Marcia S. Brose, MD, PhD

Cabozantinib (Cometriq) has demonstrated significant activity in the first-line setting for radioiodine-refractory differentiated thyroid carcinoma, according to data from a single-site phase II trial presented at the 2018 Multidisciplinary Head and Neck Cancers Symposium.¹ Treatment with cabozantinib resulted in a 54% response rate and an 80% clinical benefit rate, meeting the primary endpoint of the study. Cabozantinib was also well tolerated, the authors noted, with mostly grade 1 and 2 adverse events and no unexpected toxicities identified.

“This phase II trial showed that cabozantinib is an active agent for radioiodine-refractory differentiated thyroid carcinoma in the first-line setting and merits additional study in a large, multicenter phase III trial,” said Marcia S. Brose, MD, PhD, Associate Professor in the Department of Otorhinolaryngology: Head and Neck Surgery and Director of the Center for Rare Cancers and Personalized Therapy at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Cabozantinib is an active agent for radioiodine-refractory differentiated thyroid carcinoma in the first-line setting and merits additional study in a large, multicenter phase III trial to determine its efficacy.

— Marcia S. Brose, MD, PhD

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As Dr. Brose reported, in 2017 there were more than 56,000 new cases of thyroid cancer diagnosed in the United States, and in approximately 5% to 15% of these cases, the disease becomes refractory to radioiodine. Although the recent approval of two kinase inhibitors by the U.S. Food and Drug Administration (FDA) has helped to increase progression-free survival, the responses are not durable, and toxicities may limit efficacy.

“Sorafenib [Nexavar] and lenvatinib [Lenvima] are used sequentially to improve the progression-free interval for these patients, but patients ultimately progress and need more treatment options,” said Dr. Brose.

Cabozantinib is a multityrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR) kinase, RET, MET, and AXL and is already approved for the treatment of patients with advanced medullary thyroid and renal cell cancers. Prior data from a phase I study suggested it may have activity in those with radioiodine-refractory differentiated thyroid carcinoma who had previously been treated with one or more VEGFR inhibitors or other therapy in the salvage setting.² To further understand the activity of this agent in this patient population, Dr. Brose and colleagues conducted this single-arm, open-label, phase II study of cabozantinib in the first-line setting for this disease.

Study Details

Between March 2014 and August 2017, the investigators enrolled 35 patients with metastatic, radioiodine-refractory, unresectable or locally advanced thyroid cancer. Patients were eligible for the study if they had not received any prior kinase inhibitor therapy and had a life of expectancy of at least 3 months along with good organ and bone marrow function. Patients on study were administered 60 mg of oral cabozantinib each day, with dose reductions to 40 mg daily and then 20 mg daily. In some patients who remained on the drug for an extended period, an additional reduction to 20 mg every other day was allowed, Dr. Brose noted.

Most patients had papillary histology (63%), followed by poorly differentiated (29%) and Hürthle cell (9%) carcinomas. The median patient age was 65 years (range, 45 to 84 years), and 49% of enrolled patients were male.

Response Rates and Toxicity

Although no complete responses were observed, said Dr. Brose, 34 of 35 patients experienced tumor shrinkage, and a partial response, defined as tumor shrinkage greater than 30%, was seen in 19 patients (54%). The duration of partial responses ranged from 11 weeks to more than 174 weeks, and stable disease occurred in 15 patients (43%). Stable disease over 6 months was seen in 9 patients (26%).

As Dr. Brose reported, the median progression-free survival has not yet been reached, but progression-free survival at 6 months and at 12 months is 88% and 64%, respectively. In addition, she said, 16 patients still remain on treatment, including one of the very first patients on the study. The median time on cabozantinib treatment is 35 weeks, ranging from 3 to 198 weeks.

Although dose interruptions and dose adjustments were needed for the majority of patients at some point on treatment, cabozantinib was well tolerated. Grade 1 hyperglycemia was experienced by 80% of patients, said Dr. Brose, but it never needed to be treated. In addition to hyperglycemia, diarrhea (77%), malaise/fatigue (74%), and weight loss (71%) were the most common adverse events attributable to cabozantinib. Grade 3 or higher adverse events that occurred in more than one patient included hypertension (14%), increased lipase levels (9%), weight loss (6%), pulmonary embolism (6%), and hyponatremia (6%). According to Dr. Brose, these treatment-related adverse events are consistent with prior toxicities seen with cabozantinib in other tumor types. ■

DISCLOSURE: Dr. Brose has received grant funding from Loxo, Exelixis, Bayer, Eisai, Genzyme/Sanofi, and AstraZeneca. She has also received honoraria or consulting fees from Eisai, Loxo, Bayer, Genzyme/Sanofi, and Blueprint Medicines.

REFERENCES

1. Brose MS, Shenoy S, Bhat N, et al: A phase II trial of cabozantinib for the treatment of radioiodine-refractory differentiated thyroid carcinoma in the first-line setting. 2018 Multidisciplinary Head and Neck Cancers Symposium. Abstract 8. Presented February 16, 2018.

2. Cabanillas ME, Brose MS, Holland J, et al: A phase I study of cabozantinib (XL184) in patients with differentiated thyroid cancer. Thyroid 24:1508-1514, 2014.