Phase 1b Study Of Ramucirumab (Ram) In Combination With Fluoropyrimidine And Platinum-Based Agents In Japanese Patients (Pts) With Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma (Mgc)

Abstract Background: Fluoropyrimidine and platinum-based regimens have been established as a global standard of care, including Japan, for the 1st-line treatment of pts with mGC. RAM is a human IgG1 antibody against VEGFR-2. In the 2nd-line setting, 2 global phase 3 studies of RAM alone (REGARD) and RAM + paclitaxel (RAINBOW), demonstrated significant improvement in survival compared to placebo and paclitaxel + placebo, respectively. The subset analysis of the RAINBOW study suggested that higher RAM exposures were associated with improved survival outcome. In this study, safety, tolerability, pharmacokinetics (PK) and efficacy of a new RAM dosing schedule in combination with 3 fluoropyrimidine and platinum-based regimens in the 1st-line setting were evaluated in Japanese pts with mGC. Patients and Methods: This was a multicenter, single-arm, phase 1b study in mGC pts in the 1st-line setting. On each cycle, pts received 8 mg/kg RAM at days 1 and 8, every 3-weeks (q3w), in combination with XP q3w: capecitabine (2000 mg/m2, days 1-14, PO) + cisplatin (80 mg/m2, day 1, IV); SP every 5-weeks (q5w): S-1 (80 mg/m2/day, days 1-21, PO) + cisplatin (60 mg/m2, day 8, IV); or SOX q3w: S-1 (80 mg/m2/day, days 1-14, PO) + oxaliplatin (100 mg/m2, day 1, IV). The primary objective was to confirm safety and tolerability; secondary objectives were to evaluate PK and anti-tumor response. Results: 18 pts, 6 in each cohort, were treated. Pts received RAM for median 23.4 weeks (min 2.0 - max 69.0). Across all cohorts, only 1 dose-limiting toxicity was observed during the 1st cycle (grade 3 enterocolitis), and resolved after treatment discontinuation. Three treatment-related serious adverse events (AE) were observed: decreased appetite (n=1), pelvic venous embolism (n=1) and enterocolitis (n=1). Treatment-related AE of any grade included neutropenia (n=14), decreased appetite (n=12), constipation (n=11), nausea (n=11), and hypertension (n=9). Compared to the currently approved 8 mg/kg every 2-weeks (q2w) regimen, the new dose regimen used in this study (8 mg/kg days 1 and 8 q3w) has produced higher mean trough concentrations of RAM. Disease control rate (DCR) was 100% and overall response rate (ORR) was 45% in patients with measurable lesions (n=11). Conclusion: The new scheduling regimen of RAM (8 mg/kg, days 1 and 8, q3w) in combination with either of XP, SP or SOX, was tolerable in Japanese mGC pts in the 1st-line setting. Currently, a global phase 3 study of XP and an Asian randomized phase 2 study of SOX are ongoing to evaluate potential benefits of adding RAM to current standard 1st-line therapies. (NCT02359058) Citation Format: Shigenori Kadowaki, Kohei Shitara, Daisuke Sakai, Tomohiro Nishina, Reigetsu Yoshikawa, Yongzhe Piao, Akichika Ozeki, Koichi Inoue, Kei Muro. Phase 1b study of ramucirumab (RAM) in combination with fluoropyrimidine and platinum-based agents in Japanese patients (pts) with metastatic gastric/gastroesophageal junction adenocarcinoma (mGC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT096. doi:10.1158/1538-7445.AM2017-CT096