Abstract 485P
Background
ATR inhibition is an emerging strategy in tumors harboring elevated replicative stress. We sought to identify clinical, genomic and hematological parameters associated with ATRi benefit, and to delineate potential links between ATRi toxicity with efficacy.
Methods
Patients (pts) treated with an oral ATRi as monotherapy or in combination with a PARP inhibitor (ATRi+PARPi) on phase I/II trials at our center were identified. Retrospectively collected pt clinical data, genomic alterations and peripheral blood cell indices retrieved from complete blood count reports (CBC) pre- and during ATRi therapy, were correlated with treatment outcomes.
Results
35,007 indices from 1,843 CBC of 119 pts treated with ATRi (110 ATRi, 9 ATRi + PARPi) from 10/2017 to 1/2022, were analyzed. Pathogenic genomic alterations were most frequently found in ATM (49%), BRCA2 (14%), BRCA1 (13%) and ARID1A (10%). Median pt age was 59 years (range 31-88). Eastern cooperative oncology group performance status (ECOG PS) was 0 and 1, in 22 (18.5%) pts and 97 (81.5%) pts, respectively. Pts had a median of 4 prior lines of systemic therapy (range 0-11). On multivariate analysis, lower baseline immature reticulocyte fraction (IRF) (hazard ratio (HR)(95% CI) = 0.62 (0.44, 0.88) per fold increase, p = 0.01) and the development of grade 3 anemia within the first 6 months of ATRi treatment (HR = 0.56 (0.35, 0.90), p = 0.02), were associated with improved PFS. Amongst 111 evaluable pts, the ORR was 7.2%. Lower median baseline reticulocyte count was associated with objective response (median 1.30 vs 1.60, p = 0.03). The median OS was 15.0 months (11.4, 19.8). On multivariate analysis, ECOG PS (1 vs 0, HR = 2.73 (1.15, 6.49), p = 0.02) and higher baseline neutrophil:lymphocyte ratio (NLR)(HR = 1.55 (1.17, 2.06) per fold increase, p = 0.002) were associated with worse OS.
Conclusions
Anemia is an on-target toxicity of ATRi. The development of grade 3 anemia within first 6 months of ATRi was associated with improved PFS. Lower baseline IRF and reticulocyte count, were associated with improved PFS and objective response. Higher baseline NLR was associated with poor OS. These deserve further evaluation as biomarkers of ATRi therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
E.E. Ileana Dumbrava: Financial Interests, Institutional, Research Grant: Bayer HealthCare Pharmaceuticals Inc, Immunocore Ltd, Amgen, NCI, Aileron Therapeutics, Compugen Ltd, TRACON Pharmaceuticals Inc, Unum Therapeutics , Immunomedics, BOLT Therapeutics, Aprea Therapeutics; Financial Interests, Personal, Other: Catamaran Bio, BOLT Therapeutics. S. Fu: Financial Interests, Institutional, Funding: NIH/NCI, Abbisko, Beigene, BioAtla LLC, Boehringer Ingelheim, Eli Lilly, Exelisis, Greenfire Bio, Hookipa Biotech, IMV Inc, Innovent Biologics Co Ltd, K-Group Beta, Lyvgen BIopharm Co Ltd, MacroGenics, Millennium Pharmaceuticals, Nerviano Medical Sciences, NeuPharma Inc, NextCure Inc, Ningbo NewBay Technology Development Co Ltd, Novartis, Novocure, Parexel International LLC, Pionyr Immunotherapeutics Inc, PureTech Health LLC, Sellas Life Sciences Group, Soricimed Biopharma Inc, SQZ Biotechnologies, Sumitomo Dainippon, Taiho Oncologu and NCCN, Treadwell Therapeutics, Turnstone Biologics, Tyligand Bioscience Ltd, Nykode Therapeutics AS. A. Naing: Financial Interests, Personal, Advisory Role: Novartis, CytomX Therapeutics, OncoSec, STCube Pharmaceuticals Inc, Kymab, Genome & Company, Immune-Onc, Deka Bioscience, Nouscom; Financial Interests, Institutional, Advisory Role: Takeda, CSL Behring, Horizon Pharma; Financial Interests, Institutional, Funding: NCI, EMD Serono, Medimmune, Atterocor, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance BioSciences Inc, Healios, Lilly, Kymab, PsiOxus Therapeutics, Immune Deficiency Foundation, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, Surface Oncology, Baxalta, Jeffrey Modell Foundation, Chao Physician-Scientist Awards; Financial Interests, Institutional, Other: ARMO Biosciences. J. Rodon: Financial Interests, Personal, Advisory Board: Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners, IONCTURA SA; Financial Interests, Institutional, Other, Clinical Research: Bayer, Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GlaxoSmithKline; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics; Other, Other: VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC; Other, Travel Reimbursement: European Society for Medical Oncology. S. Piha-Paul: Financial Interests, Institutional, Funding: AbbVie Inc, ABM Therapeutics Inc, Acepodia Inc, Alkermes, Aminex Therapeutics, Amphivena Therapeutics Inc, Biomarin Pharmaceutical Inc, Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma Inc, Chugai Pharmaceutical Co Ltd, Curis Inc, Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Gene Quantum, Genmab A/S, Gilead Sciences Inc, GlaxoSmithKline, Helix Biopharma Corp, HiberCell Inc, Immunomedics Inc, Incyte Corp, Jacobio Pharmaceuticals Co Ltd, Lytix Biopharma AS, Medimmune LLC, Medivation Inc, Merck Sharp and Dohme Corp, Novartis Pharmaceuticals, Pieris Pharmaceuticals Inc, Pfizer, Phanes Therapeutics, Principia Biopharma Inc, Puma Biotechnology Inc, Purinomia Biotech Inc, Rapt Therapeutics Inc, Seattle Genetics, Silverback Therapeutics, Synlogic Therapeutics, Taiho Oncology, Tesaro Inc, Trasthera Bio, ZielBio Inc; Financial Interests, Institutional, Research Grant: NCI/NIH P30CA016672 Core Grant. V. Subbiah: Financial Interests, Personal, Advisory Board, One time advisory board: Incyte, Novartis, Eli Lilly/ Loxo Oncology; Financial Interests, Personal, Advisory Board, One time ad board: Roche, Pfizer; Financial Interests, Personal, Advisory Board, Ad hoc advisory board: Relay Therapeutics; Financial Interests, Institutional, Invited Speaker, Research funding to conduct Clinical trial: Eli Lilly/LOXO Oncology, Blueprint medicines, Novartis, Boston Pharmaceuticals, Pfizer, Turning Point Therapeutics, Amgen, Bayer, Roche/ Genentech, Exelixis, Berg Pharma, N W Biotherapeutics, Relay Therapeutics, AbbVie, Agensys, Inhibrx, Dragonfly therapeutics, TAKEDA; Financial Interests, Institutional, Invited Speaker, Research funding to conduct clinical trial: Shasqi; Other, I am employed at the University of Texas MD Anderson Cancer Center: The University of Texas MD Anderson Cancer Center; Other, I receive research funding from NCI: National Cancer Institute, USA. A.M. Tsimberidou: Financial Interests, Institutional, Funding: OBI Pharma, IMMATICS, Parker Institute for Cancer Immunotherapy, Agents, Tvardi, Boston Biomedical, Karus Therapeutics, Novocure Ltd; Financial Interests, Personal and Institutional, Advisory Role: Vincerx, Diaccurate. D.S. Hong: Financial Interests, Personal, Other, All companies listed are classified as Consulting, Speaker or Advisory role: 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,; Financial Interests, Personal, Other, All are Advisory and or Advisory/Founder: Molecular Match (Advisor), OncoResponse (Founder, Advisor), Telperian (Founder,Advisor); Financial Interests, Institutional, Research Grant: AbbVie, Adaptimmune, Adlai-Nortye, Amgen, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Deciphera, Eisai, Endeavor, Erasca, F. Hoffmann-La Roche, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa Kirin, Lilly, LOXO, Merck, M. F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Tyra Biosciences, Xencor, Zymeworks, OnCusp Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Advisory Board: Silverback Therapeutics, Zentalis, Karyopharm, Biovica, Eisai; Financial Interests, Personal, Other, Consulting: Tallac Therapeutics, Lengo Therapeutics, LOXO-Oncology, Black Diamond, Infinity Pharmaceuticals, AbbVie; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis, PPD Investigator Services; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare. T.A. Yap: Financial Interests, Personal, Other, Consultant: Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Clovis, Cybrexa, EMD Serono, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Varian, Zai Labs, AbbVie, Acrivon, Adagene, Amphista, Artios, Athena, Avoro, Baptist Health Systems, Beigene, Boxer, C4 Therapeutics, Calithera, Cancer Research UK, Diffusion, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Idience, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Kyn, MEI Pharma, Mereo, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Piper-Sandler, Prolynx, resTORbio, Theragnostics, Versant, Vibliome, Xinthera, ZielBio; Financial Interests, Personal, Other, University of Texas MD Anderson Cancer Center, where I am Medical Director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios): MD Anderson Cancer Center, Institute for Applied Cancer Sciences; Financial Interests, Personal, Stocks/Shares: Seagan; Financial Interests, Institutional, Other, Grant/Research support: Bayer, Cyteir, EMD Serono, GlaxoSmithKline, Karyopharm, Pfizer, Repare, Sanofi, Artios, AstraZeneca, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Eli Lilly, Forbius, F-Star, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, KSQ, Kyowa, Merck, Mirati, Novartis, Ribon Therapeutics, Regeneron, Rubius, Scholar Rock, Seattle Genetics, Tesaro, Vivace, Acrivon, Zenith. All other authors have declared no conflicts of interest.