619MO - Camonsertib (cam) monotherapy in patients (pts) with advanced cancers harboring ATM loss-of-function (LoF)

Background

Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) are synthetic lethal with ataxia telangiectasia-mutated (ATM) kinase LoF. Safety and dose optimization of cam (ATRi) monotherapy in TRESR (NCT04497116) was previously reported. Here we characterize the efficacy of cam monotherapy in the subset of pts with tumor ATM LoF.

Methods

TRESR enrolled 55 pts with advanced cancers and A) pathogenic ATM alterations based on NGS (tumor [n=27], germline testing [n=16], ctDNA [n=10]) or B) ATM IHC loss <10% (n=2). Central genomic and ATM IHC analysis were performed post-enrollment. Efficacy assessments included overall response (RECIST or tumor marker response), clinical benefit rate ([CBR]; response or on-treatment ≥16 wks), and progression free survival (PFS) in pts (n=46/55) treated with efficacious cam doses (>100 mg/day) with ≥1 post-baseline tumor assessment. Safety was also assessed (6 Mar 24 data cut).

Results

In the 55pts, ATM enrollment alterations were of germline (n=32) or somatic (n=19) origin and centrally confirmed in 48 pts. ATM biallelic LoF and ATM IHC loss were detected in 54% (21/39) and 63% (22/35) of tumors, respectively. In tumors with known IHC and allelic status (n=30), biallelic ATM LoF was significantly enriched for ATM protein loss (87%; 13/15) compared to non-biallelic LoF (40% [6/15], P = 0.02). The efficacy population comprised 9 pancreatic, 8 prostate, 6 colorectal, and other cancers (n=23; <5 pts/tumor type); median 3 lines prior therapy. 22% of pts were treated >12 mos, 4 pts ongoing (18-39+ mos). Overall response was 15% (7/46); 21% (7/33) excluding pts with confirmed non-biallelic LoF. Responses occurred late (median 8.3 mos) and were durable (3.1-20.8+ mos). In tumors harboring germline or somatic ATM LoF overall response was 18% (5/28) and 13% (2/15), respectively. CBR was 48% (22/46) with benefit observed in pts with NSCLC (2/2), bile duct (3/4), colorectal (3/6), and prostate (4/8) cancers. PFS at 6 mos was 46%. At the optimized dosing regimen, Gr3 anemia rate was 11% overall, 0/8 in the ATM subgroup.

Conclusions

Cam monotherapy resulted in durable responses and stable disease in multiple ATM-altered advanced cancers. Enrichment for biallelic ATM LoF may be a promising approach for ATRi monotherapy.

Clinical trial identification

NCT04497116.

Editorial acknowledgement

Justin L. Eddy, PhD, of Repare Therapeutics Inc. provided editorial and submission support during abstract development.

Legal entity responsible for the study

Repare Therapeutics, Inc.

Funding

Repare Therapeutics, Inc.

Disclosure

B.A. Carneiro: Financial Interests, Institutional, Research Funding: AstraZeneca, AbbVie, Actuate Therapeutics, Agenus, Astellas, Bayer, Daiichi Sankyo, Dragonfly Therapeutics, Pfizer, Pyxis Oncology, Repare Therapeutics. E. Rosen: Other, Personal, Other, Study Investigator: Repare Therapeutics. E. Fontana: Financial Interests, Personal, Other, Conference attendance: BicycleTx Ltd, Caris Life Science, Repare Therapeutics, Sapience Pharma, Seagen; Financial Interests, Institutional, Research Funding: Acerta Pharma, ADC Therapeutics, Amgen, Arcus Biosciences, Array BioPharma, Artios Pharma Ltd, Astellas Pharma Inc, Astex, AstraZeneca, Basilea, Bayer, BeiGene, BicycleTx Ltd, BioNTech, Blueprint Medicines, Boehringer Ingelheim, Calithera Biosciences, Inc., Carrick Therapeutics, Casi Pharmaceuticals, Clovis Oncology, Inc., Crescendo Biologics Ltd., CytomX Therapeutics, Daiichi Sankyo, Deciphera, Eli Lilly, Ellipses, Exelixis, F. Hoffmann-La Roche Ltd, Fore Biotherapeutics, G1 Therapeutics, Genentech, Gla, H3 Biomedicine Inc, Hutchinson MediPharma, Ignyta/Roche, Immunocore, Immunomedics, Inc., Incyte, Instil Bio, Iovance, Janssen, Jiangsu Hengrui, Kronos Bio, Lupin Limited, MacroGenics, Menarini, Merck KGaA, Mereo BioPharma, Merus, Millennium Pharmaceuticals, MSD, Nerviano Medical Sciences, Nurix Therapeautics Inc., Oncologie, Oxford Vacmedix, Pfizer, Plexxikon Inc., QED Therapeutics, Inc., Relay Therapeutics, Repare Therapeutics, Ribon Therapeutics, Roche, Sapience, Seagen, Servier, Stemline, Synthon BioPharmaceuticals, Taiho, Tesaro, Turning Point Therapeutics, Inc. E.K. Lee: Financial Interests, Personal and Institutional, Research Funding: Merck; Financial Interests, Personal, Other, Consulting: Aadi Biosciences. N.B. Mettu: Financial Interests, Institutional, Research Funding: AstraZeneca, Amgen, Amphivena Therapeutics, Aravive, Bristol Myers Squibb, BioMed Valley Discoveries, Erytech Pharma, Merck, Mereo Biopharma, Incyte Corporation, Genentech/Roche, Repare Therapeutics, Syros. S. Lheureux: Financial Interests, Institutional, Research Funding: AstraZeneca, GSK, Merck, Regeneron, Repare Therapeutics, Roche, Seagen; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Eisai, GSK, Merck, Novocure, Shattuck Labs; Financial Interests, Personal, Advisory Board: AstraZeneca. R. Plummer: Financial Interests, Personal, Advisory Board: AmLo, Astex Therapeutics, Bayer, Bristol Myers Squibb, Cybrexa Benevolent AI, Ellipses, Genmab, Incyte, Merck Sharp & Dohme, Nerviano, Novartis, Pierre Faber, Immunocore, Sanofi; Financial Interests, Personal, Other, Honoraria for independent data monitoring committee: Alligator Biosciences, AstraZeneca, GSK, Onxeo, SOTIO Biotech AG; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Novartis, Bayer, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis. I.M. Silverman, J.D. Schonhoft, J. Yang, G. Gomez, K. Fei, D. Ulanet, P.A. Basciano: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics. T.A. Yap: Financial Interests, Institutional, Research Funding: Acrivon, Artios, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint, Bristol Myers Squibb, Boundless Bio, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GSK, Genentech, Haihe, Ideaya ImmuneSensor, Insilico Medicine, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare Therapeutics, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tango, Tesaro, Vivace, Zenith; Financial Interests, Personal, Speaker, Consultant, Advisor: AbbVie, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Astex, AstraZeneca, Athena, Atrin, Avenzo, Avoro, Axiom, Baptist Health Systems, Bayer, BeiGene, BioCity Pharma, Blueprint, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Carrick Therapeutics, Circle Pharma, Clovis, Cybrexa, Daiichi Sankyo, Dark Blue Therapeutics, Diffusion, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Ellipses Pharma, EMD Serono, Entos, F-Star, Genesis Therapeutics, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Ideaya Biosciences, Idience, Ignyta, I-Mab, ImmuneSensor, Impact Therapeutics, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI Pharma, Mereo, Merck, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys, Nimbus, Novocure, Odyssey, OHSU, OncoSec, Ono Pharma, Onxeo, PanAngium Therapeutics, Pegascy, PER, Pfizer, Piper-Sandler, Pliant Therapeutics, Prolynx, Radiopharma Theranostics, Repare Therapeutics, resTORbio, Roche, Ryvu Therapeutics, SAKK, Sanofi, Schrodinger, Servier, Synnovation, Synthis Therapeutics, Tango, TCG Crossover, TD2, Terremoto Biosciences, Tessellate Bio, Theragnostics, Terns Pharmaceuticals, Tolremo, Tome, Thryv Therapeutics, Trevarx Biomedical, Varian, Veeva, Versant, Vibliome, Voronoi Inc, Xinthera, Zai Labs, ZielBio; Financial Interests, Personal, Stocks/Shares: Seagen; Financial Interests, Institutional, Research Grant, CA016672: NCI Cancer Center Support; Financial Interests, Institutional, Research Grant, W81XWH2210504_BC211174 and W81XWH-21-1-0282_OC200482: DOD; Financial Interests, Institutional, Research Grant, 1R01CA255074: NIH R01; Financial Interests, Institutional, Research Grant, VC2020-001: V Foundation Scholar. M. Hoejgaard: Financial Interests, Institutional, Research Funding: Amgen, AstraZeneca, Bayer, Bioinvent, Bioinvent International AB, Biopharma, Boehringer Ingelheim, BridgeBio, Bristol Myers Squibb, Dragonfly Therapeutics, Eli Lilly Pharmaceuticals/Loxo Oncology, Genmab, Incyte Corporation, Kinnate Biopharma, Monta Biosciences, Merck, MSD, Navire Pharma, Novartis, Orion Pharma, Pfizer, Puma Biotechnology, Repare Therapeutics, Roche/Genentech, Servier Oncology.