Background
Phase III randomized, double-blind, placebo-controlled trial in 171 patients (planned 340; halted early) with advanced, well-differentiated pancreatic neuroendocrine tumors (PNET) and documented progression within prior 12 months. Concurrent somatostatin analogue permitted in both arms. Conducted because antiangiogenic/antiproliferative targeting of VEGFR and PDGFR was a rational strategy in this highly vascular tumor.
Interventions and follow up
Arm A: Sunitinib 37.5 mg orally once daily, continuous
Arm B: Placebo
Primary endpoint: Progression-free survival (PFS)
Follow-up: Trial discontinued early on recommendation of independent data monitoring committee
Arm B: Placebo
Primary endpoint: Progression-free survival (PFS)
Follow-up: Trial discontinued early on recommendation of independent data monitoring committee
Results
Median PFS: 11.4 mo vs 5.5 mo, sunitinib vs placebo (HR 0.42, 95% CI 0.26-0.66, P<.001)
Objective response rate: 9.3% with sunitinib vs 0% with placebo
Overall survival (interim): favored sunitinib (HR 0.41, 95% CI 0.19-0.89, P=.02); deaths 9 vs 21
Median treatment exposure: 4.6 mo vs 3.7 mo, sunitinib vs placebo
Objective response rate: 9.3% with sunitinib vs 0% with placebo
Overall survival (interim): favored sunitinib (HR 0.41, 95% CI 0.19-0.89, P=.02); deaths 9 vs 21
Median treatment exposure: 4.6 mo vs 3.7 mo, sunitinib vs placebo
Adverse events
Hematologic: Grade 3-4 neutropenia 12%, thrombocytopenia 6%
Vascular: Grade 3-4 hypertension 7%
GI/constitutional: Diarrhea (most common any-grade AE), asthenia/fatigue, palmar-plantar erythrodysesthesia
Dose modification: Reduction to 25 mg/day in 31%, escalation to 50 mg/day in 10%
Vascular: Grade 3-4 hypertension 7%
GI/constitutional: Diarrhea (most common any-grade AE), asthenia/fatigue, palmar-plantar erythrodysesthesia
Dose modification: Reduction to 25 mg/day in 31%, escalation to 50 mg/day in 10%
Conclusions
Continuous daily sunitinib significantly improved PFS versus placebo in advanced, progressing well-differentiated pancreatic neuroendocrine tumors, establishing it as a treatment option in this disease.
Key Limitations
Trial halted early before target accrual (171 of planned 340), which can overestimate effect size; OS data immature with crossover of placebo patients to open-label sunitinib confounding survival interpretation. Restricted to pancreatic NET, not applicable to non-pancreatic (carcinoid) tumors.
Clinical Context
FDA approved sunitinib for progressive, well-differentiated pancreatic NET in 2011; EMA approval same year. ESMO guidelines list sunitinib among targeted options (alongside everolimus) for advanced progressive PNET. Choice between sunitinib, everolimus, PRRT, and chemotherapy is individualized by tumor grade, burden, and somatostatin-receptor status.