Surufatinib in Advanced Well-Differentiated Neuroendocrine Tumors: A Multicenter, Single-Arm, Open-Label, Phase Ib/II Trial

Abstract

Purpose: No antiangiogenic treatment is yet approved for extrapancreatic neuroendocrine tumors (NET). Surufatinib (HMPL-012, previously named sulfatinib) is a small-molecule inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptor 1 and colony-stimulating factor 1 receptor. We conducted a single-arm phase Ib/II study of surufatinib in advanced NETs.Patients and Methods: Patients with histologically welldifferentiated, low or intermittent grade, inoperable or metastatic NETs were enrolled into a pancreatic or extrapancreatic NET cohort. Patients were treated with surufatinib 300 mg orally, once daily. The primary endpoints were safety and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (version 1.1).Results: Of the 81 patients enrolled, 42 had pancreatic NETs and 39 had extrapancreatic NETs. Most patients had radiologic progression within 1 year prior to enrollment (32 patients in each cohort). In the pancreatic and extrapancreatic NET cohorts, ORRs were 19% [95% confidence intervals (CI), 9-34] and 15% (95% CI, 6-31), disease control rates were 91% (95% CI, 77-97) and 92% (95% CI, 79-98), and median progression-free survival was 21.2 months (95% CI, 15.9-24.8) and 13.4 months (95% CI, 7.6-19.3), respectively. The most common grade !3 treatment-related adverse events were hypertension (33%), proteinuria (12%), hyperuricemia (10%), hypertriglyceridemia, and diarrhea (6% for each), and increased alanine aminotransferase (5%).Conclusions: Surufatinib showed encouraging antitumor activity and manageable toxicities in patients with advanced NETs. Two ongoing phase III studies, validating the efficacy of surufatinib in patients with NETs, will contribute to the clinical evidence.

Systemic Treatment Selection for Patients with Advanced Pancreatic Neuroendocrine Tumours (PanNETs)

“…For many years targeted therapies achieved low RRs. However, lenvatinib has achieved a higher RR in patients with PanNETs, but the mechanism is still not clear [73]. Similarly, phase IV data from the use of sunitinib in PanNETs have also reported higher RRs than previous studies (9.3% in phase III study vs 24.5% in phase IV study) [27,68].…”

“…The median PFS for patients with PanNETs ranged from 11.7 months for pazopanib [18] to 21.8 months for cabozantinib [71]. Among the expected moderate responses (between 15-19%) [18,71,73], there was a promising 42.3% response rate reported with lenvatinib [72]. With lenvatinib, the responding patients had a significantly better PFS compared to non-responders, a finding that is even more evident for the PanNET subgroup (median PFS in responders vs. non-responders: not reached (NR) vs. 11.2 months in PanNETs (p = 0.004).…”

“…Other antiangiogenic molecules have been tested in patients with PanNETs over the last 10 years in several phase II trials, such as pazopanib (targeting VEGFR, PDGFR, c-KIT, and fibroblast growth factor receptors (FGFR)); cabozantinib (targeting hepatocyte growth factor receptor protein (MET), VEGFR, RET, GAS6 receptor (AXL), KIT, Fms-like tyrosine kinase-3 (FLT3)); lenvatinib (targeting VEGFR, FGFR, PDGFR alpha, c-Kit, and the RET proto-oncogene); and surufatinib (targeting VEGFRs, FGFR, colony-stimulating factor 1 receptor) [ 18 , 70 , 71 , 72 , 73 ]. In all of these studies, mixed populations of patients with GEP-NETs were recruited, with limited numbers of patients with PanNETs (20–55).…”

“…PRRT: Peptide receptor radionuclide therapy; SSA: somatostatin analogue. a—PROMID trial—Octreotide arm [ 20 , 21 ]; b—CLARINET trial—Lanreotide arm [ 19 , 60 ]; c—Phase II study, Yao et al, 2008—Everolimus arm [ 102 ]; d—RADIANT-1—Everolimus arm [ 22 ]; e—RADIANT-3—Everolimus arm [ 24 , 103 ]; f—SUN111—Sunitinib arm [ 26 , 27 ]; g—Retrospective, Rinzivillo et al, 2018—Sunitinib arm [ 65 ]; h—Phase II study NCT01466036—Cabozantinib arm [ 71 ]; i—Phase I/II study NCT02267967—Surufatinib arm [ 73 ]; j—TALENT trial—Lenvatinib arm [ 72 ]; k—Phase II study, Phan et al, 2010—Pazopanib arm [ 18 ]; l—PAZONET—Pazopanib arm [ 70 ]; m—Phase II study NCT01024387—Ganitumab (AMG 479) arm [ 77 ]; n—PALBONET—Palbociclib arm [ 74 ]; o—Phase II study, Salazar et al, 2018—BEZ235 arm [ 63 ]; p—SUNEVO (GETNE 1408)—Efosfamide/Sunitinib arm [ 104 ]; q—Phase II study, Bendell et al, 2016—Bevacizumab/Pertuzumab/Octreotide arm [ 105 ]; r—COOPERATE-2 trial—Everolimus/Pasireotide LAR arm [ 62 ]; t—NETTER-1 trial—177Lu-Dotatate arm [ 36 , 106 ]; u—Retrospective, T.Brabader et al, 2017—177Lu-Dotatate arm [ 37 ]; v—Prospective observational study, Garske-Román, U et al, 2018—177Lu-Dotatate arm [ 38 , 43 ]; w—Phase II study, Sansovini et al, 2017—177Lu-Dotatate arm [ 39 , 43 ]; x—Prospective trial, Bertani et al, 2016—90Y-DOTATOC/177Lu-DOTATOC arm [ 41 , 43 ]; y—Phase II study, Rogowski et al, 2016—90Y-DOTATOC arm [ 43 , 44 ]; z—Retrospective, Horsch et al, 2016—90Y-DOTATOC/177Lu-DOTATOC arm [ 43 , 47 ]; aa—Retrospective, Baum et al, 2018—90Y-DOTATOC/177Lu-DOTATOC arm [ 43 , 46 ...…”

Medical Treatment of Advanced Pancreatic Neuroendocrine Neoplasms

“…Surufatinib is a TKI targeting VEGFR, fibroblast growth factor receptor (FGFR) 1 and CSF1R, recently evaluated in a single-arm phase Ib/II study. Surufatinib resulted in an ORR of 19%, a DCR of 91% and a mPFS of 21.2 months for patients with panNETs [ 41 ].…”