Fruquintinib plus paclitaxel versus paclitaxel as second-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma (FRUTIGA): A randomized, multicenter, double-blind, placebo-controlled, phase 3 study.

Author(s): Rui-Hua Xu1,2; Feng Wang1,2; Lin Shen3; Weijian Guo4; Tianshu Liu5; Jin Li6; Shukui Qin7; Yuxian Bai8; Zhendong Chen9; Jufeng Wang10; Yueyin Pan11; Yongqian Shu12; Fuyou Zhao13; Ying Cheng14; Feng Ye15; Kangsheng Gu16; Tao Zhang17; Hongming Pan18; Haijun Zhong19; Weiguo Su20
Maem Hussein MD

Dr. Maen Hussein's Thoughts

Fruquintinib was recently approved for colorectal cancer, advanced refractory stage. It is an oral VEGF inihibitor, now in combination with taxol, showing improved progression-free survival (PFS) and trends to improve overall survival (OS), another option for those patients for second line therapy.

This PFS benefit was close to benefit of adding ramucirimab to taxol. This combination showed OS benefit, too. So, it is not surprising that adding VEGF to taxol showed superiority to taxol alone in those patients.

In both trials, immunotherapy was not used in the first line setting.


Fruquintinib (F), a highly selective and potent oral inhibitor of VEGFRs 1, 2, and 3, significantly improved the OS in metastatic colorectal cancer (Li J, et al, JAMA 2018; Dasari A, et al, LANCET 2023). FRUTIGA was a randomized, double-blind, placebo (PBO)-controlled, phase 3 study evaluating the efficacy and safety of F plus paclitaxel (PTX) vs PTX alone in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma who experienced disease progression (PD) on fluoropyrimidine- or platinum-containing first-line chemotherapy.


Eligible pts were randomized 1:1 to receive F (4 mg, once daily, 3 weeks on/1 week off) or matching PBO orally, plus PTX (80 mg/m2, intravenously, days 1/8/15 per cycle) in 4-week cycles until PD or intolerable toxicity; treatment of PTX was allowed for up to 6 cycles. PFS and OS were dual-primary endpoints with α split and recycle. The study was considered positive when at least one endpoint met statistical significance.


703 pts were randomized (F+PTX 351 vs PBO+PTX 352), and 699 pts received at least 1 dose of study drug (350 vs 349). PFS was significantly improved with F+PTX vs PBO+PTX (median PFS [mPFS] 5.55m vs 2.73m; HR = 0.569; p < 0.0001). The overall response rate was significantly higher in F+PTX group (42.5% vs 22.4%, p < 0.0001). Median OS (mOS) was 9.63m with F+PTX and 8.41m with PBO+PTX (HR = 0.956; p = 0.6064). Given an imbalance of pts receiving subsequent antitumor therapies (F+PTX 52.7% vs PBO+PTX 72.2%), post-hoc analyses were performed using cox-proportional hazards model adjusting for subsequent antitumor therapies and baseline factors. Results showed a nominal statistically significant improvement in OS with F+PTX (HR range 0.793-0.828; p range 0.0105-0.0350 with different subsequent antitumor therapy factors). Furthermore, among pts with lymph node metastases and non-diffuse G/GEJ adenocarcinoma (190 vs 208), mPFS was even more prolonged (6.08m vs 2.69m; HR = 0.454; p < 0.0001) and OS also showed a nominal statistically significant improvement (mOS 9.56m vs 7.85m; HR = 0.767; p = 0.0233). The most common TEAEs of Grade ≥ 3 were neutropenia (60.0% vs 36.4%), leukopenia (42.9% vs 23.5%), and anemia (11.7% vs 10.6%). The safety profile was consistent with F and PTX. No new safety signals were identified.


FRUTIGA (NCT03223376) was a positive study by reaching statistical significance for one primary endpoint, PFS, and demonstrated improvement in the other primary endpoint, OS, that was not statistically significant, possibly due to the imbalance of subsequent antitumor therapies. These data support F+PTX as a potential new second-line treatment option for pts with advanced G/GEJ adenocarcinoma.

Author Affiliations

1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China; 2Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China; 3Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China; 4Fudan University Shanghai Cancer Center, Shanghai, China; 5Zhongshan Hospital, Fudan University, Shanghai, China; 6Tongji University Shanghai East Hospital, Shanghai, China; 7Chinese People’s Liberation Army Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 8Harbin Medical University Cancer Hospital, Harbin, China; 9The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; 10Henan Cancer Hospital, Zhengzhou, China; 11Anhui Provincial Hospital, Hefei, China; 12The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China; 13The First Affiliated Hospital of Bengbu Medical College, Bengbu, China; 14Jilin Cancer Hospital, Changchun, China; 15The First Affiliated Hospital of Xiamen University, Xiamen, China; 16The First Affiliated Hospital of Anhui Medical University, Hefei, China; 17Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 18Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; 19Zhejiang Cancer Hospital, Hangzhou, China; 20HUTCHMED Limited, Shanghai, China

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