Editor’s Note: The field of second-line treatment for advanced gastric cancer is a current focal point in oncology research. On February 6, 2024, during the ASCO Plenary Series, Dr. Ruihua Xu from Sun Yat-sen University Cancer Center presented findings from the FRUTIGA study (NCT03223376), a phase III trial conducted in China evaluating the efficacy of fruquintinib combined with paclitaxel for second-line treatment in advanced gastric cancer. The study offers an additional treatment option for advanced gastric cancer. Oncology Frontier highlighted perspectives from Dr. Ruihua Xu and Dr. Florian Lordick, Director of the University Cancer Center Leipzig, on the significance of FRUTIGA. Here’s a summary of the discussion.Key points：
The FRUTIGA study is a randomized phase III clinical trial evaluating the efficacy and safety of fruquintinib plus paclitaxel versus paclitaxel monotherapy as a second-line treatment for patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
- Progression-Free Survival (PFS): Adding fruquintinib to paclitaxel significantly extended PFS, achieving one of the primary endpoints.
- Overall Survival (OS): While the primary endpoint of OS showed no significant improvement, FRUTIGA remains a positive trial based on its statistical design.
Key Study Results
The results demonstrated that adding fruquintinib to paclitaxel significantly improved PFS and overall response rate (ORR) in patients with advanced G/GEJ adenocarcinoma who had progressed on first-line chemotherapy. The median PFS for the fruquintinib-paclitaxel group was 5.55 months compared to 2.73 months for paclitaxel alone (HR 0.569; P < 0.0001). The ORR was 42.5% for the combination therapy compared to 22.4% with paclitaxel alone.
However, there was no significant difference in median OS between the fruquintinib-paclitaxel group (9.63 months) and the paclitaxel-only group (8.41 months; P = 0.6064). This may be attributed to an imbalance in the subsequent anti-tumor treatments received by the two groups.
Additional Findings
FRUTIGA was designed with dual primary endpoints of PFS and OS. Achieving statistical significance in either endpoint defined a positive trial outcome. While the trial was deemed successful based on PFS benefits, Professor Xu’s team explored additional factors that might explain the lack of OS improvement.
They noted a significant imbalance in the number of patients continuing anti-tumor treatments in the fruquintinib and placebo groups (52.7% vs. 72.2%). Subsequent adjustments to control for post-study treatment variables and other baseline factors showed a modest but statistically significant OS benefit in the fruquintinib-paclitaxel group (HR 0.79–0.83; P = 0.0105–0.0350, depending on the adjusted variables).
Notably, patients with lymph node metastasis and non-diffuse type G/GEJ adenocarcinoma treated with fruquintinib plus paclitaxel demonstrated significant PFS (median: 6.08 vs. 2.69 months; HR 0.454; P < 0.0001) and OS benefits (median: 9.6 vs. 7.9 months; HR 0.77; P = 0.0233) without additional safety concerns compared to monotherapy.
Safety Profile
The most common ≥ grade 3 treatment-related adverse events (TRAEs) in the fruquintinib-paclitaxel group versus the placebo-paclitaxel group were neutropenia (60.0% vs. 36.4%), leukopenia (42.9% vs. 23.5%), and anemia (11.7% vs. 10.6%).
Dr. Ruihua Xu: The FRUTIGA study findings indicate that patients with G/GEJ adenocarcinoma benefit from fruquintinib, aligning with results from the RAINBOW-Asia study, which assessed ramucirumab combined with paclitaxel in Chinese patients. The positive outcome of FRUTIGA adds further evidence to the efficacy of targeting the VEGFR signaling pathway in advanced G/GEJ adenocarcinoma.
FRUTIGA is the first randomized, placebo-controlled phase III study evaluating a small-molecule anti-angiogenic tyrosine kinase inhibitor with chemotherapy, showing statistically significant benefits in PFS and trends toward OS improvement. Fruquintinib combined with paclitaxel could be a promising second-line option for advanced G/GEJ adenocarcinoma patients who progress on first-line chemotherapy.
Dr. Florian Lordick: While it remains unclear how to best utilize fruquintinib to optimize patient outcomes, subgroup analyses of FRUTIGA might help identify patients who could benefit most, guiding selective use of this drug.
Despite the increase in PFS and ORR with fruquintinib-paclitaxel in second-line treatment, OS improvements are still desirable before this approach becomes a new standard. Fruquintinib may offer a viable sequential treatment option for advanced G/GEJ adenocarcinoma.
Further research on fruquintinib in G/GEJ adenocarcinoma will help clarify its optimal place in treatment. Fruquintinib might be beneficial after ramucirumab-paclitaxel, combined with chemotherapy options like trifluridine/tipiracil, or used post-immunotherapy or even outside immunotherapy.
Reference
Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer：the FRESCO randomized clinical trial. JAMA. 2018；319(24)：2486-2496.
Dasari A, Lonardi S, Garcia-Carbonero R, et al；FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer(FRESCO-2)：an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023；402(10395)：41-53.
Cyramza. Prescribing information. Eli Lilly；2014. Accessed February 2, 2024.
Xu RH, Zhang Y, Pan H, et al. Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-Asia)：a randomised, multicentre, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2021；6(12)：1015-1024.
