FDA Accepts sNDA for Cabozantinib in Advanced Pancreatic and Extra-Pancreatic NETs

The FDA has accepted a supplemental biologics license applications (sNDA) seeking the approval of cabozantinib (Cabometyx) for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic, well- or moderately differentiated pancreatic neuroendocrine tumors (NETs) and the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic, well- or moderately differentiated extra-pancreatic NETs.¹

The regulatory agency concurrently awarded orphan drug designation to cabozantinib for the treatment of patients with pancreatic NETs. The FDA has assigned a target action date of April 3, 2025, for the sNDA under the Prescription Drug User Fee Act.

The sNDA is supported by final data from the phase 3 CABINET trial (NCT03375320), which will be presented at the 2024 ESMO Congress in September. Initial results presented at the 2023 ESMO Congress showed that cabozantinib improved progression-free survival (PFS) compared with placebo in patients with pretreated pancreatic NETs and extra-pancreatic NETs.

Initial data showed that, at a median follow-up of 16.7 months, patients in the pancreatic NET cohort who were treated with cabozantinib (n = 62) achieved a median PFS of 11.4 months per local radiology review vs 3.0 months for those given placebo (n = 31; stratified HR, 0.27; 95% CI, 0.14-0.49; P < .0001). A statistically significant improvement in PFS was also observed per blinded independent central radiology review assessment (HR, 0.25; 95% CI, 0.12-0.54; P < .0001).²

At a median follow-up of 13.9 months for the extra-pancreatic NET cohort, the median PFS per local radiology review was 8.3 months with cabozantinib (n = 129) vs 3.2 months for placebo (n = 68; stratified HR, 0.45; 95% CI, 0.30-0.66; P < .0001). The improvement was also observed per blinded independent central radiology review assessment (HR, 0.50; 95% CI, 0.32-0.79; P < .0001).

Safety data for cabozantib were consistent with its known profile, and no new safety signals were reported.

Notably, in August 2023, the trial was unblinded and discontinued following the observed improvement in PFS with cabozantinib.³

“The FDA’s acceptance of this [sNDA] marks another important milestone in our commitment to bringing cabozantinib to patients living with difficult-to-treat cancers and who have limited treatment options,” Amy Peterson, MD, executive vice president, Product Development & Medical Affairs, and chief medical officer at Exelixis, stated in a news release. “We appreciate the opportunity to work with the FDA in the coming months as they review our application, with the goal to bring this new, effective treatment option to patients with advanced neuroendocrine tumors as quickly as possible.”

The randomized, double-blind CABINET trial enrolled patients at least 18 years of age with histologically documented unresectable, locally advanced or metastatic well- or moderately differentiated neuroendocrine tumors of pancreatic and non-pancreatic origin.⁴

Patients were required to have one of the following:

• well- or moderately differentiated neuroendocrine tumor
• low- or intermediate-grade neuroendocrine tumor
• carcinoid tumor or atypical carcinoid tumor

Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma without specification of differentiation status, adenocarcinoid tumor, or goblet cell carcinoid tumor were excluded. Disease progression after or intolerance to at least 1 FDA-approved line of therapy, excluding somatostatin analogs, was required. Patients with pancreatic NETs needed to receive at least 1 of the following as a prior line of therapy: everolimus, sunitinib (Sutent), or lutetium Lu 177 dotatate (Lutathera).

Other key inclusion criteria consisted of an ECOG performance status of 0 to 2; and adequate hematologic, liver, and renal function.

Patients were randomly assigned 2:1 to receive oral cabozantinib at 60 mg or placebo once per day in 28-day cycles. Treatment continued until disease progression or unacceptable toxicity. Notably, patients in the placebo arm were permitted to cross over to receive cabozantinib following disease progression.^1,4

PFS per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included overall survival, radiographic response rate, and safety.

References

1. Exelixis announces U.S. Food and Drug Administration (FDA) accepted the supplemental new drug application for cabozantinib for patients with advanced neuroendocrine tumors. News release. Exelixis. August 6, 2024. Accessed August 6, 2024. https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-us-food-and-drug-administration-fda-accepted
2. Detailed results from phase 3 CABINET pivotal trial evaluating cabozantinib in advanced neuroendocrine tumors presented at ESMO 2023. News release. October 22, 2023. Accessed August 6, 2024. https://ir.exelixis.com/news-releases/news-release-details/detailed-results-phase-3-cabinet-pivotal-trial-evaluating
3. Exelixis announces positive results from phase 3 CABINET pivotal trial evaluating cabozantinib in advanced pancreatic and extra-pancreatic neuroendocrine tumors. News release. Exelixis, Inc. August 24, 2023. Accessed August 6, 2024. https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-positive-results-phase-3-cabinet-pivotal
4. Testing cabozantinib in patients with advanced pancreatic neuroendocrine and carcinoid tumors. ClinicalTrials.gov. Updated July 3, 2024. https://clinicaltrials.gov/study/NCT03375320