SAN FRANCISCO – Treatment with cabozantinib was associated with objective tumor responses and encouraging progression-free survival in patients with advanced carcinoid and pancreatic neuroendocrine tumors in a two-cohort phase II trial.
Of 41 patients in the carcinoid tumor cohort, 6 achieved RECIST-defined partial response (objective response rate, 15%), and 26 had stable disease. Median progression-free survival was 31.4 months.
Of 20 patients in the pancreatic neuroendocrine tumors (pNET) cohort, 3 achieved a partial response (objective response rate, 15%), and 15 had stable disease. Median progression-free survival was 21.8 months, Jennifer A. Chan, MD, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
Although dose reduction was common – occurring in 81% of 53 patients who completed at least one treatment cycle – treatment was tolerable, said Dr. Chan of Dana-Farber Cancer Institute, Boston.
Study patients had progressive, well-differentiated grade 1-2 carcinoid tumors or pNET, and were treated with 60 mg of oral cabozantinib daily. There were no limits on prior therapy, and patients were restaged every 2 months for the first 6 months, then every 3 months thereafter.
The 41 patients with carcinoid tumors had a median age of 63 years and ECOG performance status of 0 or 1. Only 20 patients were enrolled in the pNET group, because accrual was halted, in part because of funding considerations. Patients in that group had a median age of 55 years, and also had ECOG performance status of 0 or 1, Dr. Chan said.
Dr. Jennifer A. Chan
Carcinoid tumor patients completed a median of 8 28-day treatment cycles (range, 0-44), and pNET patients completed a median of 10 cycles (range, 0-25).
The most common reasons for discontinuation were progression or death in 51% of patients, withdrawal of consent or investigator decision in 28%, and adverse events in 21%, she noted.
The most common grade 3/4 toxicities included hypertension in 13% of patients, hypophosphatemia in 11%, and diarrhea in 10%.
Unexpected grade 3/4 events included heart failure and autoimmune hemolytic anemia, which each occurred in 1 patient.
This phase II study was initiated in light of promising preclinical work, Dr. Chan said.
“There has been much progress in recent years in the treatment of advanced neuroendocrine tumors,” she said. “The VEGF pathway inhibitors have been demonstrated to show activity, and the tyrosine kinase inhibitor sunitinib is approved for patients with progressive pancreatic neuroendocrine tumors.”
Recent studies also suggest that inhibition of MET may be an effective treatment strategy. MET activation has been shown to be associated with tumor growth, expression of MET has been observed in a significant proportion of neuroendocrine tumors, and increased expression of MET has been associated with decreased overall survival in pancreatic neuroendocrine tumors, she noted.
“Cabozantinib is a tyrosine kinase inhibitor that targets multiple receptors, including the VEGF receptors MET, ASL, and RET,” Dr. Chan explained. “It improves progression-free survival in advanced renal cell carcinoma in the first-line setting, compared with sunitinib, and also in the second-line setting, compared with everolimus in patients previously treated with anti-angiogenic therapy.” Cabozantinib is also approved for use in patients with progressive, metastatic medullary thyroid carcinoma, she added.
In preclinical models of neuroendocrine tumors, cabozantinib inhibited cell viability, and in a mouse model it decreased metastasis and invasion of pNET.
The current findings provide further evidence of cabozantinib’s safety and efficacy, Dr. Chan said. The progression-free survival in this phase II study is of particularly interest in the context of historical results, she added.
“Recognizing the limitations of interpreting progression-free survival data in an uncontrolled phase II trial, as well as comparing data to previous clinical trials, the progression-free survival results that we observed do appear encouraging,” she said. “It will be important to confirm the activity of cabozantinib in a randomized phase III setting.”
Dr. Chan reported having stock or other ownership interests in Merck; having a consulting or advisory role with Bayer, Ipsen, Novartis, Pfizer, and Pozen; and receiving research funding from Novartis and Sanofi.