FDA Accepts NDA for Surufatinib for Advanced Neuroendocrine Tumors

The FDA has accepted the filing of the new drug application (NDA) for surufatinib as a potential therapeutic option for patients with pancreatic and extra-pancreatic neuroendocrine tumors (NETs).¹

The application is supported by findings from the phase 3 SANET-p (NCT02589821) and SANET-ep (NCT02588170) trials, which were conducted in patients with NETs in China, and data from a US study (NCT02549937) performed in patients with pancreatic and non-pancreatic NETs.

The FDA is slated to decide on the application by April 30, 2022, under the Prescription Drug User Fee Act.

“The NDA filing acceptance of surufatinib in the United States is a significant achievement for HUTCHMED as we expand our global operations and work to bring our innovative oncology drugs to [patients with] cancer worldwide,” Marek Kania, MD, MBA, managing director and chief medical officer of HUTCHMED International Corporation, stated in a press release. “The FDA’s acceptance of the NDA highlights the clinical value of this submission package and the importance of bringing more treatment options to [patients with] NETs [in the] United States.”

In SANET-p, a total of 172 adult patients with progressive, advanced, well differentiated pancreatic NETs were randomized 2:1 to receive either oral surufatinib at daily dose of 300 mg (n = 113) or placebo (n = 59) in 4-week treatment cycles.² Patients needed to have an ECOG performance status of 0 to 1 and have progressed on up to 2 types of prior systemic regimens for advanced disease. The primary end point of the trial was progression-free survival (PFS) per investigator assessment in the intent-to-treat (ITT) population.

The median follow-up in the investigative and control arms was 19.3 months (95% CI, 9.3-19.4) and 11.1 months (95% CI, 5.7-35.9), respectively. Results showed that the median PFS per investigator assessment was 10.9 months (95% CI, 7.5-13.8) with surufatinib vs 3.7 months (95% CI, 2.8-5.6) with placebo (HR, 0.49; 95% CI, 0.32-0.76; P = .0011). Because the trial met the early stopping criteria at the interim analysis, the independent data monitoring committee recommended termination.

A supportive analysis of PFS per a blinded independent image review committee (BIIRC) showed that in the investigative and control arms, the median PFS was 13.9 months (95% CI, 11.0-24.9) and 4.6 months (95% CI, 3.6-7.4), respectively (HR, 0.34; 95% CI, 0.21-0.55; P <.0001).

Fifteen patients were excluded from the interim ITT set for best overall response: 9 patients from the surufatinib arm and 6 from the placebo arm. These patients were on treatment but had not yet undergone post-baseline tumor assessment. Nineteen percent of patients in the surufatinib arm (n = 20/104) and 2% of those in the placebo arm (n = 1/53) experienced a partial response (PR) to treatment per investigator assessment; this translated to objective response rates (ORRs) of 19% (95% CI, 12%-28%) and 2% (95% CI, 0%-10%) in these arms (P = .0021). Overall responses per BIICR assessment proved to be comparable.

In the investigative and control arms, the disease control rates (DCRs) were 81% (95% CI, 72%-88%) and 66% (95% CI, 52%-79%), respectively (odds ratio, 2.1; 95% CI, 0.9-4.8; P = .077). The time to response (TTR) with surufatinib was 3.8 months (95% CI, 2.3-7.3) and the duration of response (DOR) was 7.4 months (95% CI, 3.7–not computable).

Additionally, 84% of 104 patients who received surufatinib experienced tumor shrinkage per investigator assessment compared with 40% of 53 patients who were given placebo. Sixty-eight percent of those on the investigative arm and 15% of those on the control arm experienced shrinkage of more than 10% compared with baseline.

Among 113 patients who received surufatinib and 59 given placebo, the most frequent grade 3 or higher treatment-related adverse effects (TRAEs) included hypertension (38% vs 7%), proteinuria (10% vs 2%), and hypertriglyceridemia (7% vs 0%). Serious TRAEs were experienced by 22% and 7% of those in the investigative and control arms, respectively. Three on-treatment deaths were observed in the surufatinib arm vs 1 on the placebo arm.

In SANET-ep, a total of 198 patients with unresectable or metastatic, well differentiated, extrapancreatic NETs were randomized 2:1 to receive oral surufatinib at a daily dose of 300 mg (n = 129) or matching placebo (n = 69).³ Patients needed to have an ECOG performance status of 0 or 1 and had to have progressed on no more than 2 prior systemic regimens. The primary end point of the trial was PFS per investigator assessment.

The median follow-up in the investigative and control arms was 13.8 months (95% CI, 11.1-16.7) and 16.6 months (95% CI, 9.2–not calculable), respectively. Results demonstrated that surufatinib resulted in an investigator-assessed median PFS of 9.2 months (95% CI, 7.4-11.1) vs 3.8 months (95% CI, 3.7-5.7) with placebo (HR, 0.33; 95% CI, 0.22-0.50; P <.0001). Because the trial met the early discontinuation criteria at the interim analysis, the study was stopped early, in accordance with a recommendation from the independent data monitoring committee.

The supportive analysis of BIIRC-assessed PFS showed a median PFS of 7.4 months (95% CI, 5.6-9.3) vs 3.9 months (95% CI, 3.7-5.8) in the surufatinib and placebo arms, respectively (HR, 0.66; 95% CI, 0.44-0.98; P = .037).

Eight patients were not included in the interim ITT set; 3 of these patients were in the surufatinib cohort and 5 were in the placebo cohort. Although these patients were on treatment, they did not undergo post-baseline tumor evaluation. In this set, 13 patients who received surufatinib (n = 126) vs no patients given placebo experienced a PR per investigator assessment; this translated to ORRs of 10% (95% CI, 5.6%-17.0%) and 0%, respectively (P = .0051).

In the investigative and control arms, the DCRs were 87% (95% CI, 79.3%-91.9%) and 66% (95% CI, 52.7%-77.1%), respectively (odds ratio, 3.3; 95% CI, 1.5-7.3). The TTR with surufatinib was 3.7 months (95% CI, 1.8-5.5) and the DOR was 5.6 months (95% CI, 2.0-17.5).

Moreover, 63% of 126 patients who received surufatinib experienced tumor shrinkage per investigator assessment compared with 22% of 64 patients who were given placebo. Compared with baseline, 36% of those on the investigative arm and 3% of those on the control arm had shrinkage of more than 10%.

Regarding safety, the most common TRAEs that were grade 3 or higher experienced by patients who received surufatinib (n = 129) or placebo (n = 68) included hypertension (36% vs 13%) and proteinuria (19% vs 0%). Serious TRAEs were experienced by 25% and 13% of those in the investigative and control arms, respectively. Treatment-related deaths occurred in 3 patients who received surufatinib and 1 patient who was administered placebo.

Lastly, a phase 1 dose-escalation and -expansion trial was conducted to examine and confirm the safety and efficacy of surufatinib in the United States.⁴ At the time of the 2021 ASCO Annual Meeting, the dose-escalation portion of the trial has been completed, and the recommended phase 2 dose was identified to be 300 mg, the same as has been assessed in prior studies.

The dose-expansion portion of the research enrolled 32 patients with heavily pretreated, progressive NETs; this included 16 patients with extra-pancreatic disease and 16 with pancreatic disease. The primary end point of the trial was PFS rate at 11 months per investigator assessment. Notably, 65.6% of patients had received 3 or more prior lines of treatment. The median lines of therapy received in the extra-pancreatic and pancreatic subsets was 2 (range, 2-5) and 4 (range, 1-8), respectively.

At a data cutoff of June 30, 2020, the median PFS was 11.499 months (95% CI, 6.472-17.478) in the overall population. In the extra-pancreatic subset, the median PFS was also 11.499 (95% CI, 6.472-11.499), and in the pancreatic subset it was 15.179 (95% CI, 5.191–not reached). The 11-month PFS rates in the overall population and the extra-pancreatic and pancreatic subsets were 55.6% (95% CI, 32.2%-73.7%), 51.1% (95% CI, 12.8%-80.3%), and 57.4% (95% CI, 28.7%-78.2%), respectively.

The ORR achieved with surufatinib in the overall population was 12.5% (95% CI, 3.5%-29.0%); in the extra-pancreatic and pancreatic subsets, the ORRs were 6.3% (95% CI, 0.2%-30.2%) and 18.8% (95% CI, 4.0%-45.6%), respectively. The overall DCR was 90.6% (95% CI, 75.0%-98.0%).

The data package submitted to the FDA will also be used to file a marketing authorization application to the European Medicines Agency, according to HUTCHMED.

References

1. US FDA accepts filing of HUTCHMED’s NDA for surufatinib for the treatment of advanced neuroendocrine tumors. News release. July 1, 2021. Accessed July 1, 2021. https://bit.ly/3ycuQdd
2. Xu J, Shen L, Bai C, et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(11):1489-1499. doi:10.1016/S1470-2045(20)30493-9
3. Xu J, Shen L, Zhou Z, et al. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(11):1500-1512. doi:10.1016/S1470-2045(20)30496-4
4. Paulson AS, Li D, Sung MW, et al. Interim analysis results of surufatinib in US patients with neuroendocrine tumors (NETs). J Clin Oncol. 2021;39(suppl 15):4114. doi:10.1200/JCO.2021.39.15_suppl.4114