Cabozantinib, a Multitargeted TKI, Active in Advanced Neuroendocrine Tumors
San Francisco, CA—The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib (Cabometyx) demonstrated encouraging activity in patients with advanced neuroendocrine tumors (NETs), including patients who previously received sunitinib (Sutent) or everolimus (Afinitor), according to results from a phase 2 clinical trial, reported Jennifer A. Chan, MD, MPH, Clinical Director, Program in Carcinoid and Neuroendocrine Tumors, Dana-Farber Cancer Institute, Boston, MA, at the 2017 Gastrointestinal Cancers Symposium.
Patients with carcinoid or pancreatic NETs derived clinical benefit (response plus stable disease) from treatment with cabozantinib. The clinical benefit rate was 90% in patients with pancreatic NETs and 78% in patients with carcinoid tumors. Both groups had an objective response rate of 15%.
The median progression-free survival (PFS) exceeded 20 months in the pancreatic NETs cohort and 30 months in the carcinoid cohort.
“The median progression-free survival for both cohorts is encouraging, within the context of historical results,” said Dr Chan. “In older studies with other tyrosine kinase inhibitors, the progression-free survival was on the order of 8 to 10 months.”
Although these results require confirmation in a larger study, they suggest that vascular endothelial growth factor (VEGF) receptor 2 and MET—both inhibited by cabozantinib—are therapeutic targets in NETs, she added.
Studies involving preclinical models of NETs showed that cabozantinib inhibited cell viability and reduced metastasis and invasion, and phase 1 studies provided additional evidence of activity and safety with cabozantinib, leading to this phase 2 clinical trial.
The phase 2 clinical trial involved patients with unresectable or metastatic, well-differentiated, grade 1 or 2 carcinoid or pancreatic NETs. Previous treatment with anti-VEGF drugs, other than cabozantinib, was allowed, and patients who received stable doses of a somatostatin analog could continue treatment concurrently.
Patients received cabozantinib 60 mg daily, and treatment continued until disease progression, withdrawal, or unacceptable toxicity. The primary end point was the objective response rate, as assessed by Response Evaluation Criteria in Solid Tumors criteria. The secondary end points included PFS, overall survival, tolerability, and safety.
The clinical trial had a target accrual of 35 patients for each cohort (ie, pancreatic NETs cohort and carcinoid tumors cohort), and ≥3 responses in each group were necessary to reject the null hypothesis.
Data analysis comprised 20 patients with pancreatic NETs and 41 patients with carcinoid tumors. In the carcinoid NETs cohort, the small intestine was the primary tumor site in 29 patients, followed by the lung in 5 patients. The majority of patients in the pancreatic NETs cohort had previous exposure to sunitinib, everolimus, and temozolomide (Temodar). In the carcinoid cohort, 12 patients had received everolimus, 6 had received bevacizumab (Avastin), 4 had received interferon, and 3 had received temozolomide.
Objective Responses and PFS
The median follow-up was 23.3 months in the entire study population. Overall, 3 of 20 patients with pancreatic NETs had objective responses and 15 patients had stable disease; the response status of the remaining 2 patients was unknown.
In the carcinoid cohort, 6 of 41 patients attained objective responses with cabozantinib, and 26 had stable disease. In addition, 2 patients had progressive disease, and the remaining 7 patients had unknown response status.
All but a few patients in each cohort had some degree of tumor shrinkage.
The pancreatic NETs cohort had a median PFS of 21.8 months, and the carcinoid cohort had a median PFS of 31.4 months. Dr Chan reviewed the median PFS from clinical trials of TKIs and other targeted agents in advanced NETs, dating back to 2008. The median PFS for patients with pancreatic NETs ranged from 7.7 months to 14.4 months, and the median PFS for patients with carcinoid tumors ranged from 10.0 months to 16.6 months.
The most common all-grade adverse events with cabozantinib in the 61 patients were fatigue (67%); increases in aspartate aminotransferase levels (59%); diarrhea (54%); thrombocytopenia (44%); hypertension (41%); increases in alanine aminotransferase levels (39%); decreased white blood cell count (39%); anemia (39%); increased alkaline phosphatase levels (33%); nausea and mucositis (31%); hypophosphatemia (25%); increases in lipase or amylase levels (21%); and increases in lymphocyte levels (11%).
Overall, 43 of 53 patients who completed 1 or more 28-day cycles of cabozantinib required at least 1 dose reduction.