FDA Approves Cabozantinib for Advanced Neuroendocrine Tumors
The FDA approved cabozantinib for previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic and extrapancreatic neuroendocrine tumors.
US FDA
- The FDA approved cabozantinib (Cabometyx) for advanced neuroendocrine cancers.
- Cabozantinib was investigated in both pancreatic and extrapancreatic neuroendocrine tumors.
- The phase 3 CABINET trial (NCT03375320) was terminated early based on interim outcomes showing benefit of cabozantinib in this setting.
The FDA announced the approval of cabozantinib for the treatment of adult and pediatric patients aged 12 years and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET) and well-differentiated extra-pancreatic neuroendocrine tumors (epNET).1
The approval was based on results from the phase 3 CABINET trial showing improved progression-free survival (PFS) with cabozantinib compared with placebo with acceptable toxicity, which were published in the New England Journal of Medicine.
The multicenter, double-blind phase 3 trial conducted by the Alliance for Clinical Trials in Oncology enrolled 203 patients with epNETs and 95 with pNETs in 2 separate cohorts and randomly assigned them on a 2:1 basis to receive 60 mg cabozantinib or placebo daily. They were stratified by concurrent somatostatin analogue use and primary tumor site (midgut gastrointestinal and unknown primary vs. nonmidgut gastrointestinal, lung, or other sites) in the epNET cohort and according to concurrent somatostatin analogue use and previous sunitinib (Sutent) therapy in the pNET cohort. The primary end point was PFS, with secondary end points including overall survival [OS], incidence of adverse events, and radiographic response rate.
Patients had to have experienced disease progression after at least 1 prior line of therapy. From October 2018 to August 2023, patients were enrolled at 62 sites in the United States. Seven patients with pNETs were mistakenly assigned to the epNET cohort, and 3 with epNETs were assigned to the pNET cohort by the registering site. The study protocol was amended in November 2020, allowing patients who were receiving placebo to cross over to receive open-label cabozantinib.
Patient characteristics were generally balanced between the arms, although patients in the epNET cohort with tumors of unknown primary site were more commonly assigned to the cabozantinib arm. In both cohorts, a median of 2 prior therapies not including somatostatin analogues had been used, and the majority had received Lu-177 dotatate (Lutathera) and everolimus.
The trial was terminated early due to interim data showing superiority of cabozantinib; unblinding took place, and crossover was permitted on August 24, 2023.
In the epNET cohort, at median follow-up of 10.2 months, there was a median PFS of 8.4 months (95% CI, 7.6-12.7) with cabozantinib vs 3.9 months (95% CI, 3.0-5.7) with placebo. There was a statistically significant PFS benefit for those receiving cabozantinib [stratified HR, 0.38; 95% CI, 0.25-0.59; P < 0.001].
The best response of stable disease (SD) was achieved in 65% of those receiving cabozantinib vs 54% of those receiving placebo; partial responses (PRs) were observed in 5% of those with cabozantinib and 0% with placebo. Any reduction of size of the target lesion was observed in 67% with cabozantinib and 29% with placebo. A best response of progressive disease (PD) was observed in 11% with cabozantinib vs 35% with placebo.
At median follow-up of 24.2 months, median OS was 21.9 months with cabozantinib vs 19.7 months with placebo [HR, 0.86; 95% CI, 0.56-1.31].
In the pNET cohort, at median follow-up of 13.8 months, median progression-free survival was 13.8 months (95% CI, 9.2-18.5) with cabozantinib and 4.4 months (95% CI, 3.0-5.9) with placebo [stratified HR, 0.23; 95% CI, 0.12-0.42; P < 0.001].
In this cohort, the best response of SD was observed in 61% of patients with cabozantinib vs 55% with placebo, and 19% had PRs with cabozantinib vs 0% with placebo. Any reduction in target lesion size was observed in 80% with cabozantinib vs 24% with placebo. The best response of PD was observed in 8% with cabozantinib vs 39% with placebo.
At median follow-up of 23.1 months, median OS was 40.0 months with cabozantinib and 31.1 months with placebo (HR, 0.95; 95% CI, 0.45-2.00].
AEs were consistent with the known AE profile of cabozantinib in other disease states. In the epNET cohort, adverse events (AEs) of any grade occurred in 98% with cabozantinib, and grade 3 AEs occurred in 62%, compared with 82% and 27%, respectively, with placebo. Dose reductions were required in 66% with cabozantinib and 10% with placebo, and discontinuation due to AEs occurred in 31% vs 15%, respectively. In the pNET cohort, adverse events (AEs) of any grade occurred in 98% with cabozantinib, and grade 3 AEs occurred in 65%, compared with 84% and 23%, respectively, with placebo. Dose reductions were required in 68% with cabozantinib and 19% with placebo, and discontinuation due to AEs occurred in 20% vs 0%, respectively.
The recommended dose of cabozantinib for adult and pediatric patients 12 years and older with a bodyweight ≥ 40 kg has been set as 60 mg orally once daily until disease progression or unacceptable toxicity. For pediatric patients 12 years and older with a bodyweight less than 40 kg, the recommended dose is 40 mg orally once daily until disease progression or unacceptable toxicity.1
