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Pancreatic neuroendocrine tumors are a rare subset of pancreatic cancers. Growth of these tumors is often indolent for several years, and patients might suffer life-threatening symptoms from tumor–hormone secretion. Some patients benefit from treatment with somatostatin analogues, which can lead to disease stabilization and reduction in hormone production. Streptozotocin-based chemotherapy is toxic and has limited therapeutic benefit, and patients with refractory disease have limited therapeutic options. Overexpression of growth-factor receptors of the vascular endothelial growth factor (VEGF), c-kit (stem-cell factor receptor), and platelet-derived growth factor (PDGF) receptor in these cancers — as well as activation of mammalian target of rapamycin (mTOR) signaling in pancreatic neuroendocrine tumorigenesis — provide a rationale to study agents that target these pathways.
Investigators now report the results of two industry-sponsored, multinational, double-blinded, randomized, placebo-controlled, phase III trials of two novel tyrosine kinase inhibitors: (1) sunitinib, which targets the VEGF, c-kit, and PDGF receptors, and (2) everolimus, which targets mTOR. Both studies required that patients experience tumor progression within 12 months of study entry and allowed crossover from placebo to active treatment at disease progression. The primary endpoint for both studies was progression-free survival (PFS).
The sunitinib trial was closed after 154 patients underwent an early interim analysis; the everolimus trial accrued all planned 410 patients. In the sunitinib trial, among patients who received sunitinib (37.5 mg daily) or placebo, 100% and 99%, respectively, had performance status of 0 or 1; 49% and 52% had nonfunctioning tumors; 19% and 17% had a Ki-67 index ≤2%; 95% and 94% had metastatic disease; and 66% and 72% had received prior chemotherapy. In the everolimus trial, among patients who received everolimus (10 mg daily) or placebo, 97% and 98%, respectively, had performance status of 0 or 1; 92% of both groups had liver metastases, and 50% of both groups had received prior chemotherapy.
Results were as follows:
Median PFS was longer for patients treated with sunitinib than with placebo (11.4 vs. 5.5 months; hazard ratio, 0.42; P<0.001) and for those treated with everolimus than with placebo (11.0 vs. 4.6 months; HR, 0.35; P<0.001).
Antitumor response was greater for patients treated with sunitinib than with placebo (9.3% vs. 0%) and in patients treated with everolimus than with placebo (5.0% vs. 2.0%).
Risk for death was lower for patients treated with sunitinib than with placebo (HR, 0.41; P=0.02); however, risk for death was similar for patients treated with everolimus or placebo (HR 1.05; P=0.59).
Crossover from placebo to active treatment was similar in the sunitinib and everolimus trials (69% and 73%).
Duration of therapy was longer in patients treated with everolimus than with sunitinib (8.8 vs. 4.6 months).
Common adverse events associated with sunitinib were diarrhea, nausea, asthenia, vomiting, and fatigue; grade 3 or 4 events included neutropenia and hypertension; one drug-related death from cardiac failure occurred.
Common adverse events associated with everolimus included stomatitis, rash, diarrhea, fatigue, and infection; grade 3 or 4 adverse events included anemia, hyperglycemia, stomatitis, thrombocytopenia, and diarrhea; one drug-related death from pneumonitis-related respiratory failure occurred.
In the sunitinib trial, quality of life was similar in treatment and placebo groups.
Raymond E et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011 Feb 10; 364:501.
Yao JC et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011 Feb 10; 364:514.
Jensen RT and Delle Fave G. Promising advances in the treatment of malignant pancreatic endocrine tumors. N Engl J Med 2011 Feb 10; 364:564.
Comment
These results indicate that sunitinib and everolimus are active new agents in the treatment of patients with refractory pancreatic neuroendocrine tumors. This observation reinforces the importance of the growth-factor pathways targeted by these agents. Both agents achieved similar benefits in PFS and response, and toxicities were manageable. The survival differences in the two trials are difficult to reconcile, given that both trials allowed patients access to the study drugs at disease progression and both had similar rates of crossover. The everolimus trial was larger and higher powered and might indicate a more realistic effect of the agent on survival. Further study of these agents and other novel therapies targeting these pathways are indicated.