Highlight
– Pazopanib significantly improved progression-free survival (PFS) compared to placebo in advanced extrapancreatic neuroendocrine tumors (epNETs).
– The majority of patients had midgut primary tumors and prior somatostatin analog (SSA) treatment.
– Despite PFS benefit, pazopanib was associated with higher rates of severe adverse events including grade 5 deaths.
– No significant overall survival benefit was observed, leading to the decision not to pursue further development of pazopanib in this indication.
Study Background and Disease Burden
Extrapancreatic neuroendocrine tumors (epNETs) comprise a heterogeneous group of well-differentiated neuroendocrine neoplasms originating outside the pancreas, commonly from the midgut. These tumors often exhibit indolent but progressive behavior and limited systemic treatment options following somatostatin analog therapy. Targeting angiogenesis pathways, such as vascular endothelial growth factor (VEGF) signaling, has emerged as a promising strategy given the angiogenic nature of these tumors. Pazopanib, an oral multikinase inhibitor targeting VEGFR-2 and -3, PDGFR-alpha/beta, and c-Kit, has shown efficacy in other solid tumors but data in epNET were limited prior to this trial. The clinical need to improve outcomes in progressive epNET patients underpinned the Alliance A021202 randomized phase II trial.
Study Design
This multicenter, randomized, double-blind, placebo-controlled phase II trial enrolled 171 patients with advanced, low- to intermediate-grade epNET who demonstrated radiologic disease progression within the preceding 12 months. Patients with midgut tumors were required to have previously received somatostatin analog therapy, and continuation of SSA during the study was permitted. Participants were randomized to receive pazopanib 800 mg once daily or matching placebo. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. Secondary endpoints included overall survival (OS) and safety. Patients on placebo with confirmed disease progression were allowed to cross over to pazopanib. The long median follow-up of 61 months enabled durable outcome assessment.
Key Findings
Among the randomized patients, 97 received pazopanib and 74 placebo. Most had midgut primary tumors (75%) and prior somatostatin analog treatment (93%), with approximately half (49%) presenting with functional tumors producing hormones.
The trial demonstrated a statistically significant improvement in median PFS with pazopanib compared to placebo: 11.8 months versus 7.6 months respectively (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.37–0.79; P < .001). This represents a 46% reduction in the risk of progression or death. Notably, 49 patients randomized to placebo crossed over to receive pazopanib upon confirmed progression.
However, despite the PFS benefit, no statistically significant difference in overall survival was observed between treatment arms. This may be attributable to crossover effects and subsequent therapies.
Safety analysis revealed substantially higher rates of grade 3 or greater adverse events in the pazopanib arm (84%) compared to placebo (47%), with statistical significance (P < .001). Moreover, grade 5 (treatment-emergent death) events occurred in 8% of pazopanib-treated patients versus none in the placebo group (P = .017). The safety profile included typical pazopanib-associated toxicities such as hypertension, elevated liver enzymes, and fatigue, contributing to the unfavorable risk-benefit balance.
Expert Commentary
The Alliance A021202 trial solidifies the VEGF signaling axis as a valid therapeutic target in advanced epNET, aligning with prior evidence supporting antiangiogenic strategies. Nonetheless, the elevated toxicity observed with pazopanib, including fatal events, raises significant clinical concerns. This safety profile contrasts with other multi-kinase inhibitors with more tolerable toxicity spectra in neuroendocrine tumors, emphasizing the importance of agent selection.
The absence of overall survival benefit, likely confounded by crossover, challenges the clinical impact assessment. Furthermore, the study population primarily included midgut tumors with prior SSA therapy, potentially limiting generalizability to other epNET subsets.
Future research should focus on more targeted and safer angiogenesis inhibitors or combinations, coupled with biomarkers identifying patients most likely to benefit. Alternative approaches such as receptor radionuclide therapy or novel targeted agents remain areas of active investigation.
Conclusion
The randomized phase II Alliance A021202 trial demonstrated that pazopanib significantly prolongs progression-free survival compared to placebo in patients with progressive advanced extrapancreatic neuroendocrine tumors, confirming the therapeutic relevance of VEGF pathway inhibition in this clinical context. However, the increased incidence of severe adverse events, including grade 5 deaths, coupled with the lack of overall survival improvement, led to the decision against further development of pazopanib for epNET treatment. Clinicians should weigh the modest efficacy gains against substantial risks and consider alternative treatment strategies. This trial underscores the ongoing challenge of balancing efficacy and safety in systemic therapies for epNET and highlights the need for novel, better-tolerated agents.
References
1. Bergsland EK, Geyer S, Asmis TR, et al. Randomized Phase II Trial of Pazopanib Versus Placebo in Patients With Advanced Extrapancreatic Neuroendocrine Tumors (Alliance A021202). J Clin Oncol. 2025 Sep 3:JCO2402644. doi:10.1200/JCO-24-02644. Epub ahead of print. PMID: 40902132.
2. Kulke MH, Siu LL, Tepper J, et al. Future directions in the treatment of neuroendocrine tumors. NET Cancer. Nat Rev Clin Oncol. 2020;17(6):357-371.
3. Pavel M, Öberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines. Ann Oncol. 2020;31(7):844-860.
4. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced neuroendocrine tumors. N Engl J Med. 2011;364(6):514-523.
