Progression-free survival [with cabozantinib] appears very encouraging, in the context of historical results [in neuroendocrine and carcinoid tumors].— Jennifer A. Chan, MD
In a phase II study reported at the 2017 Gastrointestinal Cancers Symposium, the tyrosine kinase inhibitor cabozantinib (Cometriq) was evaluated in advanced carcinoid and pancreatic neuroendocrine tumors. Radiographic responses to therapy were observed in both tumor subtypes, and compared to other drugs historically used in this setting, progression-free survival data were encouraging,1 according to Jennifer A. Chan, MD, of Dana-Farber Cancer Institute, Boston.
Vascular endothelial growth factor (VEGF) pathway inhibitors have shown activity in advanced neuroendocrine tumors. Recent studies have suggested that activation of the MET signaling pathway may also play a role in the growth of neuroendocrine tumors. Increased expression of MET correlates with decreased overall survival in pancreatic neuroendocrine tumors, Dr. Chan noted.
Cabozantinib targets VEGF receptors, MET, AXL, and RET. It has been shown to improve outcomes in advanced renal cell carcinoma patients in both the first-line and second-line settings and is also approved for progressive, metastatic medullary thyroid cancer. In preclinical neuroendocrine tumor models, cabozantinib inhibits cell viability and decreases metastases and invasion.
The study included 41 carcinoid patients (70% with disease in the small intestine) and 20 pancreatic neuroendocrine tumor patients with well-differentiated, grade 1 or 2 disease that was unresectable or metastatic. Eligible patients could have received any prior therapy, including other anti-VEGF agents, except cabozantinib. Concurrent somatostatin analog use was allowed. Patients were treated with cabozantinib starting at a dose of 60 mg/d until disease progression, unacceptable toxicity, or withdrawal from the study.
At a median follow-up time of 23.3 months, approximately 25% of patients remained on the study. The median number of cycles was 9, and 82% of patients completed at least 2 cycles, but 81% completing at least 1 cycle required dose reduction. Nevertheless, cabozantinib was considered well tolerated, with toxicity data consistent with data in other disease settings, Dr. Chan reported.
Outcomes After Single-Agent Cabozantinib
In the pancreatic neuroendocrine tumor cohort, objective responses by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1—the primary endpoint—were observed in 15% of patients, and stable disease was shown in 75%. Similarly, 15% of patients in the carcinoid population responded, and 63% had stable disease. Several responses were also observed in patients with prior treatment with everolimus (Afinitor), Dr. Chan reported.
Median progression-free survival was 21.8 months (95% confidence interval [CI] = 8.5–32.0) in the pancreatic neuroendocrine tumor group and 31.4 months (95% CI = 8.5 to not reached) in the carcinoid group. “Progression-free survival appears very encouraging, in the context of historical results. Other drugs (sunitinib [Sutent], pazopanib [Votrient], everolimus, bevacizumab [Avastin]) have yielded median progression-free survival times of 8 to 16 months,” Dr. Chan noted.
“Confirmation of cabozantinib activity in a randomized phase III trial is expected,” she said. ■
Disclosure: Dr. Chan has stock or other ownership interests in Merck; has a consulting or advisory role with Ipsen, Novartis, and Lexicon; and has received research funding from Novartis, Sanofi, and Lilly.
1. Chan JA, Faris JE, Murphy JE, et al: Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors. 2017 Gastrointestinal Cancers Symposium. Abstract 228. Presented January 20, 2017.
Cabozantinib is a very interesting drug in pancreatic [neuroendocrine tumors]—very well tolerated, and these study results are quite intriguing. But I am still uncertain how cabozantinib will impact progression-free and overall survival in this tumor.!-->!-->— Vincent J. Picozzi, ...