Randomized Phase II Trial of Pazopanib Versus Placebo in Patients With Advanced Extrapancreatic Neuroendocrine Tumors (Alliance A021202)

Abstract

Purpose: Patients with advanced, well-differentiated extrapancreatic neuroendocrine tumors (epNETs) have limited systemic treatment options. Pazopanib, an oral multikinase inhibitor with activity against vascular endothelial growth factor receptor (VEGFR)-2 and -3, PDGFR-alpha and-beta, and c-Kit, was tested for efficacy in epNET.

Patients and methods: We conducted a multicenter, randomized, double-blind, phase II study of pazopanib (800 mg once daily) versus placebo in low- to intermediate-grade epNET with radiologic progressive disease (PD) within 12 months of study entry. Previous somatostatin analog (SSA) was required for midgut tumors, and concurrent SSA was allowed. The primary end point was progression-free survival (PFS) by blinded independent central review. Unblinding and crossover were allowed if PD was confirmed by central review.

Results: One hundred seventy-one patients (97 pazopanib and 74 placebo) were randomly assigned between September 2013 and October 2015. The majority had a midgut primary site (75%) and previous SSA treatment (93%). About half (49%) of the patients had functional tumors. The median follow-up was 61 months (95% CI, 60 to 63). Median PFS was 11.8 versus 7.6 months in pazopanib versus placebo, respectively (hazard ratio, 0.54 [95% CI, 0.37 to 0.79]; P < .001); 49 placebo patients crossed over to pazopanib. There was no significant difference in overall survival between the treatment arms. Rates of grade 3 or greater adverse events (regardless of attribution) were higher in pazopanib versus placebo (84% v 47%; P < .001), as were grade 5 death events (8% v 0%, P = .017).

Conclusion: Pazopanib compared with placebo significantly improves PFS in patients with progressive epNET, confirming that the VEGF signaling pathway is a valid target for therapy in epNET. However, after integrating the associated risks relative to the benefits, further development of pazopanib in this clinical context is not planned.

Trial registration: ClinicalTrials.gov NCT01841736.

Figure 1:

CONSORT diagram Abbreviations: ITT, intent-to-treat; PD, progressive disease; AE, adverse event

Figure 2A:

Progression-free survival (PFS) by central review from time of randomization by treatment arm

Figure 2B:

Progression-free survival (PFS) by local site review from time of randomization by treatment arm

Figure 2C:

Forest plot for univariate models of key factors and subgroups of interest in relation to PFS by central review from time of randomization

Figure 3:

Quality of life and patient-reported symptom mean trajectories by arm. All estimates and standard errors are based on a repeated measures mixed model for each scale, and are model-estimated means by arm. LASA: Linear Analog Scale Assessment, EORTC QLQ-C30: European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire, EORTC QLQ-GINET21: European Organization for Research and Treatment of Cancer Gastrointestinal Neuroendocrine Tumor module. Several component scores are presented: (A) LASA Overall Quality of Life (higher is better), (B) EORTC QLQ-C30: Fatigue (lower is better), (C) EORTC QLQ-C30: Nausea and Vomiting (lower is better), (D) EORTC QLQ-C30: Diarrhea (lower is better), (E) EORTC QLQ-C30: Constipation (lower is better), (F) EORTC QLQ-C30: Pain (lower is better).