The appropriate therapeutic sequence with angiogenesis inhibitor and chemotherapy in patients with advanced gastric or gastroesophageal junction adenocarcinoma: Exploratory analysis from the phase 3 FRUTIGA study.

e16011 Background: For the second- and third-line (2/3L) treatment of advanced gastric cancer (GC), chemotherapy (C) remains the main modality, while a type of targeted therapy called angiogenesis inhibitors (AIs) have been introduced over the past decade. In China, approved AI-based treatments include ramucirumab (a monoclonal antibody AI targeting VEGFR-2) plus paclitaxel (PTX) for 2L therapy, and apatinib (a small-molecule AI targeting VEGFR-2) for 3L therapy. Both AIs and C are recommended options for 2/3L treatment of advanced GC, however, the optimal sequence of these therapies remains an open question. Here, we report exploratory analysis results from FRUTIGA to explore the proper therapeutic sequence. Methods: In the FRUTIGA study, eligible patients (pts) were randomized to receive fruquintinib (F, an AI targeting VEGFR-1/2/3) or placebo (PBO) + PTX for 2L therapy. In this analysis, pts who were treated with F+PTX, followed by C in the 3L setting, were defined as FP-C arm; pts who were treated with PBO+PTX, followed by AI monotherapy or AI plus C in the 3L setting, were defined as PP-AI arm. Efficacy outcomes were assessed based on FP-C and PP-AI arms. Results: A total of 117 pts were included in the exploratory analysis, with 58 pts in FP-C arm and 59 in PP-AI arm.The baseline demographics and disease characteristics were well balanced between arms. Main characteristics at baseline: 65.0% males, median age of 57.0 years; ECOG-0 (17.1%) and ECOG-1 (82.9%); 100.0% had adenocarcinoma with primary tumors located in stomach (84.6%) and GEJ (15.4%); 100.0% were diagnosed with metastases, 24.8% having single metastatic site and 75.2% having ≥2 metastatic sites. The commonly used C in FP-C arm were irinotecan (70.7%) and PTX (17.2%); the most commonly used AI in PP-AI arm was apatinib (93.2%). Median overall survival (OS) was 16.0 months (mo) for FP-C arm and 9.0 mo for PP-AI arm, with an HR of 0.65 (95% CI 0.44, 0.96; p =0.0295). The survival benefit of FP-C arm was also reflected in the progression-free survival (PFS). Compared with PP-AI arm, FP-C arm showed significantly longer PFS1 (PFS with 2L treatment) (median 5.6 vs 2.8 mo, HR 0.55 [95% CI 0.37, 0.83]; p =0.0038); although PFS2 (PFS with 3L treatment) was not collected per protocol, the median duration of 3L treatment was longer in FP-C arm (3.7 vs 1.7 mo), which could be a prediction of PFS2. Conclusions: This analysis revealed superior survival benefits in FP-C arm vs PP-AI arm, which indicates that compared with chemotherapy followed by angiogenesis inhibitor-based therapy, the therapeutic sequence of angiogenesis inhibitor-based therapy followed by chemotherapy may be predictive of better clinical outcomes for pts with advanced gastric or gastroesophageal junction adenocarcinoma. However, this exploratory analysis warrants further study. Clinical trial information: NCT03223376 .