Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors (pNET).

Abstract

228 Background: Activation of VEGFR2 and c-MET has been implicated in driving growth of neuroendocrine tumors (NET); additionally, expression of c-MET has been associated with shorter survival. Cabozantinib inhibits VEGFR2 and c-MET. We performed a two-cohort phase II study to evaluate the efficacy of cabozantinib in patients (pts) with advanced carcinoid or pNET (NCT01466036). Methods: Pts with progressive, well differentiated, grade 1-2 carcinoid or pNET were enrolled in parallel cohorts and treated with cabozantinib 60 mg po qd . There was no limit to prior therapy. Pts were restaged every 2 mos for the first 6 mos, then every 3 mos. The primary endpoint was objective response rate as measured by RECIST 1.1. Enrollment of approximately 35 patients of each tumor type was planned. Results: 41 pts with carcinoid (median age 63 yrs, 44% male, % ECOG PS 0/1 = 51/49) were accrued. Accrual to the pNET cohort was halted due to investigator/sponsor decision after 20 pts (median age 55 yrs, 60% male, % ECOG PS 0/1 = 40/60). Carcinoid pts completed a median of 8 (range 0-44) 28-day treatment cycles; pNET pts completed a median of 10 (0-35) cycles. 14 pts remain on treatment. Reasons for discontinuation were progression or death (51%), withdrawal of consent or investigator decision (28%), adverse events (AE, 21%). 3/20 pts with pNET achieved PR (ORR 15%, 95% CI 5-36%); 15/20 had SD. 6/41 pts with carcinoid achieved PR (ORR 15%, 95% CI 7-28%); 26/41 had SD . Median PFS was 21.8 mo (95% CI, 8.5-32.0 mo) in pts with pNET and 31.4 mo (95% CI, 8.5 mo-NR) in pts with carcinoid. Gr 3/4 toxicity in ≥ 1 pt included hypertension (13%), hypophosphatemia (11%), diarrhea (10%), lymphopenia (7%), thrombocytopenia (5%), fatigue (5%), increased lipase or amylase (8%). Unexpected Gr 3/4 AEs included heart failure and autoimmune hemolytic anemia, each in 1 pt. 81% of 53 pts completing more than 1 cycle of treatment required dose reduction from the initial 60 mg dose. Conclusions: Treatment with cabozantinib was associated with objective tumor responses and encouraging PFS durations in patients with advanced carcinoid and advanced pNET. While dose reduction was common, treatment was tolerable. Further evaluation of cabozantinib is warranted in both NET subgroups. Clinical trial information: NCT01466036.