The vascular endothelial growth factor receptor 2 blocker cabozantinib prolonged progression-free survival in radioiodine-refractory differentiated thyroid cancer following progression on first-line VEGFR inhibitors in a phase 3 trial from cabozantinib maker, Exelixis.
After a median follow up of 6.2 months, the 125 subjects on cabozantinib 60 mg every day had not reached median progression-free survival, but among the 62 randomized to placebo, mPFS was only 1.9 months.
The results led the Food and Drug Administration to grant cabozantinib breakthrough therapy status for salvage after progression on lenvatinib or sorafenib, the two VEGFR inhibitors approved for first-line treatment in radioiodine refractory differentiated thyroid cancer. Cabozantinib already carries a first-line indication for progressive, metastatic medullary thyroid cancer.
“We were all so excited to have sorafenib and lenvatinib,” but patients need another option after they develop resistance. “Cabozantinib is positioned to be the next in line,” said lead investigator Marcia Brose, MD, PhD, a thyroid specialist and professor at the University of Pennsylvania, Philadelphia, who presented the findings at the American Society of Clinical Oncology Annual Meeting.
The trial discussant, medical oncologist Nicole Chau, MD, clinical associate professor at the University of British Columbia, Vancouver, said the results “support cabozantinib as a potential second- or third-line” option, but its impact on quality of life and financial toxicity “should be evaluated.”
Subjects in the trial – dubbed COSMIC-311 – had locally advanced or metastatic disease that had progressed during or after first-line VEGFR treatment, including about 40% with lenvatinib, almost 40% with sorafenib, and over 20% with both.
The median age in the study was 66 years, and 55% of the subjects were women. Bone and liver metastases were more common in the cabozantinib arm.
Promising results
The robust of mPFS benefit (hazard ratio, 0.22; P < .0001) held across subgroups. The mPFS in the placebo arm of 1.9 months demonstrates that “these patients [progress rapidly], so you have to be ready with the next thing in line” to start it quickly, Dr. Brose said.
Overall survival favored cabozantinib (HR, 0.54) but didn’t reach statistical significance perhaps because placebo patients were allowed to cross over to cabozantinib after progression.
The overall response rate was 15% with cabozantinib versus no responders with placebo, which also didn’t meet the study’s criteria for clinical significance. Even so, the disease control rate of 60% with cabozantinib versus 27% with placebo, “is clinically meaningful in this heavily pretreated population,” Dr. Chau said.
Adverse events
Safety was consistent with previous reports and included diarrhea in 51% of cabozantinib subjects, hand-foot skin reaction in 46%, hypertension in 28%, fatigue in 27%, and nausea in 24%, all substantially higher than with placebo. Over half of cabozantinib subjects had grade 3-4 adverse events versus 26% on placebo. There were no treatment related deaths.
Adverse events led to dose reductions or holds in the majority of cabozantinib subjects, but only 5% discontinued the drug; the number might have been higher with longer follow-up, Dr. Chau said.
Genotype-targeted therapy is an option for patients with fusion alterations, but whether it should come before or after VEGFR inhibition is unclear, Dr. Brose noted.
Biomarkers to help with such treatment decisions will become “increasingly important as we move beyond the era of single-agent” VEGFR inhibitors, Dr. Chau said.
The study was funded by cabozantinib maker Exelixis, and three investigators were employees. Dr. Brose disclosed research funding and honoraria from the company, and is an adviser. Dr. Chau has no involvement with Exelixis.