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Cabozantinib: Potential New Option for Treatment-Refractory Thyroid Cancer


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The tyrosine kinase inhibitor cabozantinib appears to be an effective new option for treatment-refractory differentiated thyroid cancer, according to the phase III COSMIC-311 trial, which was stopped early for efficacy.1 COSMIC-311 is the first randomized placebo-controlled trial to evaluate the efficacy of treatment in radioactive iodine–refractory disease that progressed after treatment with the kinase inhibitors lenvatinib and/or sorafenib.

In the intent-to-treat population of COSMIC-311, median progression-free survival was not reached with cabozantinib, as compared with 1.9 months with placebo (hazard ratio [HR] = 0.22; P < .0001), Marcia S. Brose, MD, PhD, Professor of Medicine at the University of Pennsylvania and Abramson Cancer Center in Philadelphia, reported at the 2021 ASCO Annual Meeting.1


The primary endpoint of progression-free survival was met [with cabozantinib]. The curves showed an early and wide separation.
— Marcia S. Brose, MD, PhD

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At a median follow-up of 6.2 months, she said, “the interim analysis was so positive that it was considered the final progression-free survival…. Additional analyses were planned…, but the independent data safety and monitoring board reviewed the data and recommended that enrollment be stopped.”

The study had two co-primary endpoints: objective response rate in the first 100 patients and progression-free survival. Although benefit was clear for progression-free survival, the objective response rate—15% in the cabozantinib arm and 0% in the placebo arm—failed to meet the prespecified criteria for statistical significance. 

Challenging Disease to Treat

In February 2021, cabozantinib was granted Breakthrough Therapy designation in differentiated thyroid cancer that is refractory to radioactive iodine and progresses after treatment with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. Cabozantinib inhibits not only VEGFR but also MET, AXL and RET, which are implicated in the pathogenesis of this malignancy, Dr. Brose explained.

For advanced disease, the standard of care is VEGFR inhibition with lenvatinib and sorafenib. For treatment after disease progression, there are no standard options. These patients have a poor prognosis, “making the positive results of the COSMIC-311 trial an important clinical advance for this community in need of additional treatment options,” Dr. Brose said.

About COSMIC-311

The global study enrolled patients with radioactive iodine–refractory differentiated thyroid cancer and disease progression during or after treatment with no more than two VEGFR inhibitors. Almost two-thirds of patients had received lenvatinib alone or with other tyrosine kinase inhibitors, mostly sorafenib. One-fourth had been treated with two prior VEGFR inhibitors, mainly sorafenib and lenvatinib. The cabozantinib arm included more patients with bone and liver lesions, which are often associated with worse outcomes, noted Dr. Brose.

Patients were randomly assigned 2:1 to receive oral cabozantinib (60 mg daily) or placebo. Crossover from placebo was allowed upon radiographic confirmation of progressive disease. At the interim progression-free survival analysis (which became the final progression-free analysis), the intent-to-treat population included 125 patients in the investigational arm and 62 in the placebo arm.

KEY POINTS

  • The phase III COSMIC-311 trial is the first randomized, placebo-controlled study of cabozantinib in patients with treatment-refractory differentiated thyroid cancer who experience disease progression on an approved tyrosine kinase inhibitor.
  • Cabozantinib as second- or third-line treatment reduced the risk of disease progression by 78% vs placebo.
  • Median progression-free survival was not reached with cabozantinib vs 1.9 months with placebo (HR = 0.22; P < .0001).
  • The second co-primary endpoint of objective response rate, however, was not met.

Risk of Disease Progression Reduced by 78%

“The primary endpoint of progression-free survival was met. The curves showed an early and wide separation,” Dr. Brose reported. Median progression-free survival was not reached with cabozantinib and was 1.9 months with placebo (HR = 0.22; P < .0001). “The 1.9-month progression-free survival in the placebo arm indicates this study had enrolled a population with a poor prognosis,” she pointed out.

Benefit was seen in all prespecified subgroups, including patients previously treated with lenvatinib (HR = 0.26) or not (HR = 0.11), previously treated with both lenvatinib and sorafenib (HR = 0.25) or not (HR = 0.22), and patients aged 65 or younger (HR = 0.16) or older than age 65 (HR = 0.31).

A favorable overall survival trend was also seen with cabozantinib (HR = 0.54). However, probably because of crossovers, a statistically significant difference was not seen and may not emerge, Dr. Brose said.

The difference in response rate (15% vs 0%; P = .028) also was not statistically significant based on a prespecified P value of less than .01, which was designated because of the multiple primary endpoints. Of note, the disease control rate was 60% with cabozantinib and 27% with placebo, and progressive disease as best response was observed in 6% vs 55%, respectively, she reported.

The safety profile was consistent with the known toxicity profile of cabozantinib. Treatment-emergent adverse events of any grade occurred more often with cabozantinib than placebo, including grade 3 or 4 toxicities, which were observed in 57% and 26%, respectively. According to Dr. Brose, adverse events were well managed by supportive care, dose reductions, holds, or occasionally discontinuations.

DISCLOSURE: COSMIC-311 was funded by Exelixis and Ipsen. Dr. Brose has received honoraria from Bayer, Eisai, and Lilly; has served as a consultant or advisor to Bayer, Blueprint Medicines, Eisai, Exelixis, Lilly, and Loxo; and has received institutional research funding from Bayer, Blueprint Medicines, Eisai, Exelixis, Lilly, and Loxo.

REFERENCE

1. Brose MS, Robinson B, Sherman SI, et al: Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who have progressed after prior VEGFR-targeted therapy: Results from the phase 3 COSMIC-311 trial. 2021 ASCO Annual Meeting. Abstract 6001. Presented June 7, 2021.

 


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