse, Telperian; Financial Interests, Institutional, Research Grant: AbbVie, Adaptimmune, Adlai-Nortye, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Endeavor, Erasca, F. Hoffmann-LaRoche, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa Kirin, Loxo, Merck, Medimmune, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, Seagen, Takeda, TCR2, Teckro, Turning Point Therapeutics, VM Oncology, Biomea, ImmunoGenesis, Revolution Medicine, STCube. B. Wolpin: Financial Interests, Institutional, Other, Consultant (under institutional contract): Celgene, Inc; Financial Interests, Institutional, Other, Consultant: Grail; Financial Interests, Institutional, Other, Consultant (PI): Mirati Therapeutics, Inc.; Financial Interests, Institutional, Other, Research funding: Celgene, Inc; Financial Interests, Institutional, Other, Research funding (under institutional contract): Eli Lilly and Company, Novartis, Revolution Medicines. M.S. Pelster: Financial Interests, Institutional, Other, Consulting: AstraZeneca, Bayer, CytomX, Daiichi Sankyo, Ipsen, Novartis, Pfizer, Seagen; Financial Interests, Institutional, Local PI: Agenus, Arcus Biosciences, Astellas, BeiGene, BioNTech, Bristol Myers Squibb, Codiak Biosciences, Eisai, Gilead, Gritstone Oncology, HiberCell, Immune-Onc Therapeutics, Leap Therapeutics, Novartis, OncXerna Therapeutics, Panbela Therapeutics, Revolution Medicines, Surface Oncology, SQZ Biotechnologies, Translational Genomics, TransThera Sciences, ZielBio, 1200 Pharma. M. Barve: Financial Interests, Personal, Full or part-time Employment, Private practice: Texas Oncology/ US Oncology; Financial Interests, Personal, Stocks/Shares, Physician shareholder: Texas Oncology; Financial Interests, Institutional, Local PI, Research funding to the institution: 1200 Pharma, Agenus, Amgen, Inc, Artios Pharma Limited, Astellas Pharma Global Development, Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals, Inc., BeiGene USA, Inc., Bicycle Therapeutics, Bio-Path Holdings, Black Diamond Therapeutics, Boehringer Ingelheim, BriaCell Therapeutics, Bristol Myers Squibb, Compass Therapeutics Inc., Coordination Pharma, Corvus Pharmaceuticals, CStone Pharmaceuticals, Dialectic Therapeutics, Inc., Elevation Oncology, Eli Lilly and Company, EMD Serono, EpicentRx Inc, Erasca, Eutilex, Exelixis Inc., F. Hoffmann-La Roche Ltd. (Genentech), Gan & Lee Pharmaceuticals, Genprex Inc., Gilead Sciences, GSK, Gradalis, Harpoon Therapeutics, Inc., IGM Biosciences, Inc., ImmuneOnco Biopharmaceutics (Shanghai), Immvira Pharma Co. Ltd., Incyte Corporation, Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Jiangsu HengRui Medicine, Klus Pharma, Inc., Kronos Bio, LaNova Medicines Ltd., Loxo Oncology, MedImmune, Merck Sharp & Dohme Corp., Mersana Therapeutics, Inc., Mirati Therapeutics, Inc., Molecular Templates Inc, Monte Rosa Therapeutics, Nektar Therapeutics, NeoImmuneTech, Inc., Nitto BioPharma, Inc., Novartis Pharmaceuticals, Pfizer, Pionyr Immunotherapeutics, Protagonist Therapeutics, Inc., Qilu Puget Sound Biotherapeutics Corporation, Qurient Co., Ltd., RAPT Therapeutics, Inc., Revolution Medicines, Sanofi, Scholar Rock, Sermonix Pharmaceuticals, Servier Pharmaceuticals, Stemline Therapeutics, Inc., Sumitomo Dainippon Pharma Oncology (SDPO), Suzhou Kintor Pharmaceuticals, Suzhou Transcenta Therapeutics Co., Ltd., SynerGene Therapeutics, Synthorx, Tesaro, Inc., Theratechnologies Inc, Verastem, Inc., Xbiotech. A. Starodub: Financial Interests, Local PI: Adenate, Ascendis, BioAtla, Cellectar, Exelixis, Gritstone, Jubilant, Kymera, LaNova, Merck, Miracogen, Revolution Medicine, Zailab, ZhuHai. D. Sommerhalder: Financial Interests, Personal, Other, Ad-hoc advisory role: Syneos SAG; Financial Interests, Personal, Other, Medical consulting: Guidepoint; Financial Interests, Institutional, Full or part-time Employment, Employed as a physician by Texas Oncology, a for-profit entity: Texas Oncology/US Oncology; Financial Interests, Institutional, Local PI: Astellas, Biomea Fusion, Boehringer Ingelheim, BJ Biosciences, BioNTech, Fate Therapeutics, Gilead Sciences, Immuneering, Kura Oncology, Monopteros Therapeutics, Navire, Nimbus Saturn, NGM Biopharmaceuticals, Parthenon, Pfizer, Revolution Medicines, Mirati Therapeutics, Symphogen, Teon Therapeutics, MediLink Therapeutics, ZielBio. S. Chang, Y. Zhang, Z. Salman: Financial Interests, Personal, Full or part-time Employment: Revolution Medicines; Financial Interests, Personal, Stocks/Shares: Revolution Medicines. X. Wang: Financial Interests, Personal, Officer, EVP Clinical Development; Officer of Revolution Medicines: Revolution Medicines; Financial Interests, Personal, Stocks/Shares, have stock options and own shares of RVMD stocks: Revolution Medicines. C. Gustafson: Financial Interests, Personal, Full or part-time Employment: Revolution Medicines; Financial Interests, Personal, Stocks/Shares: Revolution Medicines. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med.