Cabozantinib Appears to be a Promising New Treatment Option in Radioiodine-Refractory Differentiated Thyroid Cancer

The use of cabozantinib (Cabometyx) in patients with radioiodine-refractory differentiated thyroid cancer (DTC) was found to significantly prolong progression-free survival (PFS) and could possibly be a new treatment option for a population of patients with no available standard of care, according to the results of the phase 3 COSMIC-311 trial (NCT03690388).¹

The study had a median follow-up of 6.2 months in the intent-to-treat population (ITT; range, 3.4-9.2) and 8.9 months in the objective response rate (ORR) ITT (OITT) population (range 7.1-10.5). An interim analysis of PFS by blinded independent radiology committee (BIRC) indicated that the median PFS for those in the ITT population who were treated with cabozantinib was not reached (96% CI, 5.7–not estimable) vs 1.9 months in the placebo arm (96% CI, 1.8-3.6; HR, 0.22; 96% CI, 0.13-0.36; P< .0001). The estimated PFS rate at 6 months was 57% (96% CI, 43%-69%) and 17% in both groups (96% CI, 7%-30%), respectively.

Cabozantinib, an inhibitor of several Tyrosine kinases that mediate tumor growth and angiogenesis in DTC, has previously demonstrated clinical benefit in a number of patients with pre-treated solid malignancies such as renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer.^2-4 Based on this, cabozantinib’s safety and efficacy were evaluated in COSMIC-311.

The global, multicenter, randomized, double blind, placebo-controlled study was conducted in 164 clinics across 25 countries, enrolling patients who were aged 16 years or older with a confirmed DTC diagnosis and measurable disease by RECIST 1.1 criteria. Patients needed to have previously undergone or been ineligible for treatment with iodine-131. Those who were previously treated with lenvatinib (Lenvima), sorafenib (Nexavar), and up to 2 previous VEGFR Tyrosine kinase inhibitors were eligible for the study. An ECOG performance status of 0 or 1 and adequate organ and bone marrow function were also required.

Patients were randomized 2:1 to either cabozantinib or placebo, and were stratified based on prior lenvatinib treatment and age. Those in the cabozantinib arm self-administered a 60 mg dose of the agent, and those in the placebo took a matching dose once daily.

The primary end points for the study were ORR in the first 100 randomly assigned patients and PFS in the total patient population, both of which were evaluated by BIRC. Other prespecified efficacy end points included overall survival (OS), duration of response (DOR), and changes in serum thyroglobulin concentrations, all of which were evaluated in the OITT and ITT cohorts.

Enrollment took place from February 27, 2019 to August 18, 2020 with a data cut-off of August 19, 2020. In total, 277 patients were assessed for eligibility, 187 of whom were enrolled to receive either cabozantinib (n = 125) or placebo (n = 62). The median age in the ITT population was 66 years old. The majority of patients had previously been treated with lenvatinib (63%) or sorafenib (60%), and 24% had undergone prior treatment with both agents. In total, 76% of patients experienced disease progression while receiving either agent as their most recent therapy.

Additional data from the study indicated that 15% (n = 67; 99% CI, 5.8%-29.3%) of those in the OITT population who received cabozantinib had a confirmed partial response by BIRC vs no confirmed responses in the placebo group (n = 33; 99% CI, 5.8%-29.3%; P = .0028); the difference was not found to be statistically significant. The median DOR in the cabozantinib cohort had not been reached at the time of data cut off, and 1 patient had disease progression. Moreover, 76% (n = 44/58) of those in the cabozantinib cohort with at least 1 post-baseline target lesion assessment experienced a reduction in target lesions vs 29% (n = 9/31) in the placebo cohort.

At data cutoff, 14% of those in the cabozantinib group and 23% among those in the placebo group had died. The median OS was not reached (95% CI, NE-NE) in either treatment arm (HR, 0.54; 95% CI 0.27-1.11).The estimated OS rate at 6 months was 85% in the cabozantinib group (95% CI, 75.0-91.0) and 73% (95% CI, 58.4%-83.7%) in the placebo group. In total, 2% of those in the cabozantinib cohort and 6% of those in the placebo cohort went on to receive a subsequent therapy, not counting the patients in the placebo group (31%) who crossed over to receive open-label cabozantinib.

At the time of cut-off, 89 patients continuing treatment with cabozantinib and 26 continued to receive placebo. The most common reason for treatment discontinuation across both groups was disease progression. The most common adverse effects (AEs) that led to dose reduction of cabozantinib were palmar plantar erythrodysaesthesia (19%), diarrhea (10%), and fatigue (7%) vs fatigue (2%), dyspnea (2%), dysphagia (2%), and pruritus (2%) in the placebo group.

AEs of any grade occurred in 94% of those in the experimental arm and 93% of those in the placebo arm, whereas grade 3/4 AEs occurred in 57% and 26% of both groups, respectively. The most common grade 3/4 AEs in both groups included palmar plantar erythrodysaesthesia (10% vs 0%), hypertension (9% vs 3%), fatigue (8% vs 0%), diarrhea (7% vs 0%), and hypocalcemia (7% vs 2%).

In February 2021, the FDA granted cabozantinib a breakthrough therapy designation for patients with DTC who were radioactive iodine refractory.⁵ The designation was based on the results of an interim analysis of the phase 3 COSMIC-311 trial, which offered clinically significant data to support the use of cabozantinib in this patient population.

References

1. Brose MS, Robinson B, Sherman SI, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. Published online, July 5, 2021. doi:10.1016/S1470-2045(21)00332-6
2. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639-3646. doi:10.1200/JCO.2012.48.4659
3. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917-927. doi:10.1016/S1470-2045(16)30107-3
4. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63. doi:10.1056/NEJMoa1717002
5. Exelixis announces breakthrough therapy designation granted to cabozantinib for the treatment of patients with previously treated radioactive iodine-refractory differentiated thyroid cancer. Exelixis. Published February 25, 2021. Accessed July 13, 2021. https://bit.ly/2U5IQqR