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The European Commission has approved the use of cabozantinib for use as a single agent in adult patients with locally advanced or metastatic differentiated thyroid carcinoma who are refractory or not eligible to receive radioactive iodine and who have progressed during or following previous systemic treatment.
The European Commission has approved the use of cabozantinib (Cabometyx) for use as a single agent in adult patients with locally advanced or metastatic differentiated thyroid carcinoma who are refractory or not eligible to receive radioactive iodine and who have progressed during or following previous systemic treatment.1
The decision is supported by data from the phase 3 COSMIC-311 trial (NCT03690388), in which cabozantinib (n = 125) was found to significantly improve progression-free survival (PFS) vs placebo (n = 62) in this population.2 At the time of the planned interim analysis, which had a median follow-up of 8.9 months (interquartile range, 7.1-10.5), the median PFS had not been reached (96% CI, 5.7–not estimable [NE]) in the investigative arm vs 1.9 months (96% CI, 1.8-3.6) in the control arm (HR, 0.22; 96% CI, 0.13-0.36; P < .0001), meeting a primary end point of the research.
Moreover, at this time point, the objective response rate (ORR) achieved with cabozantinib was 15% (99% CI, 5.8%-29.3%) per blinded independent radiology committee (BIRC) assessment vs 0% (99% CI, 0%-14.8%) in the placebo arm (P = .028). Although this did not meet the criteria for statistical significance, the independent data monitoring committee recommended that enrollment to the trial be stopped, and that sites and patients be unblinded.
Final data from the trial showed that at a median follow-up of 10.1 months, cabozantinib continued to demonstrate an improvement in PFS vs placebo, at 11.0 months (96% CI, 7.4-13.8) and 1.9 months (96% CI, 1.9-3.7), respectively (HR, 0.22; 96% CI, 0.15-0.32; P < .0001).3 The ORRs at this timepoint in the investigative and control arms were 11% (95% CI, 6.9%-16.9%) and 0% (95% CI, 0%-4.1%), respectively.
“The nature of radioiodine-refractory differentiated thyroid cancer means that this condition does not respond to the most commonly used standard of care for [this] cancer. As a result, people living with this form of the disease have had limited treatment options should their disease progress,” Jaume Capdevila, MD, PhD, medical oncologist at Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, stated in a press release. “I am pleased to see the entrance of a new innovative treatment in [cabozantinib], following limited progress for patients in this area for such a significant amount of time and I look forward to sharing more positive conversations with my patients on the number of options available to them.”
Patients with locally advanced or metastatic differentiated thyroid cancer were enrolled to COSMIC-311. To be eligible for participation, patients needed to be at least 16 years of age, be radioactive iodine refractory or ineligible, and have experienced radiographic progression during or following treatment with up to 2 VEGFR multikinase inhibitors that must have included lenvatinib (Lenvima) or sorafenib (Nexavar). Patients also needed to 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 cabozantinib at 60 mg once daily or placebo. Stratification factors included prior receipt of lenvatinib (yes vs no) and age (younger than 65 years vs older than 65 years). Crossover from the control arm to the cabozantinib arm was permitted if disease progression was confirmed by BIRC assessment and RECIST v1.1 criteria.
The co-primary end points of the trial included BIRC-assessed PFS and ORR by RECIST v1.1 criteria in the intent-to-treat population. Investigators also examined overall survival (OS) and safety.
Across the treatment arms, the median age of study participants was 65.5 years. Moreover, 54.5% of patients were female, 69% were White, 52% were from Europe, 47.5% had an ECOG performance status of 0, and 55% had papillary disease. Thirty-seven percent of patients previously received sorafenib but not lenvatinib and 40% received prior lenvatinib and not sorafenib; 23% received both agents. Additionally, 75% of patients previously received 1 VEGFR multikinase inhibitor.
Just under half of patients, or 44.5%, had metastatic lesions in the bone, 16% had lesions in the liver, 74.5% had them in the lung, and 86.5% had them in another area of the body that was not specified.
Additional data presented during the 2021 ESMO Congress indicated that in the subset of patients who previously received sorafenib but not lenvatinib, cabozantinib resulted in a median PFS of 16.6 months (95% CI, 11.0-NE) vs 3.2 months (95% CI, 1.9-5.5) with placebo (HR, 0.13; 95% CI, 0.06-0.26). In the subset of patients who previously received lenvatinib but not sorafenib, the median PFS in the investigative and control arms was 5.8 months (95% CI, 5.1-9.3) and 1.9 months (95% CI, 1.7-3.7), respectively (HR, 0.28; 95% CI, 0.16-0.48). In those who had received both agents previously, the median PFS was 7.6 months (95% CI, 3.8-13.8) with cabozantinib vs 1.9 months (95% CI, 1.8-3.8) with placebo (HR, 0.27; 95% CI, 0.13-0.54).
The median OS with cabozantinib was 19.4 months (95% CI, 15.9-19.4) and was not evaluable (NE; 95% CI, NE-NE) with placebo.
The any-grade treatment-emergent toxicities that were most commonly experienced in the investigative and control arms, respectively, included diarrhea (62% vs 3%), hand-foot skin reaction (47% vs 1%), hypertension (32% vs 3%), decreased appetite (31% vs 13%), fatigue (29% vs 8%), nausea (28% vs 2%), alanine aminotransferase (ALT) increase (25% vs 2%), aspartate aminotransferase increase (25% vs 2%), hypocalcemia (25% vs 3%), weight decrease (22% vs 2%), vomiting (18% vs 8%), stomatitis (18% vs 2%), asthenia (17% vs 14%), mucosal inflammation (17% vs 0%), hypomagnesemia (16% vs 3%), and proteinuria (16% vs 2%).
Grade 3 or 4 treatment-emergent toxicities reported in the cabozantinib arm included diarrhea (8%), hand-foot skin reaction (10%), hypertension (12%), decreased appetite (3%), fatigue (9%), nausea (2%), ALT increase (1%), hypocalcemia (8%), weight decrease (2%), vomiting (2%), stomatitis (4%), asthenia (2%), mucosal inflammation (2%), hypomagnesemia (1%), and proteinuria (2%).
In September 2021, the FDA approved cabozantinib for use in adult and pediatric patients aged 12 years and older with locally advanced or metastatic differentiated thyroid cancer that has progressed following previous VEGF-targeted therapy and who are radioactive iodine refractory or ineligible.4 The decision was based on findings from COSMIC-311.