Cabozantinib Shows Promise in Second- and Third-line Differentiated Thyroid Cancer

thyroid cancer

Manisha H. Shah, MD

Cabozantinib, an oral multikinase inhibitor, showed promise as second- or third-line therapy in patients with advanced differentiated thyroid cancer (DTC), according to data from a phase II trial, presented by protocol chair Manisha H. Shah, MD, at the 85th Annual Meeting of the American Thyroid Association.

“Cabozantinib is effective in inducing a durable partial response,” said Shah, a professor at The Ohio State University Comprehensive Cancer Center in Columbus. “It has statistically and clinically significant activity.”

Cabozantinib targets MET and VEGFR and is approved for progressive medullary thyroid cancer. Two multikinase inhibitor drugs targeting VEGFR, sorafenib and lenvatinib, are approved as a first-line therapy for radioiodine refractory advanced DTC, but no second- or third-line therapies have been approved.

“We have a critical need for [treatment of] cancer that progresses after the first- or second-line therapy,” Shah said.

Phase I study data, reported in 2014, anticancer activity with cabozantinib and a partial response in 53% of the participants with radioiodine refractory DTC with measurable disease. This study was led by Maria E. Cabanillas, MD, at The University of Texas MD Anderson Cancer Center, Houston, an investigator on the current study.

In the current phase II, open-label study, eight centers enrolled 25 participants in 16 months. Participants had received the standard of care: surgery, radioactive iodine, or external-beam radiation. The median age was 64 years, and 64% were men. Twenty patients had had one line and five patients had two lines of prior VEGFR-targeted therapies.

The primary endpoint was an objective response within the first 6 months of treatment. Subjects were started on cabozantinib starting 60 mg per day orally, but the dose could be increased to 80 mg if the patient failed to achieve a response within the first 4 months of therapy and were tolerating the drug or reduced to 40 mg or 20 mg. 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.

“One size does not fit all,” Shah said.

Five participants discontinued the therapy due to adverse events (AEs). Participants could continue treatment as long as they had a partial response. Participants received a CT or MRI every 2 months.

“We saw a 30% or more response in the tumor in those with a partial response,” Shah said.

Of the 25 participants, 9 achieved a partial response, 2 an unconfirmed partial response, 12 had stable disease, one experienced progressive disease, and 1 was not evaluable.

The median progression-free survival was 12.8 months. Medial overall survival was not reached.

Shah reported the drug was well tolerated. The most common related 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.”

A total of 8% of participants experienced a grade 3 or higher reaction, including one death, possibly related to the trial drug. That participant experienced a sudden onset of seizure-like activity thought to be related to bleeding. 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.

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. 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 the 85th Annual Meeting of the American Thyroid Association: Lake Buena Vista, FL; Abstract #73.