Cabozantinib Shows Significant Progression-Free Survival Benefits in Phase III Trial for Advanced Neuroendocrine Tumors

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Results from the Phase III CABINET trial (NCT03375320) demonstrated that cabozantinib (Cabometyx, Cometriq) produced a significant improvement in progression-free survival (PFS) compared to placebo in patients with advanced pancreatic neuroendocrine tumors (pNET) and advanced extra-pancreatic neuroendocrine tumors (epNET).^1,2 These findings, presented at the 2024 European Society for Medical Oncology Congress and published in The New England Journal of Medicine,³ indicate that cabozantinib could become the new standard of care for this patient population, according to the study investigators.

“The Phase III CABINET study, which was conducted through the National Cancer Institute's National Clinical Trials Network, reflects real-world clinical practice in that it enrolled a wide and heterogeneous range of patients regardless of primary tumor site, grade, somatostatin receptor expression and functional status,” CABINET trial study chair Jennifer Chan, MD, MPH, clinical director of the Gastrointestinal Cancer Center and director of the Program in Carcinoid and Neuroendocrine Tumors at Dana-Farber Cancer Institute, said in a press release. “I’m encouraged by these final results showing that cabozantinib provided a clinically meaningful treatment benefit for patients with previously treated advanced neuroendocrine tumors, including across all major clinical subgroups. The findings suggest that cabozantinib has the potential to become a new standard of care for these patients greatly in need of new treatment options.”¹

Cabozatinib, an oral small molecule tyrosine kinase inhibitor, is currently approved as monotherapy for advanced renal cell carcinoma (RCC) and combined with Opdivo (nivolumab) as first-line treatment for advanced RCC; for patients with hepatocellular carcinoma previously treated with sorafenib, and for patients 12 aged years and older with locally advanced or metastatic differentiated thyroid cancer that progressed after previous VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.¹

The multicenter, randomized, double-blinded, placebo-controlled, pivotal CABINET trial enrolled total of 298 patients at the time of the final analysis, who were randomly assigned in a 2:1 ratio to two separate cohorts (pNET, n=95; epNET, n=203) to receive cabozantinib at a dose of 60 mg or placebo The epNET cohort enrolled patients with tumors of the gastrointestinal tract, lung, unknown primary sites, and other, with each cohort randomized separately with its own statistical analysis plan.

In the pNET patient group (n=95) at a median follow-up of 13.8 months, median PFS was 13.8 months for cabozantinib versus 4.4 months in the placebo cohort (hazard ratio [HR] 0.23 [95% confidence interval [CI]: 0.12-0.42; p<0.0001]). Among patients with epNET (n=203), at a median follow-up of 10.2 months, median PFS was 8.4 months in the cabozantinib cohort compared to 3.9 months in the placebo cohort (HR 0.38 [95% CI: 0.25-0.59; p<0.0001]).

After experiencing disease progression, patients were unblinded and the placebo cohort was allowed to cross to open-label therapy with cabozantinib. In the pNET cohort, the objective response rate (ORR) as per blinded independent central review (BICR) was 19% in cabozantinib cohort vs. 0% in the placebo cohort. Among patients in the epNET cohort, ORR per BICR was 5% in the cabozantinib cohort vs. 0% in the placebo cohort.

In terms of safety, grade 3 or higher adverse events (AEs) were reported by 62% to 65% of patients administered cabozantinib compared to 23% to 27% of patients in the placebo cohort. The most frequently reported treatment-related AEs of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events.

“In this trial, cabozantinib, as compared with placebo, resulted in longer progression-free survival in patients with extrapancreatic neuroendocrine tumors or pancreatic neuroendocrine tumors that had progressed after previous therapy with Lu-177 dotatate or targeted agents, including everolimus or sunitinib,” the study authors concluded. “Adverse events, which were managed with dose reduction in a majority of the patients, were consistent with the known safety profile of cabozantinib.”

Based on these findings, in August the FDA accepted a supplemental new drug application (sNDA) for cabozantinib for the treatment of previously treated, locally advanced/unresectable or metastatic, well- or moderately differentiated pNETs and epNETs. Cabozantinib was also granted Orphan Drug Designation for the pNET indication. The FDA assigned the sNDA with a Prescription Drug User Fee Act target action date of April 3, 2025.⁴

“Patients with advanced neuroendocrine tumors face a poor prognosis with limited treatment options. These updated data reinforce the potential of cabozantinib as a new treatment to significantly delay disease progression,” said Amy Peterson, MD, executive vice president, Product Development & Medical Affairs, and chief medical officer, Exelixis, in a press release. “We believe the CABINET data indicate that cabozantinib could be practice-changing in NET, and we are working closely with the FDA to bring this differentiated option to patients with advanced NET as quickly as possible.”¹

References

1. Exelixis Announces Final Results from Phase 3 Pivotal CABINET Study Evaluating Cabozantinib in Advanced Neuroendocrine Tumors Presented at ESMO 2024 and Published in New England Journal of Medicine. News release. Exelixis. September 16, 2024. Accessed September 20, 2024. https://www.businesswire.com/news/home/20240913607414/en/Exelixis-Announces-Final-Results-from-Phase-3-Pivotal-CABINET-Study-Evaluating-Cabozantinib-in-Advanced-Neuroendocrine-Tumors-Presented-at-ESMO-2024-and-Published-in-New-England-Journal-of-Medicine

2. Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors. ClinicalTrials.gov. Updated July 3, 2024. Accessed September 20, 2024. https://clinicaltrials.gov/study/NCT03375320

3. Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors. N Engl J Med. Online. Published September 16, 2024. Accessed September 20, 2024. nejm.org/doi/full/10.1056/NEJMoa2403991.

4. Exelixis Announces US Food and Drug Administration (FDA) Accepted the Supplemental New Drug Application for Cabozantinib for Patients with Advanced Neuroendocrine Tumors. News release. Exelixis Inc. August 6, 2024. Accessed September 20, 2024. https://www.businesswire.com/news/home/20240805262570/en/Exelixis-Announces-U.S.-Food-and-Drug-Administration-FDA-Accepted-the-Supplemental-New-Drug-Application-for-Cabozantinib-for-Patients-with-Advanced-Neuroendocrine-Tumors