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Study Shows Benefit With Pazopanib in Treatment of Carcinoid Tumors


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Pazopanib significantly improved progression-free survival by 47% in patients with progressive carcinoid tumors, in a prospective randomized phase II trial presented at the 2019 ASCO Annual Meeting.1 “With these results, Alliance A021202 becomes the first randomized study to show that the vascular endothelial growth factor (VEGF) pathway may be a valid therapeutic target in carcinoid tumors,” said Emily K. Bergsland, MD, of the University of California, San Francisco.


Alliance A021202 becomes the first randomized study to show that the VEGF pathway may be a valid therapeutic target in carcinoid tumors.
— Emily K. Bergsland, MD

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“For advanced carcinoid tumors, therapies approved by the U.S. Food and Drug Administration (FDA) include lanreotide, everolimus, and lutetium Lu-177 dotatate. Eventual resistance, however, is the rule, and additional therapeutic options are needed,” she said.

The VEGF pathway appears to be a rational target in neuroendocrine tumors, since VEGF and its receptors are well expressed in gastrointestinal and pancreatic neuroendocrine tumors, she explained. Sunitinib is actually FDA-approved in pancreatic neuroendocrine tumors, and in phase II pilot studies, small molecule tyrosine kinase inhibitors have shown activity in carcinoid tumors.

Alliance A021202 Details

The study enrolled 171 patients with locally advanced or metastatic low- or intermediate-grade carcinoid tumors arising in the foregut, midgut, hindgut, or other nonpancreatic site; they all showed radiologic evidence of progressive disease within 12 months. Patients had no prior treatment with sunitinib or another VEGF inhibitor, though prior treatment with a somatostatin analog and everolimus was acceptable.

Pazopanib in Carcinoid Tumors

  • The phase II Alliance A021202 trial is the first randomized trial to show the VEGF pathway to be a valid therapeutic target for carcinoid tumors.
  • In patients with a progressive carcinoid, treatment with pazopanib significantly prolonged progression-free survival by 47%, improving from 8.5 months with placebo to 11.5 months (P = .0005).
  • Patients experienced significantly more grade ≥ 3 toxicity with pazopanib.

The median progression-free survival by central review was 11.6 months for patients receiving the VEGF inhibitor, vs 8.5 months for those receiving placebo (hazard ratio [HR] = 0.53; P = .0005), and similar results were shown by investigator review. Overall survival did not significantly differ, however, with median survival times of 41.3 months with pazopanib and 42.4 months with placebo. This finding was not unexpected, as approximately two-thirds of placebo-treated patients crossed over to receive pazopanib upon disease progression, she noted.

Although just two patients responded, both in the pazopanib arm, many fewer experienced disease progression with pazopanib (4%) than with placebo (19%; P = .0010). Some degree of tumor shrinkage was observed in 55% and 31%, respectively. Significantly more patients discontinued treatment due to disease progression on placebo, 68% vs 38% (P = .0001).

Toxicity Increased With Pazopanib

The potential benefits of pazopanib should be viewed in light of its increased risk for toxicity, Dr. Bergsland acknowledged. The rate of grade ≥ 3 toxicities deemed to be related to treatment was 61% for pazopanib and 21% for placebo. Notably, hypertension grade ≥ 3 was observed in 27% and 4%, respectively, although just one pazopanib-treated patient experienced grade 4 hypertension.Although pazopanib was also associated with more symptoms such as diarrhea, appetite loss, and fatigue, overall quality of life was similar between the treatment arms.

“Additional work is needed to identify strategies for mitigating toxicity and for selecting patients most likely to benefit from pazopanib,” Dr. Bergsland said. These predictive biomarker analyses include angiome profiling, tumor growth rate, and textural image analysis. 

DISCLOSURE: Dr. Bergsland owns stock in MORE Health, has received honoraria and royalites from UpToDate, and has served in an (unpaid) advisory role for Advanced Accelerator Applications, Hutchison MediPharma, and Crinetics Pharmaceuticals. In addition, she has received institutional research funding from Merck and Novartis.

REFERENCE

1. Bergsland EK, Mahoney MR, Asmis TR, et al: Prospective randomized phase II trial of pazopanib versus placebo in patients with progressive carcinoid tumors (Alliance A021202). 2019 ASCO Annual Meeting. Abstract 4005. Presented June 2, 2019.


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