Promising Activity Seen With Cabozantinib in Radioiodine-Refractory Differentiated Thyroid Carcinoma

Cabozantinib (Cometriq), a promising multikinase inhibitor, demonstrated encouraging antitumor activity for the treatment of radioiodine (RAI)-refractory differentiated thyroid carcinoma (DTC) in the first-line setting, according to the results of a phase II study that were presented at the 2018 Multidisciplinary Head and Neck Cancers Symposium in Scottsdale, Arizona.¹

“The recent introduction of targeted therapy with kinase inhibitors for patients with advanced thyroid cancer created a possible path to control the cancers of patients we previously could treat only with supportive care. Our trial shows that cabozantinib also is an active agent and could significantly improve the care of patients with advanced disease,” said Marcia S. Brose, MD, PhD, associate professor in the Departments of Otorhinolaryngology: Head and Neck Surgery, and Medicine, Division of Hematology/Oncology, and head of the Center for Rare Cancers and Personalized Therapy, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, in a statement.

Data from a previous phase I study suggested activity in patients with RAI-refractory DTC that had been previously treated with 1 or more VEGF inhibitors or other therapy in the salvage setting.²The phase II trial was created to further understand the activity of cabozantinib in the first-line setting for this group of patients.

The single-arm, open-label, phase II study enrolled 35 patients with RAI-refractory metastatic DTC between March 2014 and August 2017. All patients received an oral starting dose of cabozantinib at 60 mg daily. Dose reductions were permitted to 20 mg daily if needed and 20 mg every other day if the patient received the drug for many years.

The median patient age of all participants was 65 years (range, 45-84) and evenly divided between males and females; ECOG performance status was between 0 and 2. Most patients had papillary histology (63%), followed by poorly differentiated (26%) and follicular (Hürthle Cell, 9%) carcinomas. Across the study, all patients had good organ and bone marrow function, with a life expectancy of more than 3 months.

Overall response rate (ORR) by RECIST v1.1 criteria was the primary endpoint of the trial, with cabozantinib deemed to be of further interest if at least 5 of 35 patients responded. Secondary endpoints included progression-free survival (PFS), clinical benefit rate, and safety.

Thirty-four of the 35 patients experienced tumor shrinkage, with 19 (54%) achieving a partial response (PR) greater than 30% reduction. The duration of PR ranged from 11 weeks to more than 174 weeks. Stable disease (SD) was achieved in 15 patients (43%), with 9 (26%) of those 15 maintaining SD for more than 6 months. A clinical benefit rate was achieved in 28 patients (80%).

“This single-site phase II study showed that cabozantinib is an active agent for RAI-refractory DTC in the first-line setting, now confirming what was also known in the salvage setting,” Brose noted during her presentation.

The median PFS had not yet been reached, with only 6 patients experiencing disease progression at the time the study was presented. The median time on the drug is 35 weeks (range, 3-198) and there were 16 patients still receiving cabozantinib therapy as of the February 6 data cutoff.

Cabozantinib was overall well tolerated; however, dose interruptions and adjustments were needed for 23 of the 35 patients at some point during treatment. Treatment-emergent adverse events (AE) of any grade were experienced by all patients; however, they were consistent with the known AE profile of cabozantinib with no added surprises, Brose noted. The most common AE across all grades was hyperglycemia (80%), followed by diarrhea (77%), malaise/fatigue (74%), and weight loss (71%). Grade 3 or higher AEs included hypertension (14%), increased lipase (9%), pulmonary embolism (6%), and hyponatremia (6%).

“In the last 5 years, 2 FDA-approved agents have improved the situation for these patients. Both sorafenib [Nexavar] and lenvatinib [Lenvima] have shown activity in increasing progression-free survival for these patients. However, the responses are not durable and toxicities eventually may limit their efficacy,” Brose said. “Cabozantinib seems to be another agent that could provide relief for these patients.”

Due to the positive results in the phase II study, a multicenter phase III trial is now underway to determine the efficacy of frontline cabozantinib in patients with RAI-refractory DTC.

References:

1. Brose MS, Shenoy S, Bhat N, et al. A phase II trial of cabozantinib for the treatment of radioiodine (RAI)-refractory differentiated thyroid carcinoma (DTC) in the first-line setting. Presented at: 2018 Multidisciplinary Head and Neck Cancers Symposium; February 15-17, 2018; Scottsdale, Arizona. Abstract 8. headandnecksymposium.org/uploadedFiles/Head_and_Neck_Symposium/2018_Head_ and_Neck_Symposium/Abstracts/CompleteHeadNeckPapers.pdf.
2. Cabanillas ME, de Souza JA, Geyer S, et al. Cabozantinib as salvage therapy for patients with tyrosine kinase inhibitor-refractory differentiated thyroid cancer: results of a multicenter phase II international thyroid oncology group trial. J Clin Oncol. 2017;35(29):3315-3321. doi: 10.1200/JCO.2017.73.0226.