28O - TalaCom: Phase Ib investigator-initiated trial combining talazoparib and axitinib in patients with DNA damage response mutated cancers or BRCA1/2 wildtype ovarian cancer incorporating prospective intrapatient dose titration

Background

Angiogenic inhibition suppresses BRCA expression, inducing a ‘BRCAness’ tumor phenotype and sensitivity to PARP inhibitors (PARPi). We evaluated the PARPi talazoparib (tala) + VEGFR inhibitor axitib (axi) in patients (pts) with advanced cancers with or without DNA damage response (DDR) mutations (NCT04693468).

Methods

Dose escalation comprised advanced cancer pts with/without DDR mutations. Dose expansion comprised pts with (1) BRCA1/2 wildtype high grade serous ovarian cancer (HGSOC) or (2) molecularly unselected castration-resistant prostate cancer (CRPC). All pts started at tala 1mg QD + axi 5 mg BID, with axi titrated up to 10 mg BID based on individual pt tolerability every 2 weeks or to lower doses if needed. Objectives were safety, tolerability, antitumor activity, pharmacokinetics and longitudinal biomarker analysis.

Results

28 pts [M:F 15:13; ECOG PS 0:1 7:21; mean age 64y] with CRPC (n=15), HGSOC (n=12), and BRCA2m peritoneal mesothelioma (n=1) were enrolled. DDR variants: BRCA2 (n=3), BRIP1 (n=2), CDK12 (n=2), PALB2 (n=2), ATM, CHEK2, RAD51C (n=1). 14/28 (50%) pts had ≥3 prior lines of therapy; 12/28 (43%) had prior PARPi; 7/28 (25%) had prior VEGF inhibitor. G3/4 treatment-related adverse events (>10% of pts) were reversible hypertension 8/28 (30%), low platelets 8/28 (30%), neutropenia and anemia 5/28 (19%) with DLTs in 5/28 (18%) pts. 22/24 (92%) evaluable pts achieved RECIST SD or PR; 13/24 (54%) had tumor regressions, and 5/24 (21%) achieved RECIST PRs: 2 pts with BRCA2m HGSOC (one who progressed on prior olaparib, saruparib and camonsertib); 1 pt with BRCA2m peritoneal mesothelioma; 2 pts with mCRPC without DDR mutations (one who progressed on prior olaparib). Clinical benefit rate (RECIST PR + SD ≥6m) was 58.3% (14/24 pts). Axi dose titration occurred in 17/28 (60.7%) pts and median axi dose was 5mg BID (range 1-9 mg BID). The starting RP2D was established at axi 5 mg BID + tala 1 mg QD.

Conclusions

The combination of axi + tala was generally manageable with durable antitumor activity in heavily pretreated HGSOC and CRPC pts, including pts who progressed on prior PARPi. Biomarker and PK analyses are ongoing.

Clinical trial identification

NCT04693468.

Editorial acknowledgement

Legal entity responsible for the study

The University of Texas MD Anderson Cancer Center.

Funding

Pfizer.

Disclosure

N.Y.L. Ngoi: Financial Interests, Institutional, Advisory Board: MSD, Pfizer; Financial Interests, Institutional, Invited Speaker: AstraZeneca, MSD; Non-Financial Interests, Institutional, Product Samples: iOnctura, Cyclacel Ltd; Non-Financial Interests, Personal, Member: Gynecologic Cancer Group Singapore. J. Rodon: Financial Interests, Personal, Advisory Board: Ellipses Pharma, iOnctura SA, Aadi Bioscience, Envision Pharma, Molecular Partners, Mekanistic, Amgen; Financial Interests, Personal, Other, Consultancy: Clarion Healthcare, Debiopharm, Cullgen, Pfizer, Macrogenics, Oncology One, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC, Alnylam Pharmaceuticals, Bridgebio Pharma; Financial Interests, Personal, Other, Consultancy/Advisory Board: Monte Rosa Therapeutics, Merus N.V., Incyte; Financial Interests, Institutional, Other, Clinical Research: Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GSK; 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, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, Bayer, Hutchinson MediPharma; Other, Personal, Other, Other: VHIO/Ministero De Empleo Y Seguridad Social; Other, Personal, Other, Travel: European Society for Medical Oncology, Loxo Oncology. E.E. Dumbrava: Financial Interests, Institutional, Other, Research/grant funding: Bayer HealthCare Pharmaceuticals, Immunocore Ltd., Amgen, Aileron Therapeutics, Compugen Ltd., Gilead, BOLT Therapeutics, Aprea Therapeutics, Bellicum, PMV Pharma, Triumvira, Seagen Inc, Mereo BioPharma 5 Inc, Sanofi, Rain Oncology, Astex Therapeutics, Sotio, Mersana Therapeutics, Poseida, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: PMV Pharma; Financial Interests, Personal, Advisory Board: BOLT Therapeutics, Mersana Therapeutics, Orum Therapeutics, Summit Therapeutics. B. Garmezy: Non-Financial Interests, Institutional, Research Grant: AbbVie, Accutar Biotechnology; Financial Interests, Institutional, Research Grant: Arcus Biosciences, Arvinas, AstraZeneca, AVEO Oncology, CRISPR Therapeutics, Eikon Therapeutics, Exelixis, Roche/Genentech, Flare Therapeutics, Harbour BioMed, IDEAYA Biosciences, Janssen, Janux Therapeutics, Jubilant Therapeutics, Kineta, Kinnate BioPharma, Loxo, Mink Therapeutics, Nuvation Bio, Profound Bio, Takeda Therapeutics, Teon Therapeutics, Tmunity Therapeutics, Xencor, Zenshine; Financial Interests, Institutional, Other, Consulting: AbbVie, Adaptimmune, Adicent Therapeutics, AIQ Global, Amgen, Arcus Biosciences, Arvinas, AstraZeneca, AVEO Oncology, Bayer, Bicycle Tx, Eisai, EMD Serono, Exelixis, Janssen, Merck, Novartis, Pfizer, Rondo Therapeutics, Sanofi-Aventis, Seagen, Xencor. D.S. Hong: Financial Interests, Institutional, Principal Investigator: AbbVie, Adaptimmune, Adlai-Nortye, Amgen, Astellas, AstraZeneca, Bayer, Biomea, Bristol Myers Squibb, Daiichi-Sankyo, Deciphera, Eisai, Eli Lilly, Endeavor, Erasca, F. Hoffmann-LaRoche, Fate Therapeutics, Genentech, Genmab, Immunogenesis, Infinity, Kyowa Kirin, Merck, Mirati, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, Revolution Medicine, Seagen, STCube, Takeda, TCR2, Turning Point Therapeutics, VM Oncology; Financial Interests, Personal, Advisory Role, Consultant: 28Bio, AbbVie, Acuta, Adaptimmune, Alkermes, Alpha Insights, Amgen, Affini-T, Astellas, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, CARSgen, CLCC, COG, COR2ed, Cowen, Ecor1, EDDC, Erasca, Exelixis, Fate Therapeutics, F. Hoffmann-La Roche, Genentech, Gennao Bio, Gilead, GLG, Group H, Guidepoint, HCW Precision Oncology, Immunogenesis, Incyte Inc, Inhibrix Inc, Janssen, Jounce Therapeutics Inc, Lan-Bio, Liberium, MedaCorp, Medscape, Novartis, Numab, Oncologia Brasil, ORI Capital, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Projects in Knowledge, Quanta, RAIN, Ridgeline, Revolution Medicine, Seagen, Stanford, STCube, Takeda, Tavistock, Trieza Therapeutics, T-Knife, Turning Point Therapeutics, WebMD, YingLing Pharma, Ziopharm; Financial Interests, Personal, Advisory Board, Consultant: InduPro; Other, Personal, Advisory Role, Advisor: Molecular Match; Other, Personal, Other, Founder, Advisor: OncoResponse, Telperian; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AACR, ASCO, CLCC, Bayer, Genmab, SITC, Telperian. S. Piha-Paul: Financial Interests, Institutional, Other, Worked as a consultant: CRC Oncology; Financial Interests, Institutional, Other, Worked as a Consultant: Lilly USA, LLC; Financial Interests, Institutional, Invited Speaker: AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, BioMarin Pharmaceutical, Inc., Boehringer Pharmaceutical, Inc., Bristol Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Cullinan Oncology, Inc., Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Inc., Eli Lilly, ENB Therapeutics, Epigenetix, Inc., Five Prime Therapeutics, F-Star Beta, Ltd., F-Star Therapeutics, Ltd., Gene Quantum Healthcare, Genmab A/S, Gilead Sciences, Inc., GSK, Helix BioPharma Corp., Hengrui Pharmaceuticals, Co., Ltd., HiberCell, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Col, Ltd., Jazz Pharmaceuticals, Jiangsu Simcere Pharmaceutical Co., Ltd., Johnson & Johnson, Loxo Oncology, Inc., Lytix Biopharma AS, MedImmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Nectin Therapeutics, Ltd., Novartis Pharmaceuticals, NRG Oncology, Nurix, OncoNano Medicine, Inc., Pieris Pharmaceuticals, Inc., Pfizer, Phanes Therapeutics, Principia Biopharma, Inc., PofoundBio US Co., Puma Biotechnology, Inc., Purinomia Biotech, Inc., Rapt Therapeutics, Inc., Replimune, Roche/Blueprint, Seattle Genetics, Shasqi, Inc., Silverback Therapeutics, Synlogic Therapeutics, Taiho Oncology, Tallac Therapeutics, Inc., Tesaro, Inc., Theradex Oncology, Toragen Therapeutics, Inc., TransThera Bio, Xencor, Inc., ZielBio, Inc.; Financial Interests, Institutional, Funding, Grant# P30CA016672 - Core Grant (CCSG Shared Resources): NCI/NIH. A.M. Tsimberidou: Financial Interests, Institutional, Funding, No Financial Interest: OBI Pharma; Financial Interests, Institutional, Funding, No financial interest: Agenus, IMMATICS, Tachyon, Novocure, Orionis, Tempus, Tvardi; Financial Interests, Institutional, Funding, NO financial interest: Parker Institute for Cancer Immunotherapy; Financial Interests, Personal, Other, Advisory Role: Avstera Therapeutics, Bioeclipse, BrYet, Diaccurate, Macrogenics, NEX-I, VinceRx. S. Fu: Financial Interests, Institutional, Research Grant, Partial grant funding supporting facilities necessary for clinical trials.: NIH/NCI P30CA016672 – Core Grant (CCSG Shared Resources); Financial Interests, Institutional, Invited Speaker: Abbisko, Antengene, BeiGene, Ltd., BeyondSpring Phamaceuticals, Inc., BioAtla, LLC., Boehringer Ingelheim, CUE Biopharma, Inc., DEKA Biosciences, Eli Lilly & Co., Exelixis, Greenfire Bio, Inc., Hookipa Biotech, ImmavRx, Inc. (IMV), Innovent Biologics, Co., Ltd., Jazz Pharmaceuticals, K-Group Beta, Lantern Pharma Inc., Lyvgen Biopharm, Co., Ltd., MacroGenics, MediLink Therapeutics, Co. Ltd., Millennium Pharmaceuticals, inc., Nerviano Medical Sciences, NeuPharma, Inc., NextCure, Inc., Ningbo NewBay Technology Development Co., Ltd., Novartis, NovoCure, Nykode Therapeutics, Parexel International, LLC, PharmaMar USA, Inc., Pionyr Immunotherapeutics, Inc., PureTech Health, LLC, Qurgen, Inc., Sellas Life Sciences Group, Shanghai Huaota Biopharmaceutical Co., Ltd., Soricimed Biopharma, Inc., SQZ Biotechnologies, Sumitomo Dainippon, Taiho Oncology and NCCN, Treadwell Therapeutics, Turnstone Biologics, Tyligand Bioscience, Ltd., Virogin Biotech, Ltd. A. Naing: Financial Interests, Personal, Advisory Board: CTI, Deka Biosciences, Janssen Biotech, NGM Bio, PsiOxus Therapeutics, Immune-Onc Therapeutics, STCube Pharmaceuticals, OncoSec Keynote 695, Genome & Company, CytomX Therapeutics, Nouscom, Merck Sharp & Dohme Crop, Servier, Lynx Health, AbbVie, PsiOxus, GV20; Financial Interests, Institutional, Invited Speaker: AKH Inc., ASCO Direct Oncology Highlights, European Society for Medical Oncology, NCI, EMD Serono, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab PsiOxus, Arcus Biosciences, NeoImmuneTech, Immune-Onc Therapeutics, Surface Oncology, Monopteros Therapeutics, BioNTech Se, Seven & Eight Biopharma, SOTIO Biotech AG; Financial Interests, Personal, Invited Speaker: Lynx Group, Society for Immunotherapy of Cancer, Korean Society of Medical Oncology, Scripps Cancer Care Symposium, CME Outfitters, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo; Other, Personal, Other, Travel and Accommodation: ARMO BioSciences, NeoImmune Tech; Other, Personal, Other, Travel and accommodation: NGM Biopharmaceuticals. P.R. Pohlmann: Financial Interests, Personal, Other, Honoraria: Dava Oncology, OncoLive/MJH Life Sciences, Frontiers - Publisher, Seagen; Financial Interests, Personal, Advisory Role, Consulting: Pfizer, Bolt Biotherapeutics, AbbVie; Financial Interests, Institutional, Research Grant: Genentech/Roche, Pfizer, Pieris Pharmaceuticals, Cascadian Therapeutics, Bolt Biotherapeutics, Seagen, Orum Therapeutics, Carisma Therapeutics; Financial Interests, Personal, Proprietary Information, Patent: US-20140086905-A1. 2014-03-27, US-9745377-B2. 2017-08-29, US-20140134154-A1. 2014-05-15, US-9023362-B2. 2015-05-15, US-8486413-B2. 2013-07-16, US-8501417-B2. 2013-08-06. H.T. Tran: Non-Financial Interests, Personal, Other, Consultant: Abion, Oncohost. F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, OnCusp Therapeutics, Zymeworks; Financial Interests, Personal, Other, Consulting: Calibr, Ecor1, Exelixis, GT Aperion, Infinity Pharmaceuticals, LOXO-Oncology, LegoChem Bio, Lengo Therapeutics, Tallac Therapeutics, Becton Dickinson, eFFECTOR Therapeutics, Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Incyte, Karyopharm, Protai, TheraTechnologies, Zentalis, FogPharma, Harbinger Health, Mersana Therapeutics, Sanofi Pharmaceuticals; Financial Interests, Personal, Other, Consulting: Menarini Group; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Invited Speaker: Dava Oncology; 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, Jazz Pharmaceuticals, Zymeworks; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Personal, Other, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO); Other, Personal, Other, Travel Support: Cholangiocarcinoma Foundation, Dava Oncology. T.A.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, Radiopharm Theranostics, Sanofi, Ellipses Life, LRG1, Panangium, Pliant Therapeutics, Synthis, Tessellate Bio, TD2 Theragonostics, Tome Biosciences, Zentalis, Amgen Inc., Astex, Avenzo, BioCity Pharma, Blueprint, Carrick Therapeutics, Circle Pharma, Daiichi Sankyo, Dark Blue Therapeuticcs, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Entos, FoRx Therapeutics AG, Genesis Therapeutics, Ideaya Biosciences, Impact Therapeutics, Merit, Monte Rosa Therapeutics, Nested Therapeutics, Nimbus, Odyssey, Onxeo, Protai Bio, Ryvu Therapeutics, SAKK, Servier, Synnovation, Tango, TCG Crossover, Terremoto Biosciences, Terns Pharmaceuticals, Tolremo, Tome, Thryv Therapeutics, Trevarx Biomedical, Veeva, Voronoi Inc.; Financial Interests, Personal, Advisory Board, Advisor: BridGene Biosciences, Debiopharm, Grey Wolf Therapeutics, Institut Gustave Roussy, Joint Scientific Committee for Phase I Trials in Hong Kong, Prelude Therapeutics; 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, Stakeholder: Seagan; Financial Interests, Institutional, Other, Grant/Research support: Bayer, Cyteir, EMD Serono, GSK, 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, Insilico Medicine, Tango; Financial Interests, Institutional, Research Grant, Principal Investigator: Boundless Bio, Ideaya; Financial Interests, Institutional, Invited Speaker, Principal Investigator: CPRIT, Gilead, Golfers against Cancer, Exelixis, NIH/NCI, Pliant, Prelude, Roche, Synnovation, V Foundation, Zentalis. All other authors have declared no conflicts of interest.