DNA damage caused by the alkylator TMZ can sensitize tumors to PARP inhibitors. Pamiparib, an investigational oral PARP1/2 inhibitor, has shown PARP-DNA complex trapping activity, brain penetration, and synergistic cytotoxicity with LD TMZ in nonclinical studies and preliminary antitumor activity in pts with solid tumors.
This ongoing phase Ib study consists of a dose-escalation (3+3 design) and dose-expansion phase. In dose escalation, pts received pamiparib 60 mg PO BID on Days 1-28 and LD TMZ at escalating doses PO QD on Days 1-7, 1-14, or 1-28 of each 28-day cycle. Dose-expansion pts, including pts with gastric cancer and SCLC with 1-2 prior lines of chemotherapy, were treated at the recommended phase II dose of pamiparib 60 mg PO BID on Days 1-28 and LD TMZ 60 mg PO QD on Days 1-7. Tumor assessments occurred every 8 weeks. Endpoints were safety/tolerability (CTCAE v4.03) and antitumor activity (RECIST v1.1). Biomarker assessments included determination of DDR mutational status (SNV/CNV homozygous loss) of 16 core DDR genes in circulating tumor DNA and genomic instability score (GIS) by the Myriad myChoice® HRD test. Herein, we present data from the biomarker analysis.
As of 10 April 2020, 114 pts were enrolled (n=66, dose escalation; n=48, dose expansion). Median follow-up was 8.5 mo (range: 0.3, 26.5). Of 36 pts analyzed for GIS, 11 (31%) were GIS positive (GIS+ ≥33), with an ORR of 82% and disease control rate (DCR) of 91% across multiple tumor types. Antitumor activity was observed in BRCA m/GIS+ (n=5; ORR and DCR, 100%) and BRCA wt/GIS+ pts (n=6; ORR, 67%; DCR, 83%). Responses were observed in 3 GIS– pts with pancreatic cancer, pheochromocytoma, and nonsquamous NSCLC (ORR=12%; DCR, 52%). Of 104 pts analyzed for DDR mutational status, 27 (26%) were DDR+, with an ORR of 26% and DCR of 52%. In DDR– pts, ORR was 14% and DCR was 67%. Five pts were both GIS+ and DDR+.
In this limited subset of pts analyzed for GIS status, GIS+ pts derived superior benefit from pamiparib + LD TMZ, irrespective of BRCA status. GIS status appears to be the most robust biomarker to predict response to pamiparib + LD TMZ.
Clinical trial identification
Writing and editorial assistance was provided by Regina Switzer, PhD, Cathy R. Winter, PhD, and Elizabeth Hermans, PhD (OPEN Health Medical Communications, Chicago. IL) and funded by the study sponsor.
Legal entity responsible for the study
BeiGene, Ltd. The UK sites are supported as Experimental Cancer Medicine Centres by Cancer Research UK and Departments of Health.
M. Johnson: Research grant/Funding (institution): AbbVie, Acerta, Adaptimmune, Apexigen, Array Biopharma, AstraZenca, Atreca, BeiGene, Birdie, Boehringer Ingelheim, Checkpoint Therapeutics, Corvus Pharmaceuticals, CytomX, Daiichi Sankyo, Dynavax, Lilly, EMD Serono, Genentech/ Roche, Genmab, Genocea Bio; Advisory/Consultancy, Spouse: Astellas, Otsuka; Advisory/Consultancy, To institution: AbbVie, Achilles Therapeutics, AstraZenca, Atreca, Beohringer Ingelheim, Calithera Biosciences, Genentech, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Lilly, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Th; Travel/Accommodation/Expenses: AbbVie, Astellas, AstraZenca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, EMD Serono, BMS, Exelixis, Genentech/Roche, Incyte, Merck, Pfizer, Sysmex Inostics, Vapotherm, Janssen, Lilly, Novartis, Sanofi. S. Goel: Non-remunerated activity/ies, - I have a patent with a co-inventor, John Mariadason, Ph.D, entitled \"Method Of Determining The Sensitivity Of Cancer Cells To EGFR Inhibitors Including Cetuximab, Panitumumab And Erlotinib.\", Patent No. 20090258364: Patent. S.R. Chandana: Research grant/Funding (institution): BeiGene, Ltd.. M.D. Galsky: Shareholder/Stockholder/Stock options: Rappta Therapeutics; Advisory/Consultancy: Biomotiv, Janssen, Dendreon, Merck, GlaxoSmithKline, Lilly, Astellas Pharma, Genentech, BMS, Novartis, Pfizer, EMD Serono, AstraZenca, Seattle Genetics, Incyte, Aileron Therapeutics, Dracen, Inobio Pharmaceuticals, NuMab, Dragonfly Therapeutics; Research grant/Funding (institution): Janssen Oncology, Dendreon, Novartis, BMS, Merck, AstraZenca, Genentech/Roche; Non-remunerated activity/ies, Patent: Methods and compositions for treating cancer and related methods. Mount Sinai School of Medicine July 2012 Application number: 20120322792. E. Calvo: Advisory/Consultancy, Research grant/Funding (institution): Boehringer-Ingelheim, PsiOxus, Nanobiotix Janssen, AbbVie, Janseen-Cilag, Seattle Genetics, Pierre Fabre, Cerulean Pharma, EUSA, Celgene, AstraZeneca; Research grant/Funding (institution): Roche/Genentech, BMS, PharmaMar, PUMA, Sanofi, Lilly, Pfizer, Merck, Nektar, Amcure, Amgen, AstraZenca, Principia Bayer, CytomX, H3, Incyte, Kura, LOXO, Macrogenenics, Menarini, Merck Serono, Merus, Millenium, Rigontec, Tahio, Tesaro, BeiGene; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Leadership role, Full/Part-time employment, Officer/Board of Directors: START; Honoraria (self), Full/Part-time employment: HM Hospitals Group; Leadership role, Ownership: Oncoart Associated, International Cancer Consultants; Advisory/Consultancy: Nanobiotix, PsiOxus Therapeutics, AbbVie, Guidepoint Global, GLG, Pfizer, Servier, Amcure, ; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche Genentech; Officer/Board of Directors, President and founder: NPO Foundation Intheos (Investigational Therapeutics in Oncological Sciences). H. Park: Research grant/Funding (institution): BeiGene, Ambryx, Amgen Array BioPharma Bayer BeiGene BJ Bioscience Bristol-Myers Squibb Daiichi Pharmaceutical Eli Lilly EMD Serono Five Prime Therapeutics Genentech Gilead Sciences GlaxoSmithKline Hoffman-LaRoche Immunomedics Incyte MacroGenics Medimmune. T. Arkenau: Research grant/Funding (institution): Beigene, Roche, Bayer. A. Cervantes: Research grant/Funding (institution): Beigene, Genentech, Fibrogen, Amcure, Sierra Oncology, AstraZenca, Medimmune, B L. Fariñas-Madrid: Speaker Bureau/Expert testimony: MSD, AstraZenca; Advisory/Consultancy: Tesaro; Speaker Bureau/Expert testimony: Roche. S. Fu: Research grant/Funding (institution): NIH/NCI, NeuPharma, Inc, Novartis, OncoMed Pharmaceuticals, Parexel International, LLC, Sellas Life Sciences Group, Soricimed Biopharma, Inc, Tolero Pharmaceuticals; Research grant/Funding (institution): AstraZenca, Anaeropharma Science, Arrien Pharmaceuticals, BeiGene, BioAtla, LCC; Research grant/Funding (institution): Abbisko, Boehringer Ingelheim, Eli Lilly & Co, Hookipa Biotech, Huya Bioscience International, IMV, Inc, Innovent Biologics, Co, Ltd, Macrogenics, Medivir AB, Millennium Pharmaceuticals, Inc, Nerviano Medical Sciences. R. Plummer: Honoraria (self): BeiGene. J. Evans: Research grant/Funding (institution): BeiGene, AstraZeneca, Basilea, MiNa Therapeutics, Pfizer, Sierra, Lilly, Novartis, Bicycle Therapeutics, Halozyme, Johnson & Johnson, Vrtex, CytomX, Plexxikon, Boehringer, Athenex, Adaptimmune, Verastem, Immunocore, Iovance, Berg, BiolinerX; Honoraria (institution), Research grant/Funding (institution): Bayer, Celgene, BMS, Clovis, Eisai, Genentech, GlaxoSmithKline, Immunova, Nucana, Karus Therapeutics, Otsuka, Roche, MSD, Medivir. L. Horvath: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Connected Medical Solutions; Research grant/Funding (institution), Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: Janssen-Cilag; Honoraria (self), Shareholder/Stockholder/Stock options: Imagion Biosystems. A. Prawira: Research grant/Funding (institution): BeiGene, Arcusbio, Akesobio, Pfizer, Bayer, Mapkure, Roche/Genentech, BMS, Apollomics, CStone, Macrogenics, Five Prime, Henlius, Eli Lilly, Virogin, Janssen, AstraZenca, Bio Oncology, MSD, Eisai. K. Qu: Shareholder/Stockholder/Stock options, Full/Part-time employment: BeiGene, Ltd. R. Pelham: Full/Part-time employment: BeiGene, Ltd. All other authors have declared no conflicts of interest.