629P - Phase I study of pamiparib and cabozantinib in patients with metastatic solid tumors harboring homologous recombination deficiency (HRD)

Background

Tumor hypoxic microenvironment-mediated and/or tumor specific c-MET overexpression renders cancer cells resistant to PARP inhibition and/or VEGF inhibition, which may be reversed by triple inhibition of c-MET, VEGFR2, and PARP. Therefore, we conducted this phase I study of pamiparib and cabozantinib in metastatic HRD malignancies (NCT05038839).

Methods

Patients with metastatic HRD solid tumor for which there was no standard care therapy were treated with pamiparib PO BID and cabozantinib PO QD at 4 dose levels (DLs: 20/20, 20/40, 40/40, and 60/40 mg respectively) according to a BOIN design, followed by dose expansion in 20 patients to further characterize safety, antitumor activity and correlative studies.

Results

This single-center phase I study enrolled 37 evaluable patients with HRD including BRCA1/2, PALB2, ARID1a, RAD50 and ATM aberrations from 3/28/22 to 2/23/24: median age 61 yrs (range 40 to 82); median prior lines of systemic therapy 4 (range 1 to 11) including 10 VEGF inhibition and 11 PARP inhibition; 19 prior radiation; 3 ECOG PS0 and 24 PS1; 21 women; 9 sarcoma, 4 breast, 4 colon, 4 pancreatic, 4 prostate, 3 biliary tract, 3 ovarian, and 6 others. No ≥G3 treat related adverse events (TRAEs) and objective response were observed at DL1 (n=3). Among 34 patients treated at higher DLs, G3 TRAEs included neutropenia (21%), anemia (15%), thrombocytopenia (12%), hypertension (6%), fatigue, nausea and vomiting, diarrhea, and skin rash (3% each) while G4 hyponatremia and thrombocytopenia (3% each). The treatment achieved 6 partial responses (PRs: 2 colon, 2prostate, 1 breast and 1 pancreatic), 20 stable disease (SDs) including 4 SD≥6 months, and 11 progressive disease, resulting in 10 SD≥6 months/PR out of 37 patients (27%).

Conclusions

Preliminary evidence in this study showed that the treatment with oral pamiparib 60 mg BID and cabozantinib 40 mg QD was well-tolerated and has yielded modest antitumor activity in heavily pretreated patients with metastatic HRD malignancies.

Clinical trial identification

NCT05038839.

Editorial acknowledgement

Legal entity responsible for the study

The University of Texas MD Anderson Cancer Center.

Funding

BeiGene, Exelixis.

Disclosure

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, Local PI: 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.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. 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. 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: VHIO/Ministero De Empleo Y Seguridad Social; Other, Travel: European Society for Medical Oncology, Loxo Oncology. 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; Financial Interests, Institutional, Invited Speaker: AKH Inc., ASCO Direct Oncology Highlights, European Society for Medical Oncology; Financial Interests, Personal, Invited Speaker: Lynx Group, Society for Immunotherapy of Cancer, Korean Society of Medical Oncology, Scripps Cancer Care Symposium, CME Outfitters; Financial Interests, Institutional, Coordinating PI: NCI, EMD Serono; Financial Interests, Personal, Local PI: MedImmune, Healios Onc. Nutrition, Atterocor/Millendo; Financial Interests, Institutional, Local PI: 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; Other, Travel and Accommodation: ARMO BioSciences, NeoImmune Tech; Other, Travel and accommodation: NGM BioPharmaceuticals. 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/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, Local PI: 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, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO); Other, Travel Support: Cholangiocarcinoma Foundation, Dava Oncology. All other authors have declared no conflicts of interest.