1309P - A genomic scar based signature (HRDsig) and biallelic BRCA alterations identify a homologous recombination deficiency (HRD) phenotype of non-small cell lung cancer (NSCLC) potentially actionable to the PARP inhibitor rucaparib: Post-hoc analysis of lung-MAP substudy S1900A

Background

Cancers with an HRD phenotype are thought to be lineage-dependent with limited anti-tumor activity of PARP inhibitors (PARPi) demonstrated in non-canonical histologies such as NSCLC. We conducted a posthoc analysis of S1900A examining the activity of the PARPi rucaparib in advanced NSCLC patients (pts) by BRCA zygosity and a candidate genomic scar-based signature of HRD (HRDsig).

Methods

Pts enrolled on S1900A had advanced NSCLC with progression on or after platinum-based chemotherapy and/or PD(L)1 antibody and Zubrod performance status of 0-1. All pts had tumor comprehensive genomic profiling (FoundationOne®CDx; Foundation Medicine, Boston, MA). Rucaparib was administered at the FDA-approved oral dose of 600 mg twice daily until unacceptable toxicity or progression. BRCA zygosity and HRDsig were determined per previously published methods (JA Moore et al, JCO PO 2023). HRDsig score of >0.7 was considered positive. Best response was determined per RECIST 1.1. Cox Proportional Hazard Models for PFS and OS were adjusted by age and sex.

Results

53 of 59 (90%) eligible pts enrolled on S1900A had BRCA zygosity and/or HRDsig determined. 18 pts (31%) had NSCLC harboring BRCA1/2 biallelic alterations and/or HRDsig+. Of the 5 pts with a response to rucaparib, 4 had biallelic BRCA1/2 alterations and/or were HRDsig+. In a posthoc analysis, the presence of BRCA1/2 biallelic alterations and/or HRDsig+ was associated with improved PFS and OS to rucaparib (HR=0.51, 95% CI: 0.28-0.93, p=0.029; HR=0.5, 95% CI: 0.27-0.95 p=0.033). PFS and OS results were comparable for squamous (N=19, HR=0.35, p=0.089, HR=0.28, p=0.042) and non-squamous histologies (N=34, HR=0.64, p=0.30, HR=0.6, p=0.25). HRDsig was determined in 52 of 59 pts (88%) and analyzed alone was also a significant predictor of PFS and OS to rucaparib (HR=0.53, 95% CI: 0.29-1, p=0.05; HR=0.51, 95% CI: 0.26-0.99, p=0.05), respectively.

Conclusions

NSCLC harboring biallelic alterations in BRCA1/2 and/or HRDsig+ represent a potentially actionable subset of NSCLC responsive to PARP inhibition (NCT03845296).

Clinical trial identification

NCT03845296.

Editorial acknowledgement

Legal entity responsible for the study

National Cancer Institute of the United States of America.

Funding

NIH/NCI grant awards U10CA180888 and U10CA180819; Foundation for the National Institutes of Health; and in part by Clovis Oncology, Inc.

Disclosure

J.W. Riess: Financial Interests, Personal, Advisory Board: Biodesix, Merus, Bayer, Regeneron, Sanofi, Seattle Genetics, BMS, Daiichi Sankyo, Roche/Genentech, Janssen, Amgen, Catalyst; Financial Interests, Personal, Other, Consulting fees: EMD Serano, Novartis; Financial Interests, Institutional, Steering Committee Member, Research funds paid to institution: AstraZeneca; Financial Interests, Institutional, Local PI, Research funds to institution: ArriVent, Revolution Medicines; Financial Interests, Personal, Trial Chair, Research funds to institution: Merck; Financial Interests, Institutional, Coordinating PI, Research funds to institution: IO Biotech; Financial Interests, Institutional, Trial Chair, Research funds to institution: Novartis; Financial Interests, Institutional, Coordinating PI, Research Funds to Institution: Summit; Financial Interests, Institutional, Local PI, Research Funds to Institution: Seattle Genetics; Financial Interests, Institutional, Local PI, Research funding to institution: Nuvalent; Financial Interests, Institutional, Local PI, Research Funding to Institution: Kinnate. P. Wheatley-Price: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, BMS, Merck, Amgen, Lilly, Sanofi, Pfizer, Janssen; Financial Interests, Personal, Advisory Board, Advisory Board: SteriMax, GSK; Financial Interests, Institutional, Local PI: Turning Point, Jazz Pharmaceuticals, Novartis, AstraZeneca. K.L. Reckamp: Financial Interests, Personal, Other, consultant: AstraZeneca, Blueprint, Daiichi Sankyo, Genentech, GSK, Janssen, Lilly, Mirati, Novartis; Financial Interests, Personal, Advisory Board: EMD Soreno; Financial Interests, Institutional, Local PI: Genentech, Blueprint, Calithera, Daiichi Sankyo, Elevation Oncology, Janssen. D. Kozono: Financial Interests, Personal, Advisory Role: Roche/Genentech. M.J. Edelman: Financial Interests, Personal, Other, member of independent Data Safety and Monitoring Board: AstraZeneca; Financial Interests, Personal, Other, member of independent Data and Safety Monitoring Board: Takeda, GSK, Seattle Genetics; Financial Interests, Personal, Advisory Board, stock options: Creatv Biotech; Financial Interests, Personal, Advisory Board: BioAlta, GE Healthcare; Financial Interests, Personal, Other, Deputy Editor: Lung Cancer (journal); Financial Interests, Institutional, Local PI: GSK, Nektar; Non-Financial Interests, Other, member of Board of Directors and Chair of Scientific Advisory Board. Not compensated.: Lung Cancer Foundation of America. 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. R. Osarogiagbon: Financial Interests, Personal, Stocks/Shares: Bridge Bio, Eli Lilly, Gilead Sciences, Immunocore, Pfizer; Financial Interests, Personal, Advisory Role: AstraZeneca, GE Healthcare, Median Technologies, National Cancer Institute. D.R. Gandara: Financial Interests, Institutional, Research Funding: Amgen, Astex, Genentech; Financial Interests, Institutional, Advisory Role: Adagene, AstraZeneca, IO Biotech, Guardant Health, Oncocyte; Financial Interests, Personal, Advisory Board: Roche/Genentech, Merck, Novartis, Boehringer Ingelheim, Regeneron, Sanofi, Amgen. E.S. Sokol: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine. H. Borghaei: Financial Interests, Personal, Advisory Board: BMS, Genentech, Eli Lilly, Merck, EMD-Serono, AstraZeneca, Novartis, Genmab, Regeneron, Amgen, Takeda, PharmaMar, Jazz Pharma, Mirati, Daiichi Sankyo, Guardant, Natera, Oncocyte, BeiGene, iTeo, Boehringer Ingelheim, Puma, BerGenbio, Janssen; Financial Interests, Personal, Other, Training discussion: Pfizer; Financial Interests, Personal, Other, DSMB: Novartis; Financial Interests, Institutional, Other, Clinical trial support: BMS, Amgen; Financial Interests, Personal, Stocks/Shares, Options for scientific advisory role: Sonnetbio; Financial Interests, Personal, Stocks/Shares, Options for scientific advisory board: Nucleai, Inspira (Rgenix); Financial Interests, Institutional, Trial Chair, Investigator initiated trial support: BMS; Financial Interests, Institutional, Coordinating PI, Investigator initiated trial support: Amgen, Lilly; Financial Interests, Personal and Institutional, Trial Chair, Chair steering committee: Miratti; Financial Interests, Personal and Institutional, Steering Committee Member: Amgen, AstraZeneca; Financial Interests, Personal, Steering Committee Member, Also trial support: BMS; Other, DSMB: Novartis, Takeda, Incyte, Springworks. J.E. Gray: Financial Interests, Personal, Other, Consultant / Advisor: AbbVie, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Inc., EMD Serono - Merck KGaA, Gilead Sciences, Inc., IDEOlogy Health, Janssen Scientific Affairs, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co, Inc., Novartis, OncoCyte Biotechnology, Regeneron, Spectrum ODAC, Takeda Pharmaceuticals, Triptych Health Partners; Financial Interests, Institutional, Full or part-time Employment: Moffitt Cancer Center; Financial Interests, Institutional, Member of Board of Directors: SWOG; Financial Interests, Research Grant: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, EMD Serono - Merck KGaA, Genentech, Gilead Sciences, G1 Therapeutics, Ludwig Institute of Cancer Research, Merck & Co, Inc., Novartis, Panbela Therapeutics, Inc., Pfizer, Regeneron; Non-Financial Interests, Leadership Role, Department Chair, Thoracic Oncology: Moffitt Cancer Center; Non-Financial Interests, Leadership Role, Co-Leader, Molecular Medicine Program: Moffitt Cancer Center; Non-Financial Interests, Leadership Role, Chair, Lung Committee: SWOG; Non-Financial Interests, Member of Board of Directors: IASLC; Non-Financial Interests, Member of Board of Directors, Elected member - service to start on June 4th 2024: ASCO. R.S. Herbst: Financial Interests, Personal, Advisory Board, Advisory board and consulting EGFR and angiogenesis: AstraZeneca; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: Bolt Biotherapeutics, Checkpoint Therapeutics, Cybrexa Therapeutics, I-Mab Biopharma, Immunocore, Ocean Biomedical, Inc..; Financial Interests, Personal, Other, Ad hoc consulting-oncology: Bristol Myers Squibb, DynamiCure Biotechnology, LLC, Eli Lilly and Company, Foundation Medicine, Inc., Genentech/Roche, Gilead, Johnson and Johnson, Merck and Company, NextCure, Oncternal Therapeutics, Pfizer, Sanofi; Financial Interests, Personal, Advisory Board, Advisory Board - Research Advisory Board: Candel Therapeutics, Inc.; Financial Interests, Personal, Other, Clinical Advisor: eFFECTOR Therapeutics, Inc.; Financial Interests, Personal, Advisory Board, Data safety monitory committee: EMD Serono, Novartis; Financial Interests, Personal, Other, Ad hoc consulting-KRAS and angiogenesis: Mirati Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board (clinical): Ribbon Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board: Xencor, Inc.; Financial Interests, Personal, Other, Consultant: AbbVie Pharmaceuticals, Loxo Oncology; Financial Interests, Personal, Other, Consultant - Ad-Hoc Consulting - Oncology: Oncocyte, Regeneron, Seattle Genetics; Financial Interests, Personal, Advisory Board, Consultant: Revelar Biotherapeutics; Financial Interests, Personal, Member of Board of Directors, Board Member (non-executive/ independent): Immunocore Holdings Limited, Junshi Pharmaceuticals; Financial Interests, Personal, Stocks/Shares, Options: Bolt Biotherapeutics; Financial Interests, Personal, Stocks/Shares: Immuocore, Checkpoint Therapeutics, Normunity; Financial Interests, Institutional, Coordinating PI, Research Support: AstraZeneca, Genentech/Roche, Merck and Company; Financial Interests, Institutional, Funding, Research Support: Eli Lilly and Company; Non-Financial Interests, Leadership Role, Board Member/ Committee Chair: American Association for Cancer Research, International Association for the Study of Lung Cancer; Non-Financial Interests, Leadership Role, Committee Chair: Society for Immunotherapy of Cancer; Non-Financial Interests, Leadership Role, Committee Chair/ Principal Investigator: Southwest Oncology Group. All other authors have declared no conflicts of interest.