The same set of clinical data on Cabometyx and Tecentriq in prostate cancer has led to two distinct regulatory plans between Exelixis and its partner Ipsen.
Exelixis plans to file Cabometyx’s combination with Roche’s Tecentriq with the FDA for an approval in metastatic castration-resistant prostate cancer (mCRPC) despite the combo failing to show a statistically significant life extension benefit in a phase 3 trial.
Compared with a change of novel hormonal therapy, Cabometyx and Tecentriq showed a numerical improvement in overall survival (OS) with a death risk reduction of 11%, according to the final analysis of the CONTACT-02 trial presented at the European Society for Medical Oncology (ESMO) 2024 meeting. As Exelixis announced in August alongside its second-quarter financial results, the survival number didn’t reach statistical significance.
Patients in the experimental arm lived a median 14.8 months, versus about 15 months in the control group. OS is one of the dual primary endpoints of CONTACT-02.
CONTACT-02 is still considered a positive trial because it has previously met its other dual primary endpoint, progression-free survival (PFS). PFS is a clinically relevant and approvable endpoint in prostate cancer, Exelixis’ chief medical officer, Amy Peterson, M.D., told Fierce Pharma via email.
As investigators reported in January, the Cabometyx-Tecentriq combo reduced the risk of progress or death by 35% versus a second novel hormonal therapy. At that time, the numerical survival advantage for the combo was wider at 21%, with a median OS of 16.7 months, compared with 14.6 months for control. Exelixis had then postponed its plan for an FDA filing as the agency requested a more mature OS analysis.
The mCRPC treatment landscape is evolving. Available options now include androgen receptor inhibitors, chemotherapy, PARP inhibitors and immune checkpoint inhibitors and radioligand therapy.
“As a result, it may be challenging to demonstrate an effect on OS, as patients switch to new systemic therapies upon radiographic progression,” Peterson said.
Back in 2014, Cabometyx as a single agent failed to significantly improve OS in patients with heavily pretreated mCRPC in the phase 3 COMET-1 trial despite a notable PFS improvement in an exploratory analysis. That phase 3 flop triggered a 70% reduction in Exelixis’ workforce at the time .
In CONTACT-02, a nearly equal number of patients received subsequent therapies, with the majority receiving follow-on chemotherapy, Neeraj Agarwal, M.D., from the University of Utah Health, said during his presentation of the data at ESMO 2024.
Agarwal noted that CONTACT-02 appears to have enrolled a population that has poor prognosis and high-risk factors, including about a quarter of patients with liver metastases in each arm. Rana McKay, M.D., from the University of California, San Diego, who was invited by ESMO to discuss the CONTACT-02 data during a presentation, also noted that the survival lengths of the trial participants were lower than expected, highlighting a poor prognostic population.
The Cabometyx-Tecentriq pairing worked well in some of those higher-risk patients. In those with liver metastases, the combo reduced the risk of death by 32%. In patients with bone metastases, who represent about three-quarters of the trial population, the doublet lowered the risk of death by 21%.
However, in patients without bone metastases, those who took Cabometyx and Tecentriq somehow lived shorter than their peers in the comparator arm did.
Exelixis plans to submit an application for the regimen to the FDA this year, Peterson said. But she said it’s too early to comment on specific indications or whether a broad label is appropriate.
In contrast, Ipsen, which holds Cabometyx’s rights outside of the U.S. and Japan, said it will not pursue approvals for this combination regimen in mCRPC in its territories, including Europe. The French pharma cited an “anticipated challenging regulatory environment” to explain its decision.
McKay, in her presentation, highlighted that liver metastases are increasingly common in advanced prostate cancer. Those patients represent an unmet medical need as they’re associated with worse outcomes but have limited treatment options.
“Our community in prostate cancer has really voted with its feet here,” McKay said. “There had been really limited settings where rPFS alone has resulted in a regulatory drug approval in the mCRPC setting. It’s really the totality of the data of rPFS, OS, safety, toxicity and quality of life.”
In terms of toxicity, treatment-related adverse events at grades 3 or 4 occurred in 40% of the combo arm in CONTACT-02, versus 8% in the control group. The rate of treatment-related adverse events leading to discontinuation of any study component was 14% and 2%, respectively, in the two arms. No death was chalked up to treatment-related side effects.
If the CONTACT-02 regimen wins an FDA approval, most of its usage are expected to be among those with liver metastasis, William Blair analysts said in a Tuesday note. Based on past studies, the team figured that the prevalence of liver metastasis in chemotherapy-naïve mCRPC is roughly 5% to 6%, “representing a small commercial opportunity for Exelixis.”
Also at ESMO 2024, investigators provided an updated readout from the phase 3 CABINET trial for Cabometyx in advanced neuroendocrine tumors. At the final analysis, Cabometyx reduced the risk of progression or death by a whopping 77% compared with placebo in heavily pretreated advanced pancreatic neuroendocrine tumors (pNET). The reduction was 62% in advanced extra-pancreatic neuroendocrine tumors (epNET). Both analyses came from central blinded review. The trial had previously stopped early and reported data in 2023 because of strong efficacy.
On OS, Cabometyx again showed numerical improvements that did not meet statistical significance; the drug reduced the risk of death by 5% in pNET and by 14% in epNET. Given that some patients in the control group went on to receive Cabometyx upon disease progression, the William Blair team argued that the lack of an OS showing will not “preclude significant clinical utility of Cabometyx.”
The CABINET trial enrolled a heavily pretreated population, including patients who had tried Novartis’ radioligand therapy Lutathera. William Blair put the total addressable market for Cabometyx in late-line NETs at $900 million in the U.S.
Editor's Note: The story was updated at 8 a.m. ET on Sept. 17 with additional comments from William Blair and updated data from the CABINET trial.