The FDA has issued a complete response letter to surufatinib for the treatment of a pancreatic and extra-pancreatic neuroendocrine tumors.
The FDA has issued a complete response letter to surufatinib for the treatment of a pancreatic and extra-pancreatic neuroendocrine tumors (NETs), according to a press release from HUTCHMED Limited.1
Supporting data come from 2 positive phase 3 trials, SANET-p (NCT02589821) and SANET-ep (NCT02588170) in China, and a bridging study (NCT02549937) in the United States. Both studies in China examined patients with NETs while data from the United States (US) study were from evaluating patients with pancreatic and non-pancreatic NETs.
“Although this decision from the FDA is disappointing, we remain confident about the clinical value of surufatinib for NET patients and committed to making surufatinib available to patients globally. We look forward to working with the Agency to evaluate its feedback. Throughout the duration of the US review process, we have been transparent and collaborative with the FDA. There are very few treatments approved and used in these rare diseases, and patients and physicians would benefit from more options to address the unmet medical need. We look forward to continued engagement with the FDA on developing a plan to bring surufatinib to patients in the U.S,” stated Weiguo Su, MD, chief executive officer and chief scientific officer of HUTCHMED Limited, in the press release.
Surufatinib, an oral inhibitor of angiogenesis and immune modulation, demonstrated promising efficacy and safety in both the SANET-p and SANET-ep studies, which led to its approval in China for the treatment of pancreatic NETs and extra-pancreatic NETs in June 2021 and December 2020. Additionally, the results of the bridging study suggested similar safety and efficacy to the SANET studies. However, an approval is not currently supported in the United States at this time as the complete response letter indicated a multi-regional clinical trial (MRCT) is required for its approval.
While the FDA examined the how results of the SANET studies could be applicable to patients and medical practices in the United States, it was decided an MRCT is needed which includes subjects and representations of the patient population. The decision was not related to any issues in regard to safety of surufatinib, and pandemic-related issues concerning inspection scheduling and access contributed to this FDA action. HUTCHMED is working with the FDA to evaluate next steps.
Previously, the FDA accepted the filing of a new drug application for surufatinib as treatment of patients with advanced NETs in July 2021, and a Prescription Drug User Fee Act target action date was set for April 30, 2022. The agent was also granted fast track designation in April 2020 for the treatment of pancreatic and extra-pancreatic NETs and received orphan drug designation for the treatment of pancreatic NETs in November 2019.
The phase 3, randomized, double-blind, placebo-controlled, SANET-ep trial conducted in China evaluated patients with advanced extrapancreatic NETs who were treated with surufatinib 300 mg vs a matching placebo. In total, 198 patients were randomly assigned to receive surufatinib (n = 129) or placebo (n = 69).
The primary end point of the study was investigator-assessed progression-free survival (PFS) in the intention-to-treat population and it was predicted that the treatment would lead to PFS events in 70% of the patient population. Secondary end points included overall response rate, disease control rate, duration of response, time to response, overall survival, and adverse events.
At a median follow-up in the surufatinib group of 13.8 months (95% CI, 11.1-16.7) and 16.6 months (9.2–not calculable) in the placebo group, investigator-assessed median PFS was 19.2 months (95% CI, 7.4-11.1) vs 3.8 months (3.7–5.7), respectively (HR, 0.33; 95% CI. 0.22-0.50; P < .0001). The study met the pre-specified criteria of early termination based on the PFS in the surufatinib arm being significantly longer than in the placebo arm.2
Based on the efficacy results, it was suggested that surufatinib may be a new treatment option for patients with advanced extrapancreatic NET, and the agent had a good benefit-risk profile.
In regard to safety, grade 3 or higher treatment-related adverse events (TRAEs) in the surufatinib compared to in the placebo group were most commonly hypertension (36% vs. 13%, respectively) and proteinuria (19% vs. 0). Serious TRAEs were reported in 25% of the surufatinib and 13% of the placebo group. Of the patients treated with surufatinib, 3 experienced a treatment-related death as did 1 patient in the placebo arm.
In the multicenter, randomized, double-blind, placebo-controlled, SANET-p trial, patients were those with advanced pancreatic NETs who were also treated with surufatinib 300 mg or matching placebo. These patients were evaluated for the same primary end point of investigator-assessed PFS.
The median follow-up of 9.3 months (95% CI, 9.3-19.4) in the surufatinib arm vs 11.1 months (5.7-35.9) in the placebo group, showed that the investigator-assessed PFS was 10.9 months (95% CI, 7.5-13.8) compared with 3.7 months (95% CI, 2.8-5.6), respectively, for an HR of 0.49 (95% CI, 0.32-0.76; P = .0011).3
Because of the significant improvement in PFS observed with surufatinib and the tolerable safety profile of the agent as treatment of patients with advanced pancreatic NETs, this trial was also ended early.
Safety findings showed that the most common grade 3 or higher TRAEs were hypertension, reported in 38% of the surufatinib arm vs 6% of the placebo arm, proteinuria in 10% vs 2%, and hypertriglyceridaemia in 7% versus 0, respectively. Serious TRAEs were seen in 2% of the surufatinib group and 7% of the placebo group. Additionally, there were 3 treatment-related deaths with surufatinib vs 1 with placebo.