Encouraging results are being seen following the administration of cabozantinib (Cabometyx) in patients with carcinoid and pancreatic neuroendocrine tumors. Clinical benefit of the drug has been exhibited in patients enrolled in a prospective phase II trial, which was initiated in July 2012; however, a randomized phase III trial will be necessary for confirmation.
Jennifer A. Chan, MD, MPH
Encouraging results are being seen following the administration of cabozantinib (Cabometyx) in patients with carcinoid and pancreatic neuroendocrine tumors (NETs). Clinical benefit of the drug has been exhibited in patients enrolled in a prospective phase II trial, which was initiated in July 2012; however, a randomized phase III trial will be necessary for confirmation.
During the 10th Annual North American Neuroendocrine Tumor Society (NANETS) Symposium in Philadelphia, Pennsylvania, the study’s lead investigator, Jennifer A. Chan, MD, MPH, of the Dana-Farber Cancer Institute reported the recent successes of the multikinase inhibitor.
Cabozantinib targets vascular endothelial growth factor (VEGFR), among other tyrosine kinase receptors, including MET, and was approved in April 2016 for the treatment of advanced renal cell carcinoma in patients who have received prior antiangiogenic therapy.
The expression of MET has been associated with decreased overall survival, and based on data from preclinical models that suggest the drug’s ability to decrease the viability of cell lines, as well as metastasis and invasion in mass models, the phase II trial was conducted at the Dana-Farber Cancer Institute and Massachusetts General Hospital. Enrollment concluded in November 2015.
The primary endpoint of the study was objective response rate (ORR) based on RECIST v1.1 criteria and patients were stratified based on whether they had a NET of the pancreas or a carcinoid. It was hypothesized that cabozantinib would have a ORR of 12% or more. Secondary endpoints included progression-free survival (PFS), overall survival (OS), tolerability, and safety.
Sixty-one patients were dosed orally with cabozantinib at 60 mg daily by the commencement of the study, and continued treatment until disease progression, unacceptable toxicity, or withdrawal with consent. Twenty enrolled patients had previously been diagnosed with pancreatic NETs, and had received a median of 3 prior therapies (range, 0-8). The median age of these patients was 55 years, 60% were male, 40% had an ECOG performance status of 0, and 60% had a performance status of 1.
The remaining 41 patients had been diagnosed with carcinoid tumors, and the median number of previously administered therapies they had received was 1 (range, 0-6). Among the patients with carcinoids, the median age was 63 years, 44% were male, 51% had an ECOG performance status of 0, and 49% had a performance status of 1. No minimum pretreatment was necessary for inclusion.
Dose reduction was common (81%) throughout the evaluation of both groups, despite the carcinoid group being less heavily medicated prior to the start of the study.
Cabozantinib was administration over a 28-day cycle, and patients were re-staged after every 2 cycles for the first 6 cycles, followed by every 3 cycles. Patients with pancreatic NETs completed a median of 10 cycles of treatment (range, 0-35), while patients with carcinoid NETs completed a median of 8 cycles (range, 0-44).
Among the enrolled patients in the study, both those with pancreatic NETs and carcinoid tumors, the agent produced an ORR of 15% (95% CI, 5%-36%) in each group, all of which were partial responses. Data were analyzed in July of 2016 with a median follow-up time of 23.3 months, that demonstrated that median PFS was 21.8 months (95% CI, 8.5-32.0) in patients with pancreatic NETs and 31.4 months (95% CI, 8.5-not reached) in patients with carcinoid tumors.
When evaluating patients at follow-up, 15 of 20 patients with pancreatic NETs had stable disease with several experiencing a reduction in tumor size. In patients with carcinoid NETs, 26 had stable disease and 2 had progressive disease. Among grade 3/4 adverse events (AEs) experienced by the study’s subjects, hypertension (13%), hypophosphatemia (11%), and diarrhea (10%) were the most common. Patients discontinued from treatment due to cabozantinib due to progression/death in 54%, withdrawal of consent or investigator decision in 28%, and AEs in 21%.
While these results are promising, Chan stressed the need to confirm the activity of cabozantinib in a phase III setting.
“There are certainly limitations in interpreting progression-free survival durations in a relatively small single-arm phase II study,” said Chan, “but the results do look encouraging within the context of what’s been reported in prior studies of targeted therapy for neuroendocrine tumors. It will be important to confirm the activity of cabozantinib in a randomized phase III trial setting.”
The Dana-Farber Cancer Institute is currently in the final stages of planning a phase III randomized trial for the Alliance Cooperative Group of cabozantinib versus placebo in patients with advanced NETs after progression on everolimus (Afinitor).
Chan F, Fairs J, Murphy J, et al. Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors. Presented at: 10th Annual NANETS Symposium; October 19-21, 2017; Philadelphia, PA. Abstract 290.