Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results

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Authors
Yap, T. A.
Fontana, E.
Lee, E. K.
Spigel, D. R.
Højgaard, M.
Lheureux, S.
Mettu, N. B.
Carneiro, B. A.
Carter, Louise
Plummer, R.
Affiliation
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Issue Date
2023

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Abstract
Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose a recommended phase 2 dose (RP2D). Secondary objectives were to assess preliminary anti-tumor activity, to characterize camonsertib pharmacokinetics and relationship with pharmacodynamic biomarkers and to evaluate methods for detecting ATRi-sensitizing biomarkers. Camonsertib was well tolerated; anemia was the most common drug-related toxicity (32% grade 3). Preliminary RP2D was 160 mg weekly on days 1-3. Overall clinical response, clinical benefit and molecular response rates across tumor and molecular subtypes in patients who received biologically effective doses of camonsertib (>100 mg d-1) were 13% (13/99), 43% (43/99) and 43% (27/63), respectively. Clinical benefit was highest in ovarian cancer, in tumors with biallelic LOF alterations and in patients with molecular responses.
Citation
Yap TA, Fontana E, Lee EK, Spigel DR, Højgaard M, Lheureux S, et al. Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results. Nature medicine. 2023 Jun;29(6):1400-11. PubMed PMID: 37277454. Pubmed Central PMCID: PMC10287555 medical director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors; has received funding paid to their institution from Acrivon, Artios, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint, Bristol Myers Squibb, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace and Zenith; has received consultancy funding from AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, BeiGene, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GlaxoSmithKline, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI Pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper-Sandler, Prolynx, Repare, resTORbio, Roche, Schrodinger, Theragnostics, Varian, Versant, Vibliome, Xinthera, Zai Labs and ZielBio; and is a stockholder in Seagen. E.F. has received personal funding for conference attendance from Repare Therapeutics, CARIS Life Science, Seagen and Sapience Pharma and has received research funding paid to their institution by Repare Therapeutics, Bicycle Therapeutics, Artios Pharma, Seagen, Amgen, Nurix Therapeutics, BioNTech, Relay Therapeutics, Tahio Pharmaceutical, Pfizer, Roche, Daiichi Sankyo, Gilead Sciences, Basilea Pharmaceutica, Jiangsu Hengrui Medicine, Mereo Biopharma, HUTCHMED, Merus, Crescendo Biologics, GlaxoSmithKline, BeiGene, Turning Point Therapeutics and Sapience Pharma. E.K.L. has received research funding from Merck and consulting funding from Aadi Biosciences. D.R.S. has received research funding paid to their institution by Aeglea Biotherapeutics, Agios, Amgen, AnHeart Therapeutics, Apollomics, Arcus, Arrys Therapeutics, Ascendis Pharma, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, BioNTech, Blueprint Medicine, Boehringer lngelheim, Bristol Myers Squibb, Calithera, Celgene, Celldex, Clovis, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Endeavor, Erasca, Faeth Therapeutics, Fujifilm Pharmaceuticals, G1 Therapeutics, Roche/Genentech, Gilead Sciences, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Incyte, Ipsen, Janssen, Jazz Pharmaceuticals, Kronos Bio, Eli Lilly, Loxo Oncology, Lyell Immunopharma, MacroGenics, MedImmune, Merck, Molecular Template, Nektar, Neon Therapeutics, Novartis, Novocure, Pure Tech Health, Razor Genomics, Repare Therapeutics, Rgenix, Seagen, Shenzhen Chipscreen Biosciences, Sythekine, Taiho, Tango Therapeutics, Tarveda, Tesaro, Tizona Therapeutics, Transgene, The University of Texas Southwestern, Verastem and Zai Laboratory and has performed a consultant and/or advisory role paid to their institution by AstraZeneca, BeiGene, Bristol Myers Squibb, Curio Science, EMO Serano, Evidera, GlaxoSmithKline, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Eli Lilly, Molecular Templates, Monte Rosa Therapeutics, Novartis, Novocure, Pfizer, Pyxis Oncology, Regeneron Pharmaceuticals, Roche/Genentech and Sanofi. M.H. has received research funding paid to their institution by Repare Therapeutics and Roche. S.L. has received grants or contracts paid to their institution from Merck, AstraZeneca, Regeneron, Roche, Repare Therapeutics, GlaxoSmithKline and Seagen; consulting fees from Novocure, Merck, AstraZeneca, GlaxoSmithKline, Eisai and Shattuck Labs; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from AstraZeneca, GlaxoSmithKline and Eisai/Merck; and participation on a data safety monitoring board or advisory board from AstraZeneca. N.B.M. has received research funding paid to their institution by Incyte Corporation, Genentech/Roche, AstraZeneca, Amgen, Erytech Pharma, Bristol Myers Squibb, Amphivena Therapeutics, Repare Therapeutics, BioMed Valley Discoveries, Mereo Biopharma, Syros, Aravive and Merck. B.A.C. has received research funding paid to their institution by AstraZeneca, Abbvie, Actuate Therapeutics, Astellas, Bayer, Dragonfly Therapeutics, Pfizer and Repare Therepeutics. L.C. has received research funding paid to their institution by Repare Therapeutics. R.P. has received honoria for attending advisory boards from Pierre Faber, Bayer, Novartis, Bristol Myers Squibb, Cybrexa, Ellipses, CV6 Therapeutics, Immunocore, Genmab, Astex Therapeutics, Medivir, Onxeo and Sanofi; honoraria for working as an independent data monitoring committee member for Alligator Biosciences, GlaxoSmithKline and SOTIO Biotech AG; personal funding for delivery of educational talks or chairing educational meetings by AstraZeneca, Novartis, Bayer and Bristol Myers Squibb; and funds to support attendance at conferences from Merck Sharp & Dohme and Bristol Myers Squibb. G.M.C. has received funding paid to their institution by Servier Pharmaceuticals, Epizyme, PharmaMar, Macrogenics, Eisai, Merck KGaA/EMO Sereno Research and Development Institute, Bavarian-Nordic, Bayer, SpringWorks, Repare Therapeutics, Foghorn, SMP Oncology, Jazz Pharmaceuticals, RAIN Therapeutics, BioAtla, lnhibrx, lkena and C4 Therapeutics; and advisory board fees from Epizyme, PharmaMar, Eisai, Foghorn, lkena and C4 Therapeutics. F.M.B. has received research funding to their institution from Aileron Therapeutics, AstraZeneca, Bayer, Calithera, Curis, CytomX Therapeutics, Daiichi Sankyo, Debiopharm, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Takeda, Novartis, Puma Biotechnology and Taiho; funding for consultancy from AbbVie, Aduro BioTech, Alkermes, AstraZeneca, Daiichi Sankyo, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche, GT Apeiron, Genentech, Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer, Protai Bio, Samsung Bioepis, Seattle Genetics, Tallac Therapeutics, Tyra Biosciences, Xencor and Zymeworks; fees from advisory committees from Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology, Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals and Zentalis; and honoraria from Chugai Biopharmaceuticals. J.O. has received consultancy fees from Repare Therapeutics. J.D.S., M.W., A.F., D.U., M.Z., M.K., I.M.S. and V.R. are current employees and shareholders of Repare Therapeutics. Y.X. is a current employee of Repare Therapeutics. P.M. is a former employee and current shareholder of Repare Therapeutics. M.K., I.M.S., V.R. and J.S.R.F. have a provisional patent related to data disclosed in this publication. J.S.R.F. has received consultancy fees from Goldman Sachs, Paige.AI, Repare Therapeutics and Personalis; is a member of the scientific advisory boards of Volition Rx, Paige.AI, Repare Therapeutics, Personalis and Bain Capital; is a member of the board of directors of Grupo Oncoclinicas; and is an ad hoc member of the scientific advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, AstraZeneca, Daiichi Sankyo and Merck Sharp & Dohme. E.R. has no competing interests to disclose. Epub 2023/06/06. eng.
Journal
Nature Medicine
URI
http://hdl.handle.net/10541/626346
DOI
10.1038/s41591-023-02399-0
PubMed ID
37277454
Additional Links
https://dx.doi.org/10.1038/s41591-023-02399-0
Type
Article
Language
en
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