After canceling a planned advisory committee meeting, the FDA has approved Exelixis’ Cabometyx for neuroendocrine tumors.
The small-molecule drug is now allowed for patients 12 years of age and older with previously treated, advanced, well-differentiated pancreatic or extra-pancreatic neuroendocrine tumors (pNET or epNET), the FDA said Wednesday.
In an interesting and unusual item in Cabometyx’s updated label, the FDA acknowledges the potential impact that control arm patient crossovers may have had on Cabometyx’s patient survival results in a phase 3 trial.
The approval could be an encouraging sign for oncology drug developers because, as the likes of Novartis know too well, the FDA has not been very receptive to companies using patient crossovers to justify a signal that may hint at a potential detriment to patient survival. Even though it doesn’t mean just any company with a crossover trial design can now expect to win over the FDA, Cabometyx serves as living proof that the agency is open to that line of reasoning.
In Cabometyx’s case specifically, during an updated overall survival analysis of the phase 3 Cabinet trial that Exelixis used to support its NET bid, overall survival data favored placebo in both pNET and epNET patients.
The overall survival data, which were immature, tallied 48% deaths in Cabometyx arm and 52% deaths in the placebo arm, but a preliminary 1% increased risk of death for the tyrosine kinase inhibitor in pNET patients. The numbers were 63% deaths for Cabometyx and 60% for placebo in epNET patients, resulting in a 5% higher risk of death for the active drug.
The lackluster overall survival data came in stark contrast with the massive 78% and 60% progression-free survival improvements that Cabometyx has shown in the two patient subgroups, respectively.
Sometimes such a disconnect between a major tumor progression benefit and muted overall survival showing could be attributed to nasty side effects harming the patients’ overall wellbeing. But in the Cabinet trial case, investigators and Exelixis have pointed to a high rate of patients in the control arm who crossed over to receive Cabometyx later upon disease progression. As the FDA label shows, 52% of pNET patients and 37% epNET participants in the control group got open-label Cabometyx, “which may impact the OS endpoint.”
When the FDA unveiled a meeting of external experts to discuss Exelixis’ NET application, analysts suspected that the agency had questions about the survival data. The FDA then canceled the gathering in January.
The medical community has been raving about Cabometyx in a hard-to-treat tumor type, in which patients face poor prognosis. In January, the National Comprehensive Cancer Network updated its guidelines to recommend Cabometyx as a category 1—the highest—preferred regimen for the majority of previously treated well-differentiated advanced NET, plus a category 2A backing for other forms of advanced NET.
The current FDA approval is limited to well-differentiated NET even though the phase 3 Cabinet trial enrolled a small number of patients with moderately-differentiated cancers. In a Wednesday, March 26 press release, Exelixis noted that an estimated 161,000 to 192,000 people are living with unresectable, advanced NET, but the company didn’t break down how many are well-differentiated cases.
NET can develop in any part of the body, but those that start in the gastrointestinal tract or in the lungs are the most common, while pNET can be more aggressive. By William Blair’s estimate, the entire NET market is expected to reach $4.6 billion by 2030.
Also in NET, Exelixis is preparing to start a pivotal trial coded Stellar-311 to evaluate its investigational zanalintinib, a next-generation asset, versus Novartis’ Afinitor. Exelixis has high hopes for zanalintinib, having put its 2033 U.S. sales potential at $5 billion.
With the NET nod in the pocket, Exelixis might soon have to test the FDA’s tolerance of a lackluster overall survival showing again. A combination of Cabometyx and Roche’s Tecentriq previously failed to deliver a statistically significant overall survival benefit compared with a change of novel hormonal therapy in metastatic castration-resistant prostate cancer in the final analysis of the Contact-02 trial. The study did meet its other dual primary endpoint, progression-free survival.
Exelixis has said it intends to file an application with the FDA but has not done so. During a recent investors’ call, Exelixis management said the company will turn to the prostate cancer indication after it gets NET across the finish line.
In response to a Fierce Pharma inquiry Wednesday, an Exelixis spokesperson said the company will provide an update on its regulatory plans at an appropriate time.