Second-Line Cabozantinib Effective in RAI-Refractory DTC

The oral multikinase inhibitor cabozantinib showed promise as a second- or third-line therapy in patients with advanced radioactive iodine-refractory differentiated thyroid cancer.

Manisha Shah, MD

The oral multikinase inhibitor cabozantinib (Cometriq) showed promise as a second- or third-line therapy in patients with advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) following prior treatment with a VEGFR inhibitor, according to data from a phase II trial presented by Manisha H. Shah, MD, at the 2015 International Thyroid Congress.

In the 25-patient analysis, the confirmed partial response rate with cabozantinib was 36%. Additionally, 2 patients had an unconfirmed partial response. The median progression-free survival was 12.9 months. At the time of the analysis, median overall survival had not yet been reached.

“Cabozantinib is effective in inducing a durable partial response. It has statistically and clinically significant activity,” said Shah, a professor at The Ohio State University Comprehensive Cancer Center in Columbus. “We have a critical need for [treatment of] cancer that progresses after the first- or second-line therapy.”

The FDA approved cabozantinib, which targets MET and VEGFR, in 2012 for patients with progressive medullary thyroid cancer. Two multikinase inhibitors targeting VEGFR, sorafenib and lenvatinib, are approved as therapies for RAI-refractory advanced DTC.

In the open-label phase II study, 25 patients were enrolled who had received a standard of care: surgery, RAI, or external-beam radiation. The median age was 64 years and 64% were men.

One prior VEGFR-targeted therapy was administered to 80% of trial participants and 20% had received 2 prior therapies. The most common prior VEGFR-targeted therapies were sorafenib (52%) and pazopanib (28%), even though it is not FDA-approved for this indication.

Cabozantinib was administered at a starting dose of 60 mg per day orally, which could be increased to 80 mg if the patient failed to achieve a response within the first 4 months of therapy. Nine patients had no dose change, four had an increase to 80 mg, seven had a decrease to 40 mg, and five had a decrease to 40 mg and then 20 mg.

The primary endpoint of the study was an objective response within the first 6 months of treatment. The study was ruled a success, if cabozantinib elicited a response in at least 5 patients.

Overall, 9 of the 25 patients enrolled experienced a confirmed partial response (36%). Additionally, 2 patients had responses that could not be confirmed during the regular 8-week scan, Shah noted. Twelve patients had stable disease with cabozantinib, representing a disease control rate (response plus stable disease) of 92%.

“We saw a 30% or more response in the tumor in those with a partial response,” Shah said. "We exceeded the five patient expectation of success. We are happy to say that, 'yes,' cabozantinib is effective as a second- or third-line therapy for these patients."

Cabozantinib was well tolerated, Shah noted. The most common treatment-related adverse events (AEs) were fatigue, hand-foot skin reaction, anorexia, nausea, mucositis, weight loss, diarrhea, and hypertension. “There were no surprises,” Shah said. “We have learned over the decades and were able to decrease the grade of events.”

Grade >3 AEs were experienced by just 8% of patients treated with cabozantinib. There were no grade 4 events. Three patients experienced grade 3 infections. One patient each experienced grade 3 left ventricular dysfunction, grade 3 skin ulceration, and grade 3 osteonecrosis of the jaw.

Overall, 5 patients discontinued cabozantinib due to AEs. Additionally, there was one death in the trial, which may have been related to the drug. In this incidence, the patient experienced a sudden onset of seizure-like activity possibly related to bleeding.

The prospective, phase II trial was sponsored by the National Cancer Institute and International Thyroid Oncology Group in collaboration with the Cancer Therapy Evaluation Program, the Academic and Community Cancer Research United, and eight participating centers.

“This study was the first of its kind in terms of collaboration,” Shah said. “It was truly teamwork.”

Shah MH, De Souza J, Wirth L, et al. Cabozantinib in patients with radioiodine-refractory differentiated thyroid cancer who progressed on prior VEGFR-targeted therapy: results of NCI- and ITOG-sponsored multicenter phase II clinical trial. Presented at: 2015 International Thyroid Congress; October 18-23, 2015; Orlando, FL. Abstract 73.


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