Results from a phase 2 clinical trial have shown that cabozantinib (Cometriq) is active in radioiodine-refractory differentiated thyroid carcinoma in the first-line setting, according to data presented at the 2018 Multidisciplinary Head and Neck Cancers Symposium. Cabozantinib induction therapy resulted in a 54% response rate and an 80% clinical benefit, meeting the study primary end point. The treatment was also well-tolerated, with mostly grade 1 and 2 adverse events.
“This trial demonstrates that cabozantinib is an active agent for radioiodine-refractory differentiated thyroid carcinoma in the first-line setting,” said lead investigator Marcia S. Brose, MD, PhD, Director, Center for Rare Cancers and Personalized Therapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, who presented the results.
“Cabozantinib merits additional study in a large, multicenter, phase 3 trial to determine its efficacy,” she added.
There is an unmet need for patients with thyroid cancer that has become refractory to radioiodine therapy, which occurs in approximately 5% to 15% of cases. Although the FDA approval of the 2 kinase inhibitors, lenvatinib (Lenvima) and sorafenib (Nexavar), has improved progression-free survival (PFS) rates, the responses to treatment with these agents are not durable and more treatments are needed.
Cabozantinib is a multi–tyrosine kinase inhibitor that targets VEGF receptor kinase, RET, MET, and AXL, and is already FDA approved for patients with advanced medullary thyroid cancer or with renal-cell cancer. Although data from a phase 1 study suggested activity as a salvage therapy for radioiodine-refractory differentiated thyroid carcinoma, activity in the first-line setting has never been tested in this patient population.
“Excellent” Response Rates
Dr Brose and colleagues enrolled 35 patients with metastatic, radioiodine-refractory, unresectable or locally advanced thyroid cancer between March 2014 and August 2017. Patients were eligible for the study if they had not received previous kinase inhibitor therapy and had a life expectancy of ≥3 months, as well as good organ and good bone marrow function. Patients received oral cabozantinib 60 mg daily, with dose reductions to 40 mg daily, then 20 mg daily. Some patients continued the drug for an extended period and an additional reduction to 20 mg every other day was allowed.
No complete responses were observed, but 34 of 35 patients had tumor shrinkage, and a partial response (>30% tumor shrinkage) was seen in 19 (54%) patients. The duration of partial responses ranged from 11 weeks to >174 weeks, and stable disease occurred in 15 (43%) patients; 9 (26%) patients had stable disease lasting >6 months.
Although the median PFS had not yet been reached, PFS at 6 and 12 months was 88% and 64%, respectively. In addition, 16 patients continue to receive the drug, including one of the first patients enrolled. The median time of cabozantinib therapy was 35 weeks (range, 3-198 weeks).
“Dose interruptions and dose adjustments were needed for the majority of patients at some point on treatment, but cabozantinib was well-tolerated,” said Dr Brose. Grade 1 hyperglycemia was reported in 80% of patients, but never required treatment.
In addition to hyperglycemia, diarrhea (77%), malaise or fatigue (74%), and weight loss (71%) were the most common adverse events with cabozantinib. Grade ≥3 adverse events included hypertension (14%), increased lipase (9%), weight loss (6%), pulmonary embolism (6%), and hyponatremia (6%). According to Dr Brose, these treatment-related adverse events are consistent with previous toxicities seen with cabozantinib in other tumor types.