Fruquintinib combined with sintilimab and SOX as conversion therapy for unresectable locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (GC/GEJC): A single-arm, open-label, phase 2 clinical trial.

Abstract

e16021 Background: The evidence of conversion therapy for unresectable GC/GEJC is limited. Fruquintinib is an oral, highly selective VEGFR 1/2/3 inhibitor that has synergistic antitumor effects when combined with ICIs/chemotherapy. This study was conducted to evaluate the efficacy and safety of fruquintinib combined with sintilimab and SOX as a conversion therapy in patients (pts) with initially unresectable locally advanced or metastatic GC/GEJC. Methods: Eligible pts received 3 to 6 cycles of fruquintinib (4mg/d, po, qd, d1-14) combined with sintilimab (200mg, iv, d1), oxaliplatin (130 mg/m2, iv, d1) and S-1 (40-60mg based on BSA, po, bid, d1-14) every 3 weeks. One more cycle of sintilimab plus SOX was given before resection. Radiographic assessments were performed every 3 cycles and MDTs were employed to determine surgical feasibility. Primary endpoint was R0 resection rate. Secondary endpoints included pathological response, ORR, PFS, OS, and safety. Results: From May 2022 to December 2023, 34 pts (29 males/5 females) with a median age of 62 years (range: 43–76), 71% ECOG PS1, 59% GEJC were enrolled. The unresectable factors included liver metastasis 15% (5/34), peritoneal metastasis 6% (2/34), para-aortic lymph node metastasis 3% (1/34), extensive or bulky lymph nodes 53% (18/34), and local progression 38% (13/34). Five pts had more than one unresectable factors. The ORR and DCR of 29 pts who had at least one preoperative assessment were 65.5% (19 PR) and 96.6%, respectively. Among the 18 pts who had completed surgical conversion, all of them had R0 resection (100%), 2 pts (11.1%) achieved pathological complete response (pCR), and 1 pt reached AJCC-TRG1. The pathological response rate (pRR) according to JCGC (≥ Grade 1b) was 100% (18/18). Additionally, downstaging to pN0 was achieved in 13 pts (72.2%). During preoperative treatment, treatment-emergent adverse events (TEAEs) occurred in 85.3% (29/34) pts, and most events were grade 1–2. Grade 3 TEAEs included 2 cases of neutrophil count decreased, and 1 case of each (platelet count decreased, anemia, diarrhea, and immune-related pneumonitis). No severe surgery-related complication was observed. Conclusions: Fruquintinib combined with sintilimab and SOX as a conversion therapy strategy shown acceptable toxicity in unresectable GC/GEJC and induced very high R0 resection, pathological response, and downstaging rate. The study is ongoing, more data will be disclosed in the future. Clinical trial information: NCT05177068 .