Second-line chemoimmunotherapy with nivolumab and paclitaxel in immune-related biomarker-enriched advanced gastric cancer: a multicenter phase Ib/II study

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 27; no. 1; pp. 118 - 130
• Main Authors: Lee, Choong-kun, Lee, Jii Bum, Park, Se Jung, Che, Jingmin, Kwon, Woo Sun, Kim, Hyo Song, Jung, Minkyu, Lee, Seulkee, Park, Sook Ryun, Koo, Dong-Hoe, Lee, Hyun Woo, Bae, Woo Kyun, Jeung, Hei-Cheul, Hwang, In Gyu, Kim, Hyunki, Nam, Chung Mo, Chung, Hyun Cheol, Rha, Sun Young
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 2024; Springer Nature B.V
• Subjects: Abdominal Surgery; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers; Cancer Research; Cell death; Chemotherapy; Epstein-Barr virus; Epstein-Barr Virus Infections; Gastric cancer; Gastroenterology; Genetic testing; Genomic analysis; Herpesvirus 4, Human; Humans; Immunotherapy; Interleukin 1; Interleukin 1 receptor antagonist; Medicine; Medicine & Public Health; Mismatch repair; Neutropenia; Nivolumab - adverse effects; Nivolumab - therapeutic use; Oncology; Original Article; Paclitaxel; Stomach Neoplasms; Surgical Oncology; Survival analysis; Toxicity; Immune checkpoint inhibitors; Advanced gastric cancer; Nivolumab; Paclitaxel; Biomarker enriched
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-023-01435-9

Background We conducted a trial to evaluate the efficacy and safety of nivolumab and paclitaxel as second-line therapy for immune-related biomarker-enriched advanced gastric cancer (AGC). Methods This open-label, single-arm, phase Ib/II study was a part of multi-institutional, biomarker-integrated umbrella study conducted in Korea. In phase Ib, patients received nivolumab (3 mg/kg) on Days 1 and 15 and paclitaxel (dose level 1, 70 mg/m 2 or dose level 2, 80 mg/m 2 ) on Days 1, 8, 15 every four weeks. In phase II, patients with Epstein–Barr virus-related, deficient mismatch repair or programmed cell death-ligand-1-positive AGC were enrolled. The primary endpoints were recommended phase II dose (RP2D, phase Ib) and progression-free survival (PFS, phase II). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and exploratory biomarker analysis. Results Dose level 2 was selected as RP2D. In phase II, 48 patients were enrolled. The median PFS and OS were 3.9 and 11.2 months, respectively. The ORR was 23.3%, and the median response duration was 16.7 months. Grade 3 or higher treatment-related adverse events, mainly neutropenia, occurred in 20 patients (41.7%). Targeted sequencing revealed that patients with RTK/RAS pathway alterations or the HLA-A02 supertype had better survival. Patients with elevated baseline interleukin-1 receptor antagonist levels had worse survival. Conclusions Although the study did not meet its primary end point, nivolumab and paclitaxel for AGC demonstrated a durable response with manageable toxicity profiles. Genomic analysis or plasma cytokine analysis may provide information for the selection of patients who would benefit more from immunotherapy combined with chemotherapy.