FDA Issues Complete Response Letter to Surufatinib for Advanced Neuroendocrine Tumors

The FDA has issued a complete response letter (CRL) to the new drug application (NDA) seeking the approval of surufatinib for the treatment of patients with pancreatic and extra-pancreatic neuroendocrine tumors (NETs), according to an announcement from HutchMed Limited.¹

The regulatory agency decided that the current data package, which is comprised of findings from 2 positive phase 3 trials conducted in China and 1 bridging study performed in the United States, does not support an approval at this time.

In the letter, the FDA specified that a multiregional clinical trial is needed, and it should include those who are representative of the patient population in the United States and aligned to current medical practice in the country. Pandemic-associated issues regarding inspection scheduling and access were also noted to contribute to the decision. Notably, safety-related issues were not cited, and the company is working with the FDA to examine next steps.

“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,” Weiguo Su, PhD, chief executive officer and chief scientific officer of HutchMed, stated in a press release. “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.”

The NDA was supported by data from the phase 3 SANET-p (NCT02589821) and SANET-ep (NCT02588170) trials, which were performed in patients with NETs in China, and findings from a bridging study (NCT02549937) conducted in patients with pancreatic and non-pancreatic NETs in the United States. The application was accepted by the FDA for filing in July 2021, and the agency was slated to decide by April 30, 2022.²

A total of 172 adult patients with progressive, advanced, well-differentiated pancreatic NETs were enrolled to the SANET-p trial.³ To be eligible for enrollment, patients were required to have an ECOG performance status of 0 or 1 and have progressed on up to 2 types of previous systemic regimens for advanced disease.

Participants were randomized 2:1 to oral surufatinib given at 300 mg daily (n = 113) or placebo (n = 59) administered in 4-week cycles. The primary end point was investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) population.

At a median follow-up of 19.3 months (95% CI, 9.3-19.4) in the surufatinib arm and 11.1 months (95% CI, 5.7-35.9) in the placebo arm, the median PFS per investigator assessment was 10.9 months (95% CI, 7.5-13.8) and 3.7 months (95% CI, 2.8-5.6), respectively (HR, 0.49; 95% CI, 0.32-0.76; P = .0011). At the time of the interim analysis, the trial met early stopping criteria. As such, the independent monitoring committee recommended that the trial be terminated.

Data from a supportive analysis of PFS done by a blinded independent image review committee (BIIRC) indicated that the median PFS with surufatinib was 13.9 months (95% CI, 11.0-24.9) vs 4.6 months (95% CI, 3.6-7.4) with placebo (HR, 0.34; 95% CI, 0.21-0.55; P < .0001).

When evaluating best overall response to treatment, 15 patients were excluded from the interim ITT set; this included 9 patients in the investigative arm and 6 from the control arm. Surufatinib elicited an investigator-assessed objective response rate (ORR) of 19% (95% CI, 12%-28%) vs 2% (95% CI, 0%-10%) with placebo (P = .0021). Nineteen percent of the 104 patients in the surufatinib arm achieved a partial response (PR) to treatment vs 2% of the 53 patients who received placebo. Overall responses per BIICR assessment were comparable.

Moreover, the disease control rate (DCR) in the investigative arm was 81% (95% CI, 72%-88%) vs 66% (95% CI, 52%-79%) in the control arm (odds ratio [OR], 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 was 7.4 months (95% CI, 3.7–not computable [NC]). Notably, 84% of patients in the investigative arm experienced tumor shrinkage vs 40% of those in the control arm, with 68% and 15% of patients, respectively, experiencing shrinkage of more than 10% vs baseline.

Regarding safety, the most common grade 3 or higher treatment-related toxicities experienced with surufatinib (n = 113) and placebo (n = 59) were hypertension (38% vs 7%, respectively), proteinuria (10% vs 2%), and hypertriglyceridemia (7% vs 0%). Moreover, 22% of those in the investigative arm and 7% of those in the control arm experienced serious treatment-related adverse effects (TRAEs). Three patients who received surufatinib died vs 1 patients who was given placebo.

A total of 198 patients with unresectable or metastatic, well-differentiated, extrapancreatic NETs were enrolled to the SANET-ep trial.⁴ These patients needed to have an ECOG performance status of 0 or 1 and have progressed on no more than 2 previous systemic therapies.

Study participants were randomized 2:1 to receive oral surufatinib at 300 mg daily (n = 129) or placebo (n = 69). The primary end point was investigator-assessed PFS.

With a median follow-up of 13.8 months (95% CI, 11.1-16.7) for surufatinib and 16.6 months (95% CI, 9.2-NC) for placebo, the investigator-assessed median PFS was 9.2 months (95% CI, 7.4-11.1) and 3.8 months (95% CI, 3.7-5.7), respectively (HR, 0.38; 95% CI, 0.22-0.50; P < .0001). Again, the trial met early discontinuation criteria at the time of the interim analysis and was stopped early after an independent data monitoring committee recommended it.

Data from a supportive analysis done by the BIIRC showed that the median PFS with surufatinib was 7.4 months (95% CI, 5.6-9.3) vs 3.9 months (95% CI, 3.7-5.8) with placebo (HR, 0.66; 95% CI, 0.44-0.98; P = .037).

A total of 8 patients were not included in the interim ITT set; 3 of these patients were on the investigative arm and 5 were on the control arm. In these patients, surufatinib (n = 126) induced an ORR of 10% (95% CI, 5.6%-17.0%) vs 0% with placebo (P = .0051). Thirteen patients in the investigative arm experienced a PR vs no patients in the control arm per investigator assessment.

Moreover, the DCR achieved with surufatinib was 87% (95% CI, 79.3%-91.9%) vs 66% (95% CI, 52.7%-77.1%) with placebo (OR, 3.3; 95% CI, 1.5-7.3). The TTR in the investigative and control arms was 3.7 months (95% CI, 1.8-5.5) and 5.6 months (95% CI, 2.0-17.5), respectively.

Notably, 63% of those who received surufatinib experienced tumor shrinkage vs 22% of those who were given placebo, with 36% and 3% of patients, respectively, experiencing a reduction of 10% or higher.

The most common TRAEs that were grade 3 or higher in severity in the surufatinib (n = 129) and placebo (n = 68) arms, respectively, were hypertension (36% vs 13%) and proteinuria (19% vs 0%). Twenty-five percent of those in the investigative arm experienced serious TRAEs vs 13% of those in the control arm. Treatment-related deaths occurred in 3 patients in the investigative arm and 1 patient in the control arm.

The bridging study was designed to evaluate the safety and efficacy of surufatinib in patients in the United States.⁵ At the time of the 2021 ASCO Annual Meeting, the dose-escalation portion of the research was completed, and 300 mg was selected as the recommended phase 2 dose.

A total of 32 patients with heavily pretreated, progressive NETs were enrolled to the dose-expansion portion of the trial; half of these patients had extra-pancreatic NETs, and the remainder had pancreatic NETs.

The primary end point of the trial was investigator-assessed PFS rate at 11 months. Patients were heavily pretreated, with 65.6% having received 3 or more prior lines of therapy. The median number of lines of therapy received in the extra-pancreatic subset was 2 (range, 2-5) and it was 4 (range, 1-8) in the pancreatic subset.

At a June 30, 2020, data cutoff, the median PFS was 11.499 (95% CI, 6.472-17.478) in the overall population; in the extra-pancreatic and pancreatic subsets, the median PFS was 11.499 (95% CI, 6.472-11.499) and 15.179 (95% CI, 5.191–not reached). In these 3 populations, the 11-month PFS rates 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.

Surufatinib produced an ORR of 12.5% (95% CI, 3.5%-29.0%) in the overall population, 6.3% (95% CI, 0.2%-30.2%) in the extra-pancreatic subset, and 18.8% (95% CI, 4.0%-45.6%) in the pancreatic subset. The overall DCR achieved with the agent was 90.6% (95% CI, 75.0%-98.0%).

In April 2020, the FDA granted fast track designations to surufatinib for use in the treatment of patients with pancreatic NETs and extra-pancreatic NETs.⁶

References

1. HutchMed receives complete response letter from the US FDA for surufatinib for the treatment of advanced neuroendocrine tumors. News release. HutMed Limited. May 2, 2022. Accessed May 2, 2022. https://bit.ly/3LDnE0W
2. US FDA accepts filing of HutchMed’s NDA for surufatinib for the treatment of advanced neuroendocrine tumors. News release. July 1, 2021. Accessed May 2, 2022. https://bit.ly/3ycuQdd
3. 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
4. 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
5. 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
6. Chi-Med announces surufatinib granted US FDA fast track designations for the treatment of both pancreatic and non-pancreatic neuroendocrine tumors. News release. Hutchinson China MediTech Limited. April 17, 2020. Accessed May 2, 2022. https://bit.ly/3LAOHda