Exelixis’ next franchise in a drug, zanzalintinib, has hit a clinical setback, although at least two groups of analysts suggested that an FDA approval is still on the table.
A phase 3 trial for the next-generation multikinase inhibitor in patients with previously treated metastatic colorectal cancer (mCRC) failed to achieve statistical significance on a dual primary endpoint measuring overall survival in a subpopulation, Exelixis announced Monday.
The phase 3 Stellar-303 trial evaluated zanzalintinib together with Roche’s Tecentriq (atezolizumab) versus Bayer’s Stivarga (regorafenib) in previously treated patients with non-microsatellite instability (MSI)-high mCRC. At the final analysis of overall survival in a subset of patients without active liver metastases, the combo only showed a numerical 17% improvement. Patients who took the combo lived a median 15.9 months, versus 12.7 months for those in the control arm.
Despite the flop, analysts at Leerink Partners and William Blair argued that the FDA will likely still approve zanzalintinb in third-line mCRC because the Stellar-303 trial previously met the other primary endpoint—OS in all study participants regardless of their liver metastases status. The trial only needed to hit one of the two primary endpoints to be considered successful.
However, the question also comes down to whether the FDA might exclude the non-liver metastatic (NLM) subgroup from an eventual approval, the Leerink team pointed out in a Monday note.
The Stellar-303 trial could draw FDA scrutiny because Exelixis changed its primary endpoint twice. After launching the study in 2022 initially focused on all trial participants, the company tweaked its design in 2024 to make OS in NLM subjects the sole primary endpoint after Merck and Eisai’s Leap-17 trial for Keytruda and their rival VEGFR inhibitor Lenvima missed on OS in non-MSI-H mCRC.
A detailed analysis of that study later found a greater OS benefit in NLM patients, which can be explained by a less immunosuppressive environment that blunts the effects of the immunotherapy component.
Last year, Exelixis re-upgraded OS in all randomized patients from a secondary endpoint to a dual primary endpoint of Stellar-303.
Just a little over a month after disclosing that adjustment, Exelixis announced the topline success in the overall population. Detailed results linked the zanzalintinib-Tecentriq combo to a 20% OS improvement and a 1.5-month extension on median OS, which met statistical significance.
At that time, the regimen’s OS benefit appeared to be stronger in the NLM subgroup, at 23%. Now, the 17% number marks a deterioration.
As Leerink analysts see it, trial design changes do not preclude a broader label, especially as the NLM subgroup showed a positive trend. In an interview with Fierce at the J.P. Morgan Healthcare Conference in January, Exelixis CEO Michael Morrissey, Ph.D., acknowledged that being able to mount a statistically significant OS in NLM patients is important “from a marketing point of view.”
Based on the initial positive readout, the FDA has accepted Exelixis’ application in late-line mCRC, with a target decision date set for Dec. 3, 20206.
Leerink analysts currently model zanzalintinib’s unadjusted peak sales at $1.3 billion globally in the entire CRC tumor type, with NLM accounting for about half of the opportunity. Exelixis is also launching the phase 3 Stellar-316 trial in patients with resected early-stage CRC who still have molecular residual disease after definitive therapy.
In a separate note to clients on Monday, William Blair analysts said they did not see any meaningful link between the latest flop and zanzalintinib’s upcoming non-clear-cell renal cell carcinoma readout from the phase 3 Stellar-304 trial, expected later this year.
Exelixis has pinned major hopes on zanzalintinib as its second oncology franchise following Cabometyx, underpinning the company’s ambition to rank among the top 5 solid tumor companies by U.S. sales.