The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending approval of Cabometyx (cabozantinib) as a monotherapy for adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC) that is refractory or not eligible to radioactive iodine and has progressed during or after prior systemic therapy. The recommendation, announced by Ipsen on March 25, 2022, is based on compelling data from the pivotal COSMIC-311 Phase III trial.
Significant Clinical Efficacy Demonstrated
The CHMP's positive opinion was grounded in results from the COSMIC-311 Phase III trial, which showed remarkable efficacy outcomes. At a planned interim analysis with a median follow-up of 6.2 months, Cabometyx demonstrated a significant 78% reduction in the risk of disease progression or death versus placebo (hazard ratio [HR]: 0.22; 96% confidence interval [CI]: 0.13-0.36; p<0.0001).
A subsequent analysis presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2021, with a median follow-up of 10.1 months, reinforced these findings. Cabometyx continued to demonstrate superior median progression-free survival of 11.0 versus 1.9 months and maintained the 78% reduction in the risk of disease progression or death versus placebo (HR: 0.22, 96% CI: 0.15-0.32; p<0.0001).
The objective response rate (ORR), another primary endpoint, favored Cabometyx with 15% versus 0% for placebo (p=0.028) at a median follow-up of 8.9 months, though it did not meet the criteria for statistical significance.
Addressing Critical Unmet Medical Need
"Currently, for people living with radioactive iodine-refractory differentiated thyroid cancer, there are no standard-of-care treatment options should the cancer progress after first-line therapy," said Dr. Jaume Capdevila, Medical Oncologist at the Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, and a trial investigator. "As a practicing physician regularly seeing people living with this uncommon form of cancer, I am encouraged to see the potential Cabometyx may bring for these patients with so few options."
The disease burden is substantial, with over 580,000 new cases of thyroid cancer diagnosed worldwide in 2020. Thyroid cancer is the ninth most commonly occurring cancer globally, with incidence three times higher in women than in men, representing one in every 20 cancers diagnosed among women. Differentiated thyroid cancer makes up about 90 to 95% of all thyroid cancer cases, including papillary, follicular and Hürthle cell cancer.
While DTC is typically treated with surgery followed by radioactive iodine (RAI) ablation, approximately 5 to 15% of cases are resistant to RAI treatment. Patients who develop radioactive iodine-refractory DTC have a poor prognosis with an average estimated survival of three to five years.
Robust Trial Design and Safety Profile
COSMIC-311 is a multicenter, randomized, double-blind, placebo-controlled Phase III trial that enrolled 258 patients at 164 sites globally. Patients were randomized in a 2:1 ratio to receive either Cabometyx 60 mg or placebo once-daily. The primary endpoints were progression-free survival in the intention-to-treat population and objective response rate in the first 100 randomly assigned patients, both evaluated by a blinded independent radiology committee.
The safety profile identified in the COSMIC-311 trial was consistent with that previously observed for Cabometyx, and adverse events were managed with dose modifications. Exelixis sponsors COSMIC-311, with Ipsen co-funding the trial.
Regulatory Progress and Market Access
Dr. Steven Hildemann, Executive Vice President and Chief Medical Officer at Ipsen, commented: "With the promising interim results from the COSMIC-311 trial further reinforced by the maintained significant progression-free survival benefit demonstrated in the final analysis, we are pleased that the CHMP has concluded that Cabometyx may offer an important treatment option for people affected by this uncommon cancer."
This positive CHMP opinion follows the U.S. Food and Drug Administration's approval in September 2021 of Cabometyx for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic DTC that has progressed following prior vascular endothelial growth factor receptor targeted therapy and who are radioactive iodine-refractory or ineligible.
Cabometyx is already approved in the U.S. for multiple oncology indications, including advanced renal cell carcinoma, hepatocellular carcinoma previously treated with sorafenib, and as a first-line treatment for advanced RCC in combination with nivolumab. Outside the U.S., Cabometyx is currently approved in 60 countries for various cancer indications.
Ipsen holds exclusive commercialization rights for Cabometyx outside the U.S. and Japan, while Exelixis markets the drug in the U.S. and Takeda handles distribution in Japan. The company now awaits the final decision from the European Commission, which would bring Cabometyx closer to reaching European patients with this rare and challenging cancer.
