The combination of the small molecule inhibitor of VEGFR fruquintinib and the chemotherapy paclitaxel presents a potential new second-line treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma, according to data presented during the ASCO Plenary Series: February 2024 Session.1
Results of the phase III FRUTIGA study (conducted in China) showed significantly improved progression-free survival in patients with advanced gastric or gastroesophageal junction adenocarcinoma treated with the novel combination compared with paclitaxel alone (5.6 months vs 2.7 months). A higher response rate was also observed in the experimental arm vs the control arm (42.5% vs 22.4%).
The study authors emphasized that this is the first randomized, placebo-controlled, phase III trial of a small-molecule antiangiogenic tyrosine kinase inhibitor combined with chemotherapy to demonstrate a statistically significant progression-free survival benefit and a trend for overall survival benefit, supporting fruquintinib plus paclitaxel as a treatment alternative to therapy with the monoclonal antibody ramucirumab in the second-line setting of advanced gastric or gastroesophageal junction adenocarcinoma.
“The positive results of FRUTIGA further enrich the evidence for the effectiveness of the VEGFR signaling pathway acting on advanced gastric or gastroesophageal adenocarcinoma, which had been previously supported by the efficacy of ramucirumab,” said lead study author Rui-Hua Xu, MD, PhD, of Sun Yat-sen University Cancer Center, Guangzhou, China.
Rui-Hua Xu, MD, PhD
Fruquintinib, a highly selective, oral VEGF receptor inhibitor is already approved in the United States 2 and China for third- and later-line treatments of patients with metastatic colorectal cancer, based on data demonstrating significantly improved overall survival.3 According to Dr. Xu, blocking VEGF receptors stops the formation of new blood vessels, which are used to deliver nutrients for a tumor to grow and spread, essentially “starving” the tumor.
Study Details
The FRUTIGA trial evaluated the efficacy and safety of fruquintinib plus paclitaxel vs placebo plus paclitaxel in patients with advanced gastric or gastroesophageal junction adenocarcinoma that progressed on fluoropyrimidine- or platinum-containing first-line chemotherapy. The dual primary endpoints of the study were progression-free survival and overall survival. A total of 703 patients were enrolled in the study, with 699 receiving at least one dose of fruquintinib.
The study met the predefined criteria for progression-free survival, demonstrating a significant improvement with fruquintinib plus paclitaxel vs placebo plus paclitaxel in patients with advanced gastric or gastroesophageal junction adenocarcinoma who had disease progression on first-line chemotherapy (median = 5.6 vs 2.7 months, hazard ratio [HR] = 0.57, P < .0001). Objective response rate in the fruquintinib group was nearly twofold higher than the placebo group (42.5% vs 22.4%, respectively).
After a median follow-up of 31.7 months, fruquintinib plus paclitaxel demonstrated a trend for overall survival benefit, but this difference was not statistically significant (median = 9.6 vs 8.4 months, HR = 0.96, P = .6064). Post hoc analyses adjusting for confounding effects supported the overall survival benefit of fruquintinib plus paclitaxel, with a hazard ratio ranging from 0.73 to 0.91.
Dr. Xu noted that median progression-free survival was extended even more among nondiffuse gastric or gastroesophageal adenocarcinoma patients with lymph node metastases (6.1 months in the fruquintinib group vs 2.7 months in the placebo group, P < .0001), and overall survival also showed a nominal statistically significant improvement (9.6 vs 7.9 months, P = .0233).
According to Dr. Xu, similar rates of treatment-emergent adverse events were observed in both groups. However, the incidence of grade 3 or higher adverse events was increased in patients randomly assigned to receive fruquintinib plus paclitaxel.
DISCLOSURE: This study was funded by HUTCHMED Limited. Dr. Xu has received consulting fees from HengRui, JunShi, HUTCHMED, QiLu, CPPC, Roche, and Merck Serono; and participated on a data safety monitoring board or advisory board for Astellas, MSD, AstraZeneca, JunShi, HengRui, BeiGene, Innovent, CPPC, and Keymed Biosience.
REFERENCES
2. Dasari A, et al: Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2). Lancet 402:41-53, 2023.
3. Li J, et al: Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer. JAMA 319:2486-2496, 2018.
EXPERT POINT OF VIEW
Abstract discussant of the FRUTIGA trial, medical oncologist Florian Lordick, MD, PhD, Director of the University of Leipzig Cancer Center, Germany, acknowledged several strengths of the “well-powered” study for progression-free and overall survival analysis. According to Dr. Lordick, baseline characteristics were balanced, and there was a “promising effect size for progression-free survival” as well as “an interesting increase in response rate.”
Florian Lordick, MD, PhD
However, Dr. Lordick also noted study weaknesses, including an imbalance in treatment after disease progression and a lack of subgroup analysis. In addition, he added, there were no data on quality of life or symptom control, and the dual primary endpoint of overall survival was negative. “I would expect to see an improvement in overall survival before [the combination of] fruquintinib and paclitaxel becomes a new standard of care in second-line advanced gastric cancer,” said Dr. Lordick. “However, fruquintinib could become another option in the sequential treatment of advanced gastric cancer.”
Dr. Lordick noted the potential benefits of combining fruquintinib with immunotherapy for gastric cancer. “I would love to see a study that investigated the effects of VEGF therapy plus immunotherapy as well as data on antiangiogenic therapy such as fruquintinib after immunotherapy,” he stated. “The 10% of patients who received immunotherapy prior to treatment in the FRUTIGA trial are probably not sufficient for a robust subgroup analysis, but the sequence could be quite interesting.”
Finally, said Dr. Lordick, it would be interesting to integrate fruquintinib into a first-line study where immunotherapy is applied, although he acknowledged there may be safety issues. “We would need to see some phase II data before we embark on a larger trial,” he said.
DISCLOSURE: Dr. Lordick reported financial relationships with Eli Lilly, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, BioNTech, Servier, Merck KGaA, Roche, Medscape, Incyte, Art Tempi, Medi Update, Streamed Up, Daiichi Sankyo, Novartis, Falk Foundation, Astellas Pharma, Page, Takeda, and Boehringer Ingelheim.
