Cabozantinib Improves PFS for Advanced Neuroendocrine Tumors

Cabozantinib (Cabometyx) significantly improved progression-free survival (PFS) in patients with previously treated, progressive advanced extrapancreatic or pancreatic neuroendocrine tumors (NETs), according to final results from the phase III CABINET trial.

In the group of 203 patients with extrapancreatic NETs, the median PFS was 8.4 months with cabozantinib compared with 3.9 months with placebo (HR 0.38, 95% CI 0.25-0.59, PP

“CABINET represents one of the first randomized studies specifically designed to evaluate the efficacy of therapy following treatment with Lu-177 dotatate (Lutathera) and/or targeted therapy,” Chan said at the European Society for Medical Oncology congress in Barcelona. “These results suggest cabozantinib should be a new treatment option for patients with previously treated extrapancreatic or pancreatic NETs.”

The study was also published simultaneously in the New England Journal of Medicine.

CABINET’s statistical design required a total of 164 PFS events in the extrapancreatic NETs cohort and 149 in the pancreatic NETs cohort, but on the basis of interim analyses showing superior efficacy with cabozantinib, the data and safety monitoring board recommended early termination of the trial. The total number of PFS events was 111 in the extrapancreatic NETs cohort and 57 in the pancreatic NETs group.

Invited discussant Nicola Fazio, MD, PhD, of the European Institute of Oncology in Milan, pointed out that the HR assumption for PFS in CABINET’s statistical plan translated into a corresponding median PFS of 7 months with placebo versus 12 months with cabozantinib in the extrapancreatic NETs cohort, which overestimated the real results.

On the other hand, in the pancreatic NETs cohort, the HR assumption translated into a corresponding median PFS of 5 months with placebo versus 8.8 months with cabozantinib — which underestimated the real results.

“So there is a discrepancy between the statistical estimation and real results in both cohorts,” he pointed out. “What is the reason? Is it drug-related effects, or population characteristics?”

Extrapancreatic NETs Cohort

Partial responses were seen in 5% of patients in the cabozantinib group and 0% in the placebo group, with a best response of stable disease observed in 65% and 54% of the two groups, respectively.

Any reduction in target lesions was observed in 67% and 29% of the patients in the cabozantinib and placebo groups, respectively.

Median overall survival (OS) was 21.9 months with cabozantinib and 19.7 months with placebo (HR 0.86, 95% CI 0.56-1.31), a nonsignificant difference.

Subsequent anticancer therapy was received by 45% of the patients in the cabozantinib group and 67% of the patients in the placebo group, including 20 patients (33%) who crossed over to open-label cabozantinib.

The incidence of adverse events (AEs) of any grade attributed to cabozantinib and placebo was 98% and 82%, with an incidence of grade 3 or higher treatment-related AEs of 62% and 27%, respectively. The most common treatment-related grade 3 or 4 AEs with cabozantinib were hypertension (21%), fatigue (13%), and diarrhea (11%).

In the trial, there were four grade 5 AEs deemed at least possibly related to treatment — all in the extrapancreatic group, and all among patients who received cabozantinib.

Chan noted that dose reductions were needed for about two-thirds of patients receiving cabozantinib.

Pancreatic NETs Cohort

Partial responses were observed in 19% of patients in the cabozantinib group compared with 0% in the placebo group. A best response of stable disease occurred in 61% and 55%, respectively.

Any reduction in target lesions was observed in 80% of patients in the cabozantinib group and in 24% of the placebo group.

Median OS was 40 months with cabozantinib versus 31.1 months with placebo (HR 0.95, 95% CI 0.45-2.00), which was not significantly different.

Subsequent anticancer therapy was received by 51% of patients in the cabozantinib group and 62% of patients in the placebo group, including 12 patients (41%) who crossed over to open-label cabozantinib.

The incidence of AEs of any grade attributed to cabozantinib and placebo was 98% and 84%, respectively, with an incidence of grade 3 or 4 treatment-related AEs of 65% and 23%. The most common treatment-related grade 3 or 4 AEs with cabozantinib were hypertension (22%), fatigue (11%), and thromboembolic events (11%).

Study Details

For this study, Chan and colleagues enrolled two independent cohorts of patients at 62 sites in the U.S. — those with extrapancreatic NETs and those with pancreatic NETs — who had received peptide receptor radionuclide therapy or targeted therapy or both. They were assigned 2:1 to receive cabozantinib 60 mg daily or placebo.

The researchers noted that the cabozantinib and placebo groups were balanced with regard to demographic and disease characteristics at baseline in both cohorts, with the exception that patients assigned to receive cabozantinib in the extrapancreatic NETs cohort had more tumors of unknown primary site than patients assigned to placebo.

In the extrapancreatic NETs cohort, patients in both the cabozantinib and placebo groups had received a median of two previous lines of therapy not including somatostatin analogues. The majority had received Lu-177 dotatate and everolimus.

In the pancreatic NETs cohort, patients in the cabozantinib and placebo groups had received a median of three and two previous lines of therapy, respectively, and most patients had received Lu-177 dotatate, everolimus (Afinitor), and temozolomide-based therapy.

Chan and colleagues acknowledged that a limitation of the study was the fact that it used placebo in the comparator arm.

“Placebo was selected because the efficacy of therapy for patients with advanced neuroendocrine tumors whose disease has progressed after treatment with Lu-177 dotatate or targeted agents (or both) has not been well established,” they wrote.

In addition, while everolimus, sunitinib (Sutent), and Lu-177 dotatate are approved agents, they pointed out that trials evaluating these agents “primarily involved patients who had not yet received molecularly targeted therapy or peptide receptor radionuclide therapy.”