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April 2017 VOL 8, NO 4
Cabozantinib Active in Advanced Neuroendocrine Tumors
The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib demonstrated encouraging activity in patients with advanced neuroendocrine tumors (NETs), including patients previously treated with sunitinib or everolimus, a preliminary clinical study showed.
Separate patient cohorts with carcinoid and pancreatic NETs (pNETs) derived clinical benefit (response plus stable disease) from treatment with cabozantinib. Clinical benefit rates of 90% and 78% were observed in patients with pNETs and carcinoid tumors, respectively. Both groups had objective response rates of 15%.
Median progression-free survival (PFS) exceeded 20 months in the pNET cohort and 30 months in the carcinoid cohort, as reported at the 2017 Gastrointestinal Cancers Symposium.
“The median progression-free survival for both cohorts are encouraging, within the context of historical results,” said Jennifer A. Chan, MD, Clinical Director of the Neuroendocrine Tumor Program at Dana-Farber Cancer Institute in Boston, MA. “In older studies of other tyrosine kinase inhibitors, the progression-free survival was on the order of 8 to 10 months.”
Although the results require confirmation in a larger study, the results suggested 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 decreased metastasis and invasion. Phase 1 investigations provided additional evidence of activity, as well as safety, leading to the phase 2 trial reported by Dr Chan.
The trial involved patients with unresectable or metastatic, well-differentiated, grade 1/2 NETs. Prior treatment with anti-VEGF agents other than cabozantinib was allowed, and patients on stable doses of a somatostatin analog could continue treatment concurrently.
Patients received cabozantinib 60 mg/day, and treatment continued until disease progression, withdrawal, or development of unacceptable toxicity. The primary end point was objective response by RECIST. Secondary end points included PFS, overall survival, tolerability, and safety.
The trial had a target accrual of 35 patients for separate cohorts with pNETs and carcinoid tumors, and 3 or more responses in each group were necessary to reject the null hypothesis.
Data analysis comprised 20 patients with pNETs and 41 with carcinoid tumors. In the carcinoid cohort, the small intestine was the primary tumor site in 29 patients, followed by the lung in 5 patients. In the pNET cohort, a majority of patients had prior exposure to sunitinib, everolimus, and temozolomide. In the carcinoid cohort, 12 patients had received everolimus, 6 had received bevacizumab, 4 had prior exposure to interferon, and 3 had exposure to temozolomide.
The entire study population had a median follow-up of 23.3 months. The data showed that 3 of 20 patients with pNETs had objective responses and 15 had stable disease. The response status of the remaining 2 patients was unknown.
Dr Chan reported that 6 of 41 patients in the carcinoid cohort attained objective responses with cabozantinib, and 26 others had stable disease. Two 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.
Data on safety/tolerability for all 61 patients showed that the most common adverse events (all grades) were fatigue (67%); AST increase (59%); diarrhea (54%); thrombocytopenia (44%); hypertension (41%); ALT increase, decreased white blood cell count, and anemia (39% each); increased alkaline phosphatase (33%); nausea and mucositis (31%); hypophosphatemia (25%); lipase/amylase increase (21%); and lymphocyte increase (11%).
Dr Chan said 43 of 53 patients who completed 1 or more 28-day cycles of cabozantinib required at least 1 dose reduction.
The pNET cohort had a median PFS of 21.8 months, whereas the carcinoid cohort had a median PFS of 31.4 months. Dr Chan displayed a graphic with median PFS from trials of TKIs and other targeted agents in advanced NETs dating back to 2008. The median values for patients with pNETs ranged from 7.7 to 14.4 months. For cohorts with carcinoid tumors, the median ranged from 10.0 to 16.6 months.