Pazopanib Offers Another Option for Pancreatic NETs

Veronica Hackethal, MD

May 15, 2015

Pazopanib (Votrient) could provide a new treatment option for patients with advanced pancreatic neuroendocrine tumors (NETs), according to a phase 2 study published online May 6 in the Lancet Oncology.

Pazopanib is a kinase inhibitor that acts on VEGF receptors. It has already been approved for the treatment of advanced renal cell carcinoma and soft tissue sarcoma.

"Our results suggest that pazopanib has antitumor activity in pancreatic NETs. The objective responses and progression-free survival in our cohort with pancreatic NETs are similar to results seen in the phase 3 studies of other effective drugs for this disease," write Alexandria Phan, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues.

Few treatment options exist for patients with advanced-stage NETs, which include pancreatic NETs and carcinoid tumors, they note. Because patients often present with metastatic disease at diagnosis, treatment usually focuses on relieving symptoms and slowing tumor growth rather than aiming for a cure.

Approved drugs for pancreatic NETs include somatostatin analogues like octreotide and lanreotide, which control the oversecretion of hormones and possibly slow tumor growth, the mTOR inhibitor everolimus (Afinitor), and the kinase inhibitor sunitinib (Sutent).

Only one drug — lanreotide (Somatuline) — has been granted approval for advanced carcinoid tumors.

Study Details

The parallel-cohort study was conducted at the M.D. Anderson Cancer Center and the Dana-Farber Cancer Institute in Boston from April 2007 to July 2009. It involved patients with metastatic or locally advanced grade 1/2 carcinoid tumors (n = 20) or pancreatic NETs (n = 32).

All patients received pazopanib 800 mg orally once daily, plus octreotide. Octreotide-naïve patients received 30 mg every 28 days. Patients previously treated with octreotide received up to 40 mg every 3 weeks. Patients continued treatment until disease progression or the completion of 12 treatment cycles.

Seven patients with pancreatic NETs responded to pazopanib (objective response rate [ORR], 21.9%; 95% confidence interval [CI], 11.0 - 38.8). Because no patients with carcinoid tumors responded to pazopanib, the researchers closed enrolment in this group.

Six (29%) of 21 patients with pancreatic NETs and progressive disease achieved an objective response (ORR, 28.6%; 95% CI, 11.3 - 52.2).

In the group with pancreatic NETs, median progression-free survival was 14.4 months (95% CI, 5.9 - 22.9) and median overall survival was 25.0 months (95% CI, 15.5 - 34.4). In the group with carcinoid tumors, median progression-free survival was 12.2 months (95% CI, 5.3 - 19.0) and median overall survival was 18.5 months (95% CI, 15.0 - 22.0).

Pazopanib seemed to be well tolerated. The most common adverse effects included fatigue (75%), nausea (63%), diarrhea (63%), and hypertension (54%). One patient developed grade 4 hypertriglyceridemia, and one patient developed grade 4 thrombosis.

More studies looking at pazopanib in NETs are needed, according to Dr Phan and colleagues. Currently, a phase 2 randomized study is comparing pazopanib with placebo in patients with progressive NETs. In addition, a phase 3 randomized controlled trial is being planned that will compare pazopanib with best supportive care in patients with advanced-stage pancreatic NETs who have failed treatment with other drugs.

Could Be "True Addition"

This study "is likely to add another drug to the range of approved drugs for the treatment of NETs," writes Dik Kwekkeboom, MD, PhD, from Erasmus Medical Center in Rotterdam, the Netherlands, in an accompanying comment.

Dr Kwekkeboom points out that the median progression-free survival in patients with pancreatic NETs who received pazopanib was similar to that reported in studies of everolimus and sunitinib. In studies of pazopanib in renal cell carcinoma, he adds, the drug was effective even in patients with progressive disease who had received other VEGF inhibitors.

"If this finding is also true for patients with pancreatic NETs, this drug could be a true addition to the range of effective drugs available for these patients," Dr Kwekkeboom writes.

Other drugs and interventions seem to be effective but have not been granted formal approval, such as chemoembolization, radioembolization, bland embolization, and peptide-receptor radionuclide therapy with somatostatin analogues.

This study raises many questions about the use of pazopanib and these other therapies, Dr Kwekkeboom writes. What is best: combination or sequential therapy? Combination therapy could increase efficacy, but at the expense of quality of life, he explained. And sequential therapy leads to more questions, such as which treatment to use first: the most effective one or the one with fewest adverse effects?

Although "this new study of treatment with pazopanib shows encouraging outcomes in a subgroup of NET patients, it also presents future challenges for selection of treatment choices," Dr Kwekkeboom concludes.

The study was funded by the United States National Cancer Institute and the National Institutes of Health. Some of the authors report grants, consulting fees, stock holdings, and/or consulting fees from one or more of the following: National Cancer Institute, Novartis, Sanofi, Ipsen, Merck, and GE Healthcare. Dr Kwekkeboom has disclosed no relevant financial relationships.

Lancet Oncol. Published online May 6, 2015. Abstract, Comment

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