The FDA has granted a priority review designation to a supplemental new drug application for cabozantinib for the treatment of patients with differentiated thyroid cancer who have progressed after previous therapy and who are radioactive iodine refractory.
The FDA has granted a priority review designation to a supplemental new drug application (sNDA) for cabozantinib (Cabometyx) for use in the treatment of patients aged 12 years and older with differentiated thyroid cancer who have progressed after previous therapy and who are radioactive iodine refractory.1
The application is supported by data from the phase 3 COSMIC-311 trial (NCT03690388), in which cabozantinib was found to result in a 78% reduction in the risk of disease progression or death vs placebo in previously treated, radioactive iodine–refractory differentiated thyroid cancer, meeting one of the primary end points of the trial.2 The median progression-free survival (PFS) with cabozantinib had not yet been reached (95% CI, 5.7–not evaluable [NE]) vs 1.9 months (95% CI, 1.8-3.6) with placebo (HR, 0.22; 95% CI, 0.13-0.36; P < .0001).
Additionally, cabozantinib elicited an objective response rate (ORR) of 15% (95% CI, 2.8%-29.3%) vs 0% (95% CI, 0%-14.8%) with placebo (P = .028). However, the primary end point of ORR was not met (critical P value of .01).
The regulatory agency is expected to reach a decision on the sNDA by December 4, 2021, under the Prescription Drug User Fee Act.
“The FDA’s acceptance of our sNDA with priority review is an important step toward our goal of bringing [cabozantinib] to patients with previously treated radioactive iodine–refractory differentiated thyroid cancer,” Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, stated in a press release. “Considering the lack of a standard of care in the treatment of this cancer following anti-VEGFR therapy, the PFS benefit demonstrated in the phase 3 COSMIC-311 pivotal trial means [cabozantinib], if approved, could become an important new treatment for these patients.”
The double-blind phase 3 trial enrolled 300 patients with locally advanced or metastatic differentiated thyroid cancer who were radioactive iodine refractory or ineligible, and who experienced radiographic progression during or after treatment with up to 2 previous VEGFR multikinase inhibitors which must have included lenvatinib (Lenvima) or sorafenib (Nexavar).
Patients also needed to be at least 16 years of age, have an ECOG performance status of 0 or 1, and a serum thyroid stimulating hormone of less than 0.5 mIU/L.
Study participants were randomized 2:1 to receive either cabozantinib at a once-daily dose of 60 mg (n = 125) or placebo (n = 62). Stratification factors included previous receipt of lenvatinib (yes vs no) and age (≤65 years vs >65 years). Notably, crossover was permitted at the time of blinded independent review committee (BIRC)–confirmed progression per RECIST v1.1 criteria.
The co-primary end points of the trial were PFS and ORR in the intent-to-treat population per RECIST v1.1 criteria and BIRC assessment. Other end points of interest included overall survival (OS) and safety.
The median age of study participants across the arms was 65.5 years, 54.5% were female, 69% were White, 52% were from Europe, 47.5% had an ECOG performance status of 0, and 55% had papillary disease. Moreover, 37% of patients previously received sorafenib but not lenvatinib, 40% had prior lenvatinib but not sorafenib, and 23% had previously received both agents. The majority, or 75%, of patients had received 1 prior VEGFR multikinase inhibitor. Additionally, 44.5% of patients had metastatic lesions in the bone, 16% had them in the liver, 74.5% had them in the lung, and 86.5% had then in another area of the body.
Notably, the PFS benefit observed with cabozantinib over placebo was observed across all prespecified subgroups, which included age, number of prior VEGFR TKIs received, and prior sorafenib, lenvatinib, or both.
Additional data from the trial presented during the 2021 ASCO Annual Meeting demonstrated that the disease control rate achieved with cabozantinib was 60% vs 27% with placebo. Moreover, the duration of response had not been reached (95% CI, 4.1–NE) in the investigative arm.
The median OS had not yet been reached in either arm (HR, 0.54; 95% CI, 0.27-1.11). At 6 months of minimum follow-up, cabozantinib reduced target lesions by 76% vs 29% with placebo.
Regarding safety in the investigative (n = 125) and control (n = 62) arms, adverse effects (AEs) proved to be consistent with the known safety profile of cabozantinib and were managed with supportive care, as well as dose holds and modifications.
Seventy-eight percent of patients who received cabozantinib required dose modifications because of toxicities vs 27% of those who were given placebo; 72% vs 27%, respectively, had doses held because of AEs, and 57% vs 5%, respectively, required dose reductions.
Any-grade AEs were experienced by 94% of those in the cabozantinib arm vs 84% of those in the placebo arm; these toxicities were grade 3 in 51% and 23% of patients, respectively, and grade 4 in 6% and 3%, respectively.
The most frequently experienced AEs in the investigative and control arms, respectively, included diarrhea (any-grade, 51% vs 3%; grade 3, 7% vs 0%), hand–foot skin reaction (any-grade, 46% vs 0%; grade 3, 10% vs 0%), hypertension (any-grade, 28% vs 5%; grade 3, 8% vs 3%; grade 4, 1% vs 0%), fatigue (any-grade, 27% vs 8%; grade 3, 8% vs 0%), and increased alanine transaminase (any-grade, 24% vs 2%; grade 3, 1% vs 0%), among others.
Five percent of patients on the cabozantinib arm discontinued treatment because of AEs vs none the placebo arm.