604O - Phase I dose escalation and initial dose expansion results of AMG 193: A MTA-cooperative PRMT5 inhibitor, in patients (pts) with MTAP-deleted solid tumors

Background

Methylthioadenosine phosphorylase (MTAP) deletion occurs in ∼10-15% of solid tumors. AMG 193 is an oral central nervous system penetrant methylthioadenosine (MTA)-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor designed to selectively induce synthetic lethality in MTAP-deleted tumors while sparing normal cells. We report completed results of dose escalation (dES) and initial results from tumor-specific dose expansion (dEX) of the AMG 193 first-in-human study.

Methods

Pts with advanced MTAP-deleted non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer (BTC), and other solid tumors received AMG 193 orally (once [QD] or twice daily) in dES and dEX. The study objectives were to evaluate safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics.

Results

As of March 28, 2024, 80 pts in dES (40–1600 mg) and 63 pts in dEX (1200 mg) with a median of two prior lines of therapy received AMG 193. The most common treatment-related adverse events were nausea (50%), fatigue (30%), vomiting (29%), and decreased appetite (19%). In dES, 2/18 pts in the 1200 mg QD cohort reported dose-limiting toxicities (grade 3 vomiting, grade 3 hypokalemia). No dose-limiting cytopenias were reported. The maximum tolerated dose was 1200 mg QD. At active dose levels (800 mg, 1200 mg), 2/11 NSCLC pts, 2/16 PDAC pts, and 2/11 BTC pts had an objective response (with one additional unconfirmed response in NSCLC and PDAC; Table). The median duration of response was 8.3 months. Transcriptional analysis of paired tumor biopsies confirmed perturbation of the RNA splicing, cell cycle, and DNA damage response pathways.

Conclusions

AMG 193 demonstrated a favorable safety profile, no evidence of clinically significant myelosuppression as observed with first generation PRMT5 inhibitors, and encouraging antitumor activity in solid tumors, including NSCLC, PDAC and BTC. Table: 604O

Antitumor activity

CI, confidence interval; CR, complete response; DCR, disease control rate; NE, not estimable; ORR, objective response rate; PD, progressive disease; c/u PR, confirmed/unconfirmed partial response; QD, once daily; SD, stable disease.

Clinical trial identification

NCT05094336.

Editorial acknowledgement

Medical writing support was provided by Qais Al-Hadid (Amgen).

Legal entity responsible for the study

Amgen.

Funding

Amgen.

Disclosure

A.G. Sacher: Financial Interests, Institutional, Coordinating PI: Genentech-Roche, BMS, AstraZeneca; Financial Interests, Institutional, Local PI: Amgen, Iovance, CRISPR Therapeutics, Merck, Pfizer, GSK, Spectrum, Lilly, BridgeBio, Hotspot Therapeutics. M. Villalona-Calero: Financial Interests, Institutional, Research Grant: Amgen, Kronos Bio, Cyclacel, IDEYA, Hummingbird, Nectin; Financial Interests, Personal, Stocks/Shares: Moderna. J. Rodon: Financial Interests, Personal, Proprietary Information: Blueprint Medicines; Financial Interests, Personal, Speaker’s Bureau: Merck Sharp & Dohme, Hummingbird, Astra Zenneca, Yingli, Vall d'Hebron Institute of Oncology/Cancer, Core Europe. T. Doi: Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Taiho, MSD, Daiichi Sankyo, Pfizer, Chugai, AbbVie, PRA Healthscience, Ono, Shionogi, Amgen, Rin Institute, Bayer, KyowaKirin, GSK; Financial Interests, Personal, Advisory Role: Rakuten Medical. S. Postel-Vinay: Financial Interests, Institutional, Research Grant: Hoffman LaRoche IMCore; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Institutional, Research Funding: AstraZeneca, Amgen, Oxford Biotherapeutics, Clever therapy, Novartis, GSK. F. Ghiringhelli: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Amgen, Merck Serono, MSD. N. Yamamoto: Financial Interests, Institutional, Research Grant: Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, ONO, Janssen Pharma, MSD, Merck, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, Toray, Kaken, AstraZeneca, Cmic, InventisBio, Rakuten Medical; Financial Interests, Personal, Advisory Role: Eisai, Takeda, Boehringer Ingelheim, Cmic, Chugai, Merck, Healios; Financial Interests, Personal, Speaker’s Bureau: Chugai, Daiichi Sankyo, Eisai. S. Wahlroos: Financial Interests, Institutional, Invited Speaker, Invited speaker to give an overview of BTC cancer and its treatments: AstraZeneca. L. Villaruz: Financial Interests, Personal, Advisory Board: Sanofi, Gilead, Johnson and Johnson, EMD Serono, Daiichi Sankyo, AstraZeneca; Financial Interests, Institutional, Local PI: Regeneron, GSK, BioAtla, BeiGene, Fujifilm, Amgen, Boehringer Ingelheim, Merck; Financial Interests, Institutional, Coordinating PI: Genentech. A. El-Helali: Financial Interests, Institutional, Invited Speaker: Roche, Bayer; Financial Interests, Institutional, Local PI: Pfizer, Amgen. Y. Fujiwara: Financial Interests, Institutional, Research Grant: AbbVie, Amgen, AnHeart, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Incyte, Merck KGaA, Merck Sharp & Dohme, Taiho Pharmaceutical; Financial Interests, Personal, Advisory Role: AstraZeneca, Chiome Bioscience, Daiichi Sankyo, Micron, Otsuka Pharmaceutical, Ono Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Amgen, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Merck Biopharma, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Takeda, Taiho Pharmaceutical. A. Addeo: Financial Interests, Institutional, Advisory Board: BMS, AZD, Roche, Eli Lilly; Financial Interests, Personal, Advisory Board: Pfizer, Takeda, MSD; Financial Interests, Institutional, Invited Speaker: Novartis. C. Lin: Financial Interests, Personal, Other, Travel support: BeiGene, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Novartis, AbbVie, PharmaEngine, Merck KGaA, Boehringer Ingelheim, Anbogen, IMPACT Therapeutics; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Roche; Financial Interests, Personal, Other, Travel Support: IMPACT Therapeutics; Financial Interests, Institutional, Other, Local principal investigator: Nuvalent. E. Fontana: Financial Interests, Personal, Invited Speaker: Caris Life Science, Repair Therapeutics; Financial Interests, Personal, Other, Conference attendance: Sapience Pharma; Financial Interests, Personal, Invited Speaker, Conference Attendance: Bicycles Therapeutics; Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International; Financial Interests, Personal, Officer: EORTC; Financial Interests, Institutional, Coordinating PI: Repair Therapeutics, Amgen, Taiho Pharmaceutical; Financial Interests, Institutional, Local PI: Bicycle Therapeutics, Artios Pharma, Seagen, Nurix Therapeutics, BioNTech SE, Relay Therapeutics, Pfizer, Roche, Daiichi Sankyo, Gilead Science, Basilea Pharmaceutica, Jiangsu Hengrui Medicine, Mereo Biopharma, Hutchmed, Merus, Crescendo Biologics, GSK plc, BeiGene, Turning Point Therapeutics, Sapience Pharma, Arcus Bioscience, Exelixis, Nerviano Medica, Elipsees, Deciphera, Ribon Therapeutics. C. Chuang, C. Liu, T. Eggert: Financial Interests, Personal, Stocks or ownership: Amgen; Financial Interests, Personal, Full or part-time Employment: Amgen. N. Penel: Financial Interests, Institutional, Research Grant, Research grant for clinical trials in sarcoma filed: Bayer HealthCare. H. Prenen: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, Roche; Financial Interests, Institutional, Invited Speaker: Bayer, Ipsen, Sanofi. All other authors have declared no conflicts of interest.