sNDA Withdrawn for Fruquitinib Plus Paclitaxel in Second-Line Gastric Cancer in China

The supplemental new drug application (sNDA) for fruquintinib (Fruzaqla) in combination with paclitaxel for the treatment of second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma in China has been voluntarily withdrawn, according to an announcement by HUTCHMED.¹

Findings from the phase 3 FRUTIGA study (NCT03223376) supported the original acceptance of this sNDA in April 2023, showing statistically significant improvements in its coprimary end point of progression-free survival (PFS). However, discussions with the Centre for Drug Evaluation of China’s National Medical Products Administration (NMPA) and an additional internal review of the current data package led to the company concluding that the interpretation of overall survival (OS) data from the study was unlikely to support an approval in China at this time. Accordingly, the company determined that further research must be undertaken.

“Whilst disappointed by this outcome, we remain optimistic about the utility of fruquintinib in the treatment of gastric cancer,” Weiguo Su, PhD, CEO and chief scientific officer of HUTCHMED, stated in the news release. “The dataset from FRUTIGA demonstrates that fruquintinib plus paclitaxel could offer a promising new treatment option to certain patients in future, and we are driven to investigate this possibility thoroughly. We look forward to evaluating a path forward and would like to thank both the patients and principal investigators who took part in this study for contributing to a better understanding of this devastating disease.”

According to data presented first during the February 2024 ASCO Plenary Series, and subsequently at the 2024 ASCO Annual Meeting, patients treated with the fruquintinib regimen (n = 351) achieved a median PFS of 5.6 months (95% CI, 4.6-6.4) vs 2.7 months (95% CI, 2.7-3.5) with paclitaxel alone (n = 352). This translated to a 43% reduction in the risk of disease progression or death (HR, 0.57; 95% CI, 0.48-0.68; P < .0001).²

At a median follow-up of 31.7 months, fruquintinib plus paclitaxel numerically improved median OS vs paclitaxel, at 9.6 months (95% CI, 8.9-10.8) vs 8.4 months (95% CI, 7.8-9.4), respectively (HR, 0.96; 95% CI, 0.81-1.13; P = .6064). However, the improvement was not deemed statistically significant, which may be explained by an imbalanced proportion of patients undergoing subsequent antitumor therapy between the 2 arms (52.7% vs 72.2%).

A trend towards improved OS with fruquintinib plus paclitaxel vs paclitaxel alone regardless of subsequent antitumor therapy administration, was observed after correcting for these potentially confounding effects. In the fruquintinib arm, patients who did not receive subsequent treatment (n = 166) achieved a median OS of 6.9 months vs 4.8 months in the placebo arm (n = 98; HR, 0.72; 95% CI, 0.53-0.99; P = .0422). For patients who underwent subsequent treatment, the median OS in the fruquintinib (n = 185) and placebo (n = 254) arms was 12.2 months vs 10.0 months, respectively (HR, 0.90; 95% CI, 0.73-1.11; P = .3262).

No new safety signals were observed, and the combination was deemed tolerable.

“Gastric cancer is the fifth most common cancer worldwide and patients in China are currently underserved by available treatment options,” Rui-Hua Xu, MD, PhD, professor in the Department of Medical Oncology, at Sun Yat-sen University Cancer Center in Guangzhou, China, added in the news release.¹ “Although the current data package would not support approval on this occasion, the [FRUTIGA] study demonstrated clear benefits of this fruquintinib combination across many clinically meaningful end points and the team are committed to evaluating all options. Promising subgroup analyses are helping us to better understand how we can effectively combat this disease, and we remain hopeful that this study forms part of an important journey to a much-needed new therapy.”

Fruquintinib is currently approved in China and the European Union for use in the third-line treatment of patients with metastatic colorectal cancer (mCRC). Additionally, the FDA approved fruquintinib in November 2023 for use in adult patients with mCRC who previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy, if they had RAS wild-type disease and treatment was medically appropriate.³

In April 2024, an NDA for fruquintinib in combination with sintilimab (Tyvyt) in endometrial cancer was accepted for priority review by China’s NMPA.¹ A phase 2/3 trial (NCT05522231) evaluating this regimen in renal cell carcinoma was also initiated in China, and completed enrollment in December 2023.⁴

FRUTIGA Trial Design

FRUTIGA was a double-blind, placebo-controlled, trial enrolling patients with advanced gastric or GEJ adenocarcinoma who experienced disease progression on fluoropyrimidine- or platinum-containing chemotherapy and had an ECOG performance status of 0 or 1.²

A total of 703 patients were enrolled onto the study and randomly assigned 1:1 to receive 4 mg of fruquintinib daily for 3-weeks-on/1-week-off. This was administered alongside 80 mg/m2 of paclitaxel on days 1, 8, and 15 of each cycle or placebo plus paclitaxel at the same dose and schedule. Treatment continued until disease progression by RECIST 1.1 criteria or unacceptable toxicity. Patients were stratified according to primary tumor location (GEJ vs stomach), presence of peritoneal metastasis (yes vs no), and performance status (0 vs 1).

In addition to the dual primary end points of PFS and OS, objective response rate, disease control rate, duration of response, safety, and quality of life served as key secondary end points.

References

1. HUTCHMED provides update on fruquintinib for second-line gastric cancer in China. News Release. HUTCHMED. August 30, 2024. Accessed August 30, 2024. https://www.simcere.com/en/news/detail.aspx?mtt=459#:~:text=On%20June%2025%2C%202024%2C%20Simcere,in%20collaboration%20with%20Mabpharm%20Limited%20(
2. Xu R-H, Wang F, Shen L, et al. 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. J Clin Oncol. 2024;42(suppl 36):438780. doi:10.1200/JCO.2024.42.36_suppl.43878
3. FDA approves fruquintinib in refractory metastatic colorectal cancer. FDA. November 8, 2023. Accessed August 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fruquintinib-refractory-metastatic-colorectal-cancer
4. HUTCHMED Initiates a phase II/III trial of fruquintinib in combination with sintilimab for advanced renal cell carcinoma in China. News Release. HUTCHMED. October 27, 2022. Accessed August 30, 2024.https://www.hutch-med.com/fruquintinib-sintilimab-advanced-rcc/