Abstract CT159: Open label, single-arm, multi-center phase Ib/II study to evaluate the safety and efficacy of nivolumab in combination with paclitaxel in Epstein-Barr virus (EBV)-related, or microsatellite instability-high (MSI-H), or programmed cell death ligand 1 (PD-L1) positive advanced gastric cancer (AGC)
Authors: Young Rha Sun , Lee Jii Bum , Kim Hyo Song , Jung Minkyu , Lee Choong-kun , Park Sook Ryun , Koo Dong-Hoe , Lee Hyun Woo , Bae Woo Kyun , Jeung Hei Cheul , Chung Hyun Cheol 
Published: July 2021

Abstract
Background: Pembrolizumab monotherapy did not improve overall survival compared with paclitaxel in second-line treatment for AGC in Keynote-061. Here, we report the results of patients (pts) with evaluable lesions treated with combination of nivolumab (Nivo) and paclitaxel (PTX) in AGC who progressed on first-line chemotherapy with a platinum and fluoropyrimidine. Methods: This open label, single arm, phase 1b/2 study is part of biomarker-integrated umbrella study conducted at multi-centers in South Korea. Phase 1b included 6 all-comer pts irrespective of biomarkers in a 3+3 design. In phase 2, 47 pts with either EBV-related, deficient mismatch repair (dMMR)/MSI-H or PD-L1 positive were enrolled. PD-L1 was defined as combined positive score (CPS) of &gt;1. The primary endpoints were determining maximum tolerated dose (MTD) and recommended phase II dose (RP2D) for phase 1b, and progression-free survival (PFS) for phase 2. Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), PFS rate at 6 months and toxicity. Results: In phase 1b, dose limiting toxicities were not observed, and the RP2D was Nivo (3 mg/kg on days 1 and 15) combined with PTX (80 mg/m2 on days 1, 8 and 15) every 28 days. Phase 2 pts included CPS &gt;1 (n=41), EBV positive (n=2), and 4 patients showed more than one biomarkers: CPS &gt;1, EBV positive (n=2), CPS &gt;1, dMMR/MSI-H (n=1), and CPS &gt;1, EBV positive, dMMR/MSI-H (n=1). With a median follow-up period of 12.1 months, 7 pts remain on treatment (treatment duration: 1.1 to 23.1 months) as of August, 2020. In patients with measurable lesions (n=33), ORR was 24% (CR 9%, PR 15%) and DCR was 39%. Median duration of response was 18.4 months (95% CI, 3.2-19.8). Median PFS was 3.9 months (95% CI, 2.9-4.9) and PFS rate at 6 months was 32%. Median OS was 18.9 months (95% CI, 8.8-28.9). There was no statistical difference in PFS or OS by all biomarkers, including CPS cutoff for 1, 5, and 10. Of the 40 pts who had disease progression, 23 pts (49%) were treated with subsequent therapy. Treatment-related AEs (≥G3) occurred in 22 pts (47%), and immune-related AE (&gt;G3) was observed in 3 pts (6%), including pneumonitis (G3) (n=1, 2%). Exploratory analysis of 13 cytokines from plasma at baseline showed an increase of interleukin-1 receptor antagonist (IL-1ra) (p=0.05), and increasing tendency of IL-8 and IL-12 in non-responders (PFS &lt;3 mo.) compare to responders (PFS &gt;8 mo.). Conclusion: Combination of Nivo and PTX demonstrated antitumor activity with manageable toxicity profiles as second-line treatment for AGC. Genomic analysis of tumor tissues by targeted next-generation sequencing are awaiting. Clinical trial information: NCT02951091
Citation Format: Rha Sun Young, Jii Bum Lee, Hyo Song Kim, Minkyu Jung, Choong-kun Lee, Sook Ryun Park, Dong-Hoe Koo, Hyun Woo Lee, Woo Kyun Bae, Hei Cheul Jeung, Hyun Cheol Chung. Open label, single-arm, multi-center phase Ib/II study to evaluate the safety and efficacy of nivolumab in combination with paclitaxel in Epstein-Barr virus (EBV)-related, or microsatellite instability-high (MSI-H), or programmed cell death ligand 1 (PD-L1) positive advanced gastric cancer (AGC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT159.