Abstract
Background: Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus, dose and schedule optimization requires extended follow-up to assess prolonged treatment effects. Methods: Long-term safety, tolerability, and antitumor efficacy of 3 camonsertib monotherapy dosing regimens were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on, 4 days off (160 3/4; the preliminary recommended Phase II dose [RP2D]) and two step-down groups of 120 mg QD 3/4 (120 3/4) and 160 mg QD 3/4, 2 weeks on, 1 week off (160 3/4, 2/1w). Safety endpoints included incidence of treatment-related adverse events (TRAEs), dose modifications, and transfusions. Efficacy endpoints included overall response rate, clinical benefit rate, progression-free survival, and circulating tumor DNA (ctDNA)-based molecular response rate. Results: The analysis included 119 patients: 160 3/4 (n = 67), 120 3/4 (n = 25), and 160 3/4, 2/1w (n = 27) treated up to 117.1 weeks as of the data cutoff. The risk of developing grade 3 anemia was significantly lower in the 160 3/4, 2/1w group compared with the preliminary RP2D group (hazard ratio = 0.23, 2-sided P =. 02), translating to reduced transfusion and dose reduction requirements. The intermittent weekly schedule did not compromise antitumor activity. Conclusion: The 160 3/4, 2/1w dose was established as an optimized regimen for future camonsertib monotherapy studies offering a substantial reduction in the incidence of anemia without any compromise to efficacy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1439-1449 |
| Number of pages | 11 |
| Journal | Journal of the National Cancer Institute |
| Volume | 116 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2024 |
Funding
Elizabeth K. Lee has received research funding from Merck and consulting funding from Aadi Biosciences. This work was supported by Repare Therapeutics, Inc. The authors would like to thank the patients, their families, and all investigators involved in this study. Medical writing and editorial support, including referencing, figure preparation, formatting, and proofreading were provided by Allison Alwan TerBush, PhD, Peter Gray, PhD, and Rosie Henderson, MSc, of Onyx (a division of Prime, London, UK) and Justin L. Eddy, PhD (Repare Therapeutics, Cambridge, MA) supported by Repare Therapeutics according to Good Publication Practice guidelines (Link). The sponsor was involved in the study design, collection, analysis, and Timothy A. Yap is an employee of The University of Texas MD Anderson Cancer Center, where he is Vice President, Head of Clinical Development in the Therapeutics Discovery Division, which has a commercial interest in DNA damage response and other inhibitors (IACS30380/ART0380 was licensed to Artios); has received funding paid to their institution from Acrivon, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, Bristol Myers Squibb, Boundless Bio, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, Ideaya ImmuneSensor, Insilico Medicine, Ionis, Ipsen, Jounce, Karyopharm, KSQ Therapeutics, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tango, Tesaro, Vivace, and Zenith; has received consultancy funding from 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 Pharma, Globe Life Sciences, GlaxoSmithKline, 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, resTORbio, Roche, Ryvu Therapeutics, SAKK, Sanofi, Schrodinger, Servier, Synnovation, Synthis Therapeutics, Tango, TCG Crossover, TD2 Translational Drug Development, Terremoto Biosciences, Tessellate Bio, Theragnostics, Terns Pharmaceuticals, Tolremo, Tome, Thryv Therapeutics, Trevarx Biomedical, Varian, Veeva, Versant, Vibliome, Voronoi Inc, Xinthera, Zai Labs, and ZielBio; and is a stockholder in Seagen. He was supported by the National Cancer Institute Cancer Center Support Grant CA016672 to The University of Texas MD Anderson Cancer Center, DOD grants W81XWH2210504_BC211174 and W81XWH-21-1-0282_OC200482, V Foundation Scholar Grant VC2020-001, and NIH R01 grant 1R01CA255074. Acknowledgments This work was supported by Repare Therapeutics, Inc.
ASJC Scopus subject areas
- Oncology
- Cancer Research
