Today, the U.S. Food and Drug Administration (FDA) approved the tyrosine kinase inhibitor cabozantinib (Cabometyx) for 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 extrapancreatic neuroendocrine tumors (epNET).
CABINET Trial
The efficacy of cabozantinib for patients with NETs was evaluated in CABINET (ClinicalTrials.gov identifier NCT03375320), a double-blind, placebo-controlled, multicenter trial with two separate, randomized cohorts (pNET and epNET) of 298 patients with unresectable, locally advanced, or metastatic NET that had progressed on prior therapy.
In both cohorts, the major efficacy outcome measure was progression-free survival, assessed by blinded independent radiology review committee per Response Evaluation Criteria in Solid Tumors version 1.1. Additional efficacy outcome measures included overall response rate and overall survival.
The pNET cohort included 99 patients randomly assigned 2:1 to receive cabozantinib at 60 mg orally once daily or placebo until disease progression or unacceptable toxicity. Median progression-free survival was 13.8 months (95% confidence interval [CI] = 8.9–17.0 months) in the cabozantinib arm and 3.3 months (95% CI = 2.8–5.7 months) in the placebo arm (hazard ratio [HR] = 0.22, 95% CI = 0.12–0.4, P < .0001). The overall response rate was 18% (95% CI = 10%–30%) and 0% (95% CI = 0%–11%) in the respective arms. Overall survival data were not mature, with 32 deaths (48% of patients enrolled) in the cabozantinib arm and 17 deaths (52% of patients enrolled) in the placebo arm (HR = 1.01, 95% CI = 0.55–1.83). Fifty-two percent of placebo arm patients crossed over to receive open-label cabozantinib, which may potentially impact the evaluation of overall survival.
The epNET cohort included 199 patients randomly assigned 2:1 to receive the above regimen of cabozantinib or placebo until disease progression or unacceptable toxicity. Median progression-free survival was 8.5 months (95% CI = 6.8–12.5 months) in the cabozantinib arm and 4.2 months (95% CI = 3.0–5.7 months) in the placebo arm (HR = 0.40, 95% CI = 0.26–0.61, P < .0001). The overall response rate was 5% (95% CI = 2.2%–11%) and 0 (95% CI = 0%–5%) in the respective arms. Overall survival data were not mature, with 83 deaths (63% of patients enrolled) in the cabozantinib arm and 40 deaths (60% of patients enrolled) in the placebo arm (HR = 1.05, 95% CI = 0.71–1.54). Thirty-seven percent of those receiving placebo crossed over to receive open-label cabozantinib, which may potentially impact the evaluation of overall survival.
The safety profile for cabozantinib was consistent with the approved product label.
The recommended cabozantinib dose for adult and pediatric patients 12 years and older with a bodyweight ≥ 40 kg is 60 mg orally once daily until disease progression or unacceptable toxicity. The recommended dose for pediatric patients 12 years and older with a bodyweight < 40 kg is 40 mg orally once daily until disease progression or unacceptable toxicity.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.
This review also used rolling review and the Assessment Aid, a submission from the applicant to facilitate the FDA’s assessment.
