FDA Approves Exelixis' Cabometyx for Neuroendocrine Tumors, Acknowledging Crossover Impact on Survival Data

The U.S. Food and Drug Administration (FDA) has granted approval to Exelixis' Cabometyx for the treatment of neuroendocrine tumors (NET), marking a significant advancement in the field of oncology. The approval comes with an unusual acknowledgment from the FDA regarding the potential impact of patient crossovers on survival data, potentially setting a precedent for future drug approvals.

Approval Details and Clinical Trial Results

Cabometyx, a small-molecule tyrosine kinase inhibitor, is now indicated for patients 12 years and older with previously treated, advanced, well-differentiated pancreatic or extra-pancreatic neuroendocrine tumors (pNET or epNET). The approval is based on the phase 3 Cabinet trial, which demonstrated substantial progression-free survival (PFS) improvements of 78% and 60% in pNET and epNET patients, respectively.

However, the overall survival (OS) data presented a more complex picture. In pNET patients, there was a preliminary 1% increased risk of death for Cabometyx, while in epNET patients, the drug showed a 5% higher risk of death compared to placebo. These results came despite the significant PFS benefits observed.

FDA's Acknowledgment of Crossover Impact

In an unprecedented move, the FDA has explicitly recognized the potential impact of control arm patient crossovers on the overall survival results. The updated Cabometyx label notes that 52% of pNET patients and 37% of epNET participants in the control group received open-label Cabometyx upon disease progression, which "may impact the OS endpoint."

This acknowledgment could have far-reaching implications for oncology drug development, as it suggests the FDA's openness to considering the effects of crossover designs in clinical trials. While this doesn't guarantee approval for all drugs with crossover trial designs, it does provide a potential pathway for companies to justify survival data that may be affected by such study designs.

Market Implications and Future Developments

The approval of Cabometyx for NET represents a significant opportunity in a market expected to reach $4.6 billion by 2030, according to William Blair estimates. Exelixis estimates that 161,000 to 192,000 people are living with unresectable, advanced NET, although the company did not specify the number of well-differentiated cases.

Looking ahead, Exelixis is preparing to start a pivotal trial, Stellar-311, to evaluate its next-generation asset, zanalintinib, against Novartis' Afinitor in NET patients. The company has projected U.S. sales potential for zanalintinib at $5 billion by 2033, underscoring the significant market opportunity in this therapeutic area.

As the pharmaceutical industry continues to navigate the complex landscape of oncology drug development, the FDA's approach to Cabometyx's approval may signal a more nuanced consideration of survival data in the context of crossover trial designs. This development could potentially influence future clinical trial strategies and regulatory submissions in the oncology field.