Significant PFS Benefit Observed With Surufatinib in Pancreatic NETs

A statistically significant and clinically meaningful improvement in progression-free survival (PFS) was observed with the use of surufatinib compared with placebo in patients with advanced pancreatic neuroendocrine tumors (pNETs), meeting the primary end point of the randomized phase 3 SANET-p study.¹

The median investigator-assessed PFS was 10.9 months (95% CI, 7.5-13.8) with the novel VEGFR, FGFR, and CSF-1R inhibitor versus 3.7 months (95% CI, 2.8-5.6) with placebo, (stratified HR, 0.491; 95% CI, 0.319-0.755; P = .0011), according to results presented during the 2020 European Society of Medical Oncology Virtual Congress.

Based on the efficacy of surufatinib in this preplanned interim analysis, the SANET-p trial was terminated early per recommendation of the independent data safety monitoring committee.

Moreover, the PFS benefit favored surufatinib across all major subgroups, including NET pathological grade, previous systemic treatment, ECOG performance status, age, gender, number of organs involved by tumor, prior treatment with somatostatin analogues (SSAs), prior systemic chemotherapy, time from disease diagnosis to randomization, and baseline chromogranin A.

A supportive analysis confirmed that the PFS benefit by blinded independent image review committee (BIIRC) was consistent with the investigator-assessed PFS. By BIIRC, the median PFS was 13.9 months with surufatinib (95% CI, 11.0-24.9) versus 4.6 months with placebo (95% CI, 3.6-7.4; stratified HR, 0.339; 95% CI, 0.209-0.549; P <.0001).

“Results from SANET-p support surufatinib as an effective addition to the clinical armamentarium for treating [well-differentiated] pNETs,” said lead study author Jianming Xi, MD, a clinician at the Academy of Military Medical Sciences in Beijing, China, in a virtual presentation of the data.

Surufatinib is a small-molecule kinase inhibitor that simultaneously targets angiogenesis and modulates the tumor microenvironment. Phase 1 data demonstrated that surufatinib elicited an objective response rate (ORR) of 19% among patients with advanced pNETs (95% CI, 9%-34%).² Moreover, findings from the phase 3 SANET-ep trial showed a significant improvement in PFS with surufatinib versus placebo in patients with NETs originating outside of the pancreas.³

Patients enrolled in the SANET-p trial were randomized 2:1 to receive 300 mg of surufatinib once daily or placebo. Upon progressive disease, patients on placebo could cross over to receive surufatinib.

An interim analysis of the trial was planned when 70% of the planned PFS events for final analysis were observed (n = 92 events). Additionally, the study was subject to early termination for superiority if the P value was less than .015.

Eligible patients had to have well-differentiated, pathological grade 1 or 2 pNETs and locally advanced disease, or disease with distant metastasis. Additionally, patients had to have documented radiological disease progression within the past year, progression on 2 or fewer types of systemic therapy for advanced disease, and no prior progression on VEGF/VEGFR inhibitors. Patients with functional NETs that required treatment with long-acting SSAs were excluded from the study.

Overall, 172 patients were randomized. In the surufatinib arm (n = 113), 57.5% of patients discontinued treatment compared with 69.5% in the placebo arm (n = 59). Of the patients on placebo who discontinued treatment, 52.5% received open-label treatment with surufatinib.

Additionally, 100% of patients in both arms were included in the intent-to-treat (ITT) safety analysis. Ninety-two percent of patients on surufatinib and 89.8% of patients on placebo were included in the interim ITT (iTT) analysis; 9 and 6 patients were excluded from the ITT set, respectively.

Baseline patient characteristics were similar between arms. Over 80% of patients had pathological grade 2 tumors, over 90% had nonfunctional tumors, and over 90% had liver metastasis. Additionally, over 60% of patients had previous systemic antitumor treatment for advanced disease, including chemotherapy, SSAs, and everolimus (Afinitor).

Regarding secondary end points, the ORR was 19.2% with surufatinib (95% CI, 12.2%-28.1%) versus 1.9% with placebo (95% CI, 0.0%-10.1%; P = .0021). The rates of disease control were 80.8% (95% CI, 71.9%-87.8%) and 66.0% (95% CI, 51.7%-78.5%), respectively (P = .0774).

With surufatinib, the time-to-response was 3.8 months (95% CI, 2.3-7.3) compared with 7.4 months with placebo. Additionally, the median duration of response with surufatinib was 7.4 months.

At the interim analysis, overall survival (OS) was immature, and 16.9% of OS events were observed.

Regarding safety, patients were exposed to surufatinib (n = 113) for a median of 229 days versus 123 days with placebo (n = 59). The mean dose intensity with surufatinib was 266.89 mg/day versus 292.88 mg/day with placebo. Moreover, the relative dose intensity was 88.96% and 97.63%, respectively.

Although most treatment-emergent adverse effects (TEAEs) were manageable with dose modification, surufatinib was associated with a higher rate of toxicity compared with placebo. Any-grade TEAEs were observed in 95.6% of patients receiving surufatinib versus 91.5% of patients receiving placebo.

Moreover, grade 3 or greater TEAEs occurred in 69.9% and 27.1% of patients, respectively. Serious adverse effects were observed in 25.7% and 8.5% of patients, respectively.

Of the patients receiving surufatinib, 45.1% required dose interruption, 38.9% required dose reduction, and 10.6% required dose discontinuation due to TEAEs. Of patients receiving placebo, these rates were 23.7%, 5.1%, and 6.8%, respectively.

The most common TEAEs observed with surufatinib were hypertension, proteinuria, diarrhea, increased blood thyroid stimulating hormone, hypertriglyceridemia, increased blood bilirubin, hypoalbuminemia, positive occult blood, increased aspartate aminotransferase, abdominal pain, and hyperuricemia. Grade 3 or greater TEAEs included hypertension (n = 44), proteinuria (n = 11), diarrhea (n = 5), hypertriglyceridemia (n = 8), increased blood bilirubin (n = 2), increased aspartate aminotransferase (n = 2), abdominal pain (n = 2), and hyperuricemia (n = 2).

Comparatively, grade 3 or greater TEAEs among patients who received placebo included hypertension (n = 5), proteinuria (n = 1), diarrhea (n = 1), and increased aspartate aminotransferase (n = 1).

Based on these findings, in April 2020, the FDA granted Fast Track Designations to surufatinib for the treatment of patients with advanced and progressive pNETs and extra-pNETs in patients who are not amendable for surgery.⁴

References:

_{1. Xu J, Shen L, Bai C, et al. #1712 Efficacy and safety of surufatinib in patients with well-differentiated advanced pancreatic neuroendocrine tumors (NETs): results from the randomized phase III study (SANET-p) (NCT02589821). Presented at: 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract: 1156O.}

_{2. Xu J, Li J, Bai C, et al. Surufatinib in advanced well-differentiated neuroendocrine tumors: a multicenter, single-arm, open-label, phase Ib/II trial. Clin Cancer Res. 2019;25(12):3486-3494. doi:10.1158/1078-0432.CCR-18-2994}

_{3. Xu J, Shen L, Zhou Z, et al. Efficacy and safety of surufatinib in patients with well-differentiated advanced extrapancreatic neuroendocrine tumors (NETs): results from the randomized phase III study (SANET-ep). Presented at: 2019 ESMO Congress; September 27-October 1, 2019. Abstract 4979.}

_{4. Chi-Med announces surufatinib granted U.S. FDA fast track designations for the treatment of both pancreatic and non-pancreatic neuroendocrine tumors. April 17, 2020. September 20, 2020. https://bit.ly/2VihBav.}