Abstract 424P
Background
Combined platinum-based Chemotherapy (Ctx) with a PD-1 Inhibitor is the current standard first-line treatment in HER2-negative esophagogastric adenocarcinomas (EGA), leading to a median overall survival (OS) of 12-13 months. Alterations in the homologous repair (HR) pathway are found in 15-20% of EGA. PARP inhibitors have shown activity in patients with different tumor types with a pronounced effect in the platinum-sensitive setting. Preclinical data suggest a synergistic effect of combined PD-1 blockade and PARP inhibition, paving the path to a Ctx-free consolidation therapy.
Methods
POLESTAR is a multicenter single arm phase II trial exploring efficacy and safety of first-line induction Ctx with FOLFOX or CAPOX and pembrolizumab (P) for 12 weeks, followed by consolidation therapy with olaparib (O) and P in advanced, HER2-negative EGA. Primary endpoint is the 1-year overall survival (OS) rate. Secondary endpoints include overall response rate (ORR), progression-free survival (PFS) and safety/toxicity. Translational analyses include centralized analysis of tumor tissue PD-L1 expression, panel sequencing, and blood-based analysis of cellular immune responses. Here, we report the first efficacy data including the primary endpoint.
Results
Between Sep. 2022 and Jan. 2023 31 patients have been enrolled of which 3 are still in treatment and another 10 in follow up. The primary endpoint 1-year OS was met (61.3%), resulting in a median OS of 13.4 months. ORR according to RECIST 1.1 was 48.4%. 27 (87.1%) patients had treatment-related AEs, with 14 (45.2%) patients experiencing a treatment-related grade ≥3 AE. No P/O-related grade 4 or 5 AEs occurred.
Conclusions
Induction Ctx with FOLFOX/CAPOX and P followed by consolidation O&P shows clinical activity and is associated with a manageable toxicity pattern, consistent with known safety profiles of O and P. Translational analyses are ongoing to correlate HR alterations with efficacy. Updated data will be presented at the meeting.
Clinical trial identification
NCT05268510; EudraCT 2021-000150-26.
Legal entity responsible for the study
Frankfurter Institut für Klinische Krebsforschung IKF GmbH - Represented by its Managing Director - Prof. Dr. med. Salah-Eddin Al-Batran Steinbacher Hohl 2-26 60488 Frankfurt.
Funding
MSD Sharp & Dohme GmbH.
Disclosure
G.M. Haag: Non-Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Non-Financial Interests, Personal, Advisory Board: MSD Sharp & Dohme, Lilly, Novartis, Daiichi Sankyo, Servier, Pierre Fabre, AstraZeneca; Financial Interests, Personal, Invited Speaker: Servier, MSD Sharp & Dohme, Lilly, Bristol Myers Squibb, AstraZeneca, MCI Conventions, Swiss cancer League; Financial Interests, Personal and Institutional, Research Grant: DKFZ Heidelberg, MSD Sharp & Dohme; Other, Personal, Other: Bristol Myers Squibb, Lilly, Servier, MSD Sharp & Dohme, Daiichi Sankyo. T.O. Goetze: Non-Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Foundation Medicine, Lilly, MCI, MSD Sharp & Dohme, Novartis, Roche, Sanofi Aventis, Servier, Deciphera, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Amgen, BMS, Lilly, MSD, Novartis, Sanofi Aventis, Servier, Roche, GSK; Financial Interests, Personal, Research Grant: Lilly, AstraZeneca, Incyte, DFG, Gemeinsamer Bundesausschuss, Deutsche Krebshilfe; Financial Interests, Personal, Other: Servier, Amgen, AstraZeneca, BMS, Lilly, Merck Serono, Roche, Sanofi Aventis, Servier, Pierre Fabre. P.C. Thuss-Patience: Financial Interests, Personal, Advisory Board: Lilly, BMS, MSD, Merck Serono, Roche, Servier, AstraZeneca, Pfizer, Astellas, Novartis, Daiichi Sankyo, BeiGene; Financial Interests, Personal, Research Grant: Merck Serono, Novartis; Non-Financial Interests, Personal, Other: Merck Serono, AstraZeneca. S. Lorenzen: Financial Interests, Personal, Invited Speaker: Servier, Lilly, MSD, BMS, AstraZeneca; Financial Interests, Personal, Advisory Board: Astellas. T. Walle: Financial Interests, Personal, Stocks/Shares: Roche, Bayer, Innate Pharma, Illumina, FibroGen, AstraZeneca, Merck KGaA; Financial Interests, Personal and Institutional, Research Grant: CanVirex AG, IKF Klinische Krebsforschung; Other, Personal, Other: Roche. A. Stenzinger: Financial Interests, Personal, Advisory Board: Aignostics, AstraZeneca, Janssen, Bayer, Seattle Genetics, Pfizer, MSD, Eli Lilly, Illumina, Thermo Fisher, Amgen, Astellas, Agilent, Qlucore, QuiP, Sanofi; Financial Interests, Institutional, Advisory Board: BMS, Takeda, Novartis; Financial Interests, Personal, Invited Speaker: Roche, Incyte, Servier; Financial Interests, Institutional, Research Grant: Bayer, Chugai, BMS, Incyte, MSD. S. Al-Batran: Financial Interests, Personal, Stocks/Shares: Institut für Klinische Krebsforschung GmbH, Immutep; Other, Personal, Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, AstraZeneca/Daiichi Sankyo, Eli Lilly Germany; Other, Personal, Speaker’s Bureau: Lilly, AIO G GmbH, Bristol Myers Squibb, MCI Group; Financial Interests, Personal, Research Grant: Celgene, Lilly, Sanofi, German Cancer Aid, German Research Foundation, Federal Ministry of Education and Research, Roche, Vifor Pharma, Eurozyto, Immutep, Ipsen, Bristol Myers Squibb, MSD Sharp & Dohme, AstraZeneca. A. Stein: Financial Interests, Institutional, Advisory Board: BMS, MSD, Amgen, Merck, Daiichi Sankyo, Roche, GSK, Servier, Taiho; Financial Interests, Institutional, Invited Speaker: Lilly, Daiichi Sankyo, Novartis; Financial Interests, Institutional, Research Grant: BMS, MSD, Servier, German Cancer Aid, Pierre Fabre, Merck; Non-Financial Interests, Member: DGHO, ASCO. All other authors have declared no conflicts of interest.