On August 30, 2024 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:HCM; HKEX:13) reported that it has voluntarily withdrawn its supplemental New Drug Application ("NDA") in China for fruquintinib in combination with paclitaxel for the treatment of second-line advanced gastric or gastroesophageal junction adenocarcinoma and will evaluate a new route forward (Press release, Hutchison China MediTech, AUG 30, 2024, View Source [SID1234646233]). Following an additional internal review of the current data package, in light of recent discussions with the National Medical Products Administration of China ("NMPA"), HUTCHMED has determined that the submission is unlikely to support an approval in China at this time.
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This supplemental NDA for fruquintinib was based on data from the Phase III FRUTIGA study, which was declared positive due to a statistically significant improvements in many clinically meaningful endpoints, including progression-free survival ("PFS"), which served as one of two primary endpoints. However, while an improvement was also observed in the second primary endpoint of median overall survival ("OS"), it was not statistically significant. Extensive subsequent analyses conducted indicate that, although the high and imbalanced proportion of patients receiving subsequent antitumor therapies confounded the OS effect, fruquintinib plus paclitaxel demonstrated meaningful clinical benefit and favorable OS trends through a variety of models. Furthermore, no new safety signals were observed, and fruquintinib plus paclitaxel showed a tolerable safety profile. However, it became clear from dialogue with the Centre for Drug Evaluation (CDE) of the NMPA and its external committee members that the current understanding and interpretation of the OS results could not serve as the basis of the supplemental NDA approval, and that further work needs to be undertaken.
Dr Weiguo Su, Chief Executive Officer and Chief Scientific Officer of HUTCHMED, commented, "Whilst disappointed by this outcome, we remain optimistic about the utility of fruquintinib in the treatment of gastric cancer. The data set 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."
Dr Rui-Hua Xu, Professor at the Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, added, "Gastric cancer is the fifth most common cancer worldwide and patients in China are currently underserved by available treatment options. Although the current data package would not support approval on this occasion, the Phase III study demonstrated clear benefits of this fruquintinib combination across many clinically meaningful endpoints 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 approved in China, the US and Europe for the treatment of previously-treated patients with metastatic colorectal cancer ("CRC"), and regulatory applications for this indication are progressing as expected in over a dozen jurisdictions. It works as an anti-cancer therapy by blocking tumor angiogenesis, a proliferation of blood vessels that is critical for cancer growth. It is a selective oral inhibitor of vascular endothelial growth factor receptors ("VEGFRs") 1, 2 and 3, and this pathway plays a key role in the pathogenesis of many solid tumors including gastric cancer.
An NDA in China for fruquintinib in combination with sintilimab in endometrial cancer was accepted with priority review status in April 2024, and a Phase III trial in China of fruquintinib in combination with sintilimab in renal cell carcinoma was fully enrolled in December 2023.
About the Phase III FRUTIGA Trial
FRUTIGA (NCT03223376) was a 1:1 randomized, double-blind, Phase III study conducted across 35 sites in China. It evaluated fruquintinib in combination with paclitaxel chemotherapy, compared with paclitaxel monotherapy, for second-line treatment in 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma. The study was declared positive due to a statistically significant improvement in progression-free survival ("PFS"), one of two dual primary endpoints. Median PFS for patients who received fruquintinib plus paclitaxel was 5.6 months, compared to 2.7 months for those who received paclitaxel monotherapy (stratified hazard ratio ["HR"] = 0.569; p < 0.0001). An improvement was also observed in the dual primary endpoint of median overall survival (OS), (9.6 months vs. 8.4 months) but this was not statistically significant. Fruquintinib plus paclitaxel demonstrated statistically significant improvements in multiple other endpoints including objective response rate (ORR), disease control rate (DCR) and duration of response (DoR). It was well tolerated, with a safety profile consistent with expectations and previously reported studies.
Results were published in Nature Medicine and presented at the ASCO (Free ASCO Whitepaper) 2024 Annual Meeting, concluding that fruquintinib plus paclitaxel could be a promising second-line treatment option for patients with advanced gastric or gastroesophageal adenocarcinoma, who have failed fluoropyrimidine- or platinum-containing chemotherapy.
About Gastric Cancer
Gastric cancer is a cancer that starts in the stomach. It is the fifth most common cancer worldwide in 2022. It was estimated to have caused approximately 660,000 deaths worldwide.[2] In China, it was estimated that over 359,000 people were diagnosed with gastric cancer, and approximately 260,000 people died from gastric cancer.
About Fruquintinib
Fruquintinib is a selective oral inhibitor of VEGFR-1, -2 and -3. VEGFR inhibitors play a pivotal role in inhibiting tumor angiogenesis. Fruquintinib was designed to have enhanced selectivity that limits off-target kinase activity, allowing for high drug exposure, sustained target inhibition, and flexibility for the potential use as part of combination therapy. Fruquintinib has demonstrated a manageable safety profile and is being investigated in combinations with other anti-cancer therapies.
About Fruquintinib Approval for metastatic CRC in China
Fruquintinib is approved for marketing in China, where it is co-marketed by HUTCHMED and Lilly under the brand name ELUNATE. It was included in the China National Reimbursement Drug List (NRDL) in January 2020. The approval was based on data from the FRESCO study, a Phase III pivotal registration trial of fruquintinib in 416 patients with metastatic CRC in China, which were published in The Journal of the American Medical Association, JAMA. Since its launch, fruquintinib has benefited over 100,000 patients in China.