A phase II biomarker-oriented study to evaluate paclitaxel, olaparib, and durvalumab combination in patients with advanced gastric cancer.

Abstract

404 Background: DNA damage response (DDR) gene alterations are observed in 27% of gastric cancer (GC), therefore, targeting DDR might be an interesting strategy in GC. Olaparib plus paclitaxel showed numerically improved overall survival (OS) compared to paclitaxel in 2L GC patients (pts), even though it did not meet the endpoint. (Lancet Oncol 2017). Besides DNA damage repair, olaparib induces immune modulation. The role of immune checkpoint inhibitor (ICI) is established in 1L and 3L+ GC. The combination of cytotoxic chemotherapy, DDR acting agent and ICI might have synergistic effects in GC, which has not been tested in clinical studies. Here, we report biomarker-oriented phase II study of paclitaxel/olaparib/durvalumab combination in 2L GC. (NCT03579784). Methods: Advanced GC pts who have failed to 1L chemotherapy were enrolled. During 1st cycle, paclitaxel (80 mg/m2, D1, 8, 15 Q 4wk) and olaparib (150mg bid, D1-28) was administered. From 2nd cycle, durvalumab (1500 mg, D1 Q 4wk) was added on them. Tumor biopsy (pretreatment, after 1st cycle, at disease progression) and blood collection (every cycle) was mandatory. Primary endpoint was the disease control rate (DCR). Secondary endpoints included ORR, DoR, PFS, OS and safety. For biomarker study, multiplex IHC, NGS, ctDNA, and cytokines and angiogenic factors analysis were performed. Efficacy analysis set (ES) and safety analysis set (SS) were defined as pts who underwent at least one tumor assessment and all pts who received cycle1 day1 or more, respectively. Results: Fifty pts were enrolled (6 screening fail or withdrawal of consent, 44 in SS, 38 in ES) HER2+ GC were 13.2%. Among 38 in ES, DCR and ORR were 84.1% (95% CI, 72.5-95.7) and 39.5% (95% CI, 24.0-55.0) (1 CR, 14 PR and 17 SD). PFS, DoR and OS were 6.7 (95% CI, 4.5-10.3), 6.5 (95% CI, 5.1-10.7) and 11.4 (95% CI, 9.2-13.2) months. Homologous recombination repair (HRR) genetic alterations (9.6 vs. 5.9 in PFS, p=0.037), high CD8/CD3 ratio (8.8 vs. 3.7 in PFS, p=0.008), high PD-L1 (CPS≥10) (9.6 vs 5.1 in PFS, p=0.031), low ATM IHC (13.3 vs. 9.8 in OS, p=0.066), and low serum IL-6 (12.9 vs. 8.3 in OS, p=0.001) were associated with prolonged PFS or OS. In SS, most adverse events (AEs) were mild, and Gr 3/4 leukopenia and anemia were observed in 52.2% and 31.8%. There were no treatment related AEs resulted in study discontinuation. Conclusions: Paclitaxel/olaparib/durvalumab is a promising combination in 2L GC, and is worth to be further explored, especially in biomarker-enriched patients with HRR, specific T-cells subsets, high PD-L1, low ATM and IL-6. Clinical trial information: NCT03579784 .