1450P - Pembrolizumab and olaparib in advanced HER2 negative esophagogastric adenocarcinoma (EGA): Biomarker results of the phase II AIO IKF-038/POLESTAR trial

Background

Platinum-based Chemotherapy (Ctx) and PD-1 Inhibition is the current standard of care treatment for HER2 negative EGA. Preclinical data suggest a synergistic effect of combined PD-1 blockade and PARP inhibition, making it a potentially attractive combination for a Ctx-free consolidation therapy. POLESTAR is a phase II trial exploring firstline induction Ctx with FOLFOX/CAPOX and pembrolizumab (P), followed by consolidation therapy with olaparib (O) and P in advanced, HER2 negative EGA. The primary endpoint was met (1-year overall survival [OS] rate in all patients (pts.) 61%). First results have demonstrated clinical activity and an acceptable safety profile. Here we report preplanned subgroup and biomarker analyses.

Methods

31 pts. were enrolled, receiving 12 weeks of FOLFOX/CAPOX & P followed by O & P until tumor progression or limiting toxicity occurred. Tumor tissue was centrally tested for PD-L1 expression (DAKO 22C3 mAB). Panel sequencing is performed using Truesight Oncology 500 panel (Illumina Inc.), including determination of tumor-mutational burden (TMB) and analysis of the homologous recombination deficiency (HRD) score as previously reported (Ball et al. 2024).

Results

Of 30 evaluable pts. for PD-L1 analysis, 21 (70%) had a PD-L1 combined prognostic score (CPS) ≥1 and 5 pts. (16.7%) had a PD-L1 CPS ≥10. 1-year OS rate was 62% (median OS 13.4 months) for the PD-L1 CPS ≥1 subgroup versus 56% (median OS 12.2 months) in pts. with PD-L1 CPS<1 (p=0.55). 1-year OS rate for pts. without previous neoadjuvant treatment (n=26) was 62 %, resulting in a median OS of 15.6 months. TMB is currently evaluable in 20 pts., all pts. were classified as TMB low (<10 Mutations/Megabase).

Conclusions

In comparison to data from international phase III trials, the majority of patients had a low PD-L1 CPS. No significant difference in clinical efficacy of FOLFOX/CAPOX & P followed by consolidation O & P in pts. with PD-L1 CPS ≥1 versus CPS <1 was observed. Translational analyses including TMB and HRD status are ongoing and updated data will be presented at the meeting.

Clinical trial identification

NCT05268510; EudraCT: 2021-000150-26.

Editorial acknowledgement

Legal entity responsible for the study

Frankfurter Institut für Klinische Krebsforschung IKF GmbH.

Funding

MSD Sharp & Dohme GmbH.

Disclosure

G.M. Haag: Non-Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD Sharp & Dohme, Lilly, Novartis, Daiichi Sankyo, Servier, Pierre Fabre, AstraZeneca; Financial Interests, Personal, Royalties: Servier, MSD Sharp & Dohme, Lilly, Bristol Myers Squibb, AstraZeneca, MCI Conventions, Swiss cancer League; Financial Interests, Personal, Research Funding: 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 Board: Amgen, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Foundation Medicine, Lilly, MCI, MSD Sharp & Dohme, Novartis, Roche, Sanofi Aventis, Servier, Deciphera, Boehringer Ingelheim; Financial Interests, Personal, Royalties: Amgen, BMS, Lilly, MSD, Novartis, Sanofi Aventis, Servier, Roche, GSK, Lilly; Financial Interests, Personal, Research Funding: 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: Non-Financial Interests, Personal, Advisory Board: Lilly, BMS, MSD, Merck Serono, Roche, Servier, AstraZeneca, Pfizer, Astellas, Novartis, Daiichi Sankyo, BeiGene; Financial Interests, Personal, Research Funding: 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.J. Ettrich: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Bayer, Amgen, MSD, Merck, Ipsen, Sanofi Aventis, Pierre Fabre Pharma, Incyte, Lilly, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: MSD, Ipsen, Eisai; Financial Interests, Institutional, Research Grant: Servier. T. Walle: Financial Interests, Personal, Stocks or ownership: Roche, AstraZeneca, Bayer, Innate Pharma, FibroGen, Illumina, 10x Genomics; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Research Funding: CanVirex AG, Basel Switzerland, Frankfurter Institut für Klinische Krebsforschung IKF GmbH. S. Al-Batran: Financial Interests, Personal, Advisory Board: Lilly, Bristol Myers Squibb, MSD Sharp & Dohme; Financial Interests, Personal, Invited Speaker: MCI Deutschland GmbH; Financial Interests, Personal, Ownership Interest, CEO: Institut für Klinische Krebsforschung IKF GmbH; Financial Interests, Institutional, Research Grant: Sanofi, Roche, Celgene, Lilly, Eurozyto, Immutep, Ipsen, Bristol Myers Squibb, MSD Sharp & Dohme, AstraZeneca, German Cancer Aid (Krebshilfe), German Research Foundation, Federal Ministry of Education and Research. A. Stenzinger: Financial Interests, Personal, Advisory Board: Agilent, Aignostics, Amgen, Astellas, AstraZeneca, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Qlucore, QuiP, Roche, Sanofi, Seagen, Servier, Takeda, Thermo Fisher; Financial Interests, Personal, Research Grant: Bayer, BMS, Chugai, Incyte, MSD. A. Stein: Financial Interests, Institutional, Research Funding: BMS, GBA Innovationsfond, Deutsche Krebshilfe, Merck KGaA, MSD, Servier; Financial Interests, Institutional, Advisory Board: Amgen, Astellas, AstraZeneca, BeiGene, BMS, Daiichi Sankyo, Merck, MSD, Roche, Sanofi, Servier, Taiho, Takeda. All other authors have declared no conflicts of interest.