Differentiated thyroid cancer (DTC) accounts for 90–95% of newly diagnosed thyroid cancers and includes papillary (80%) and follicular (10–15%) carcinomas, and the less frequent Hürthle cell and poorly differentiated histologies (5–10%).1, 2, 3 Treatment strategies for DTC are multimodal, with a risk-adaptive approach that can include active surveillance, surgery, and radioiodine therapy.4, 5 The prognosis for patients is relatively favourable,6 but up to 15% of patients develop radioiodine-refractory metastatic disease and have a poor prognosis.1, 7 Treatment options for these patients include the tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib.8, 9
Research in context
Evidence before this study
We searched PubMed on Feb 25, 2021, with the term “phase 3 trials in differentiated thyroid cancer”; our search yielded ten reports. These included the following two placebo-controlled phase 3 trials in radioiodine-refractory differentiated thyroid cancer (DTC): the DECISION trial, which showed improved progression-free survival and objective response rate with sorafenib in patients without previous vascular endothelial growth factor receptor (VEGFR)-targeted therapy; and the SELECT trial, which showed improved progression-free survival and objective response rate with lenvatinib in patients with or without up to one previous VEGFR-targeted therapy. The other reports included five subgroup analyses derived from the SELECT study and review articles on DTC. We did not find any phase 3 studies exclusively in patients with radioiodine-refractory DTC whose cancer progressed during or after previous VEGFR-targeted therapies approved for radioiodine-refractory DTC (sorafenib and lenvatinib), indicating an unmet need in this population. Cabozantinib, a multikinase inhibitor that targets VEGFR2, MET, AXL, and RET, is approved for patients with metastatic medullary thyroid cancer and has also shown clinical benefit in phase 1 and 2 studies of patients with radioiodine-refractory DTC with or without previous VEGFR-targeted therapies.
Added value of this study
In this study, cabozantinib showed improved progression-free survival versus placebo in patients with radioiodine-refractory DTC who progressed during or after treatment with one or two previous VEGFR-targeted therapies. With no established standard of care after disease progression on lenvatinib or sorafenib, these results represent an important clinical advancement for these patients. Moreover, to our knowledge, this is the first randomised, phase 3 trial in DTC to evaluate a VEGFR-targeting tyrosine kinase inhibitor (TKI) in patients who have been previously treated with lenvatinib, sorafenib, or both.
Implications of all the available evidence
Patients with radioiodine-refractory DTC who have progressed on one or two prior VEGFR-targeting TKIs have aggressive disease and require additional treatment options. Our results show that cabozantinib significantly prolongs progression-free survival and might provide a new treatment option for these patients who have no available standard of care.
Sorafenib and lenvatinib target the vascular endothelial growth factor receptor (VEGFR) and other kinase receptors involved in tumour proliferation, survival, and angiogenesis.8, 9, 10 Although the majority of patients with radioiodine-refractory DTC initially achieve disease control with sorafenib or lenvatinib, most will eventually develop treatment resistance and have disease progression.8, 9 These patients have few treatment options with no standard of care and are a population with high unmet medical need.11, 12 Disease progression can be associated with debilitating symptoms, and median overall survival for patients with radioiodine-refractory metastatic DTC is less than 5 years.1, 7, 12, 13
Cabozantinib is an inhibitor of several tyrosine kinases that mediate tumour growth and angiogenesis in DTC, including VEGFR2, AXL, MET, and RET.14, 15, 16, 17, 18, 19, 20, 21 MET and AXL have also been implicated in resistance to vascular endothelial growth factor (VEGF) pathway inhibition;22, 23, 24 and RET gene rearrangements resulting in RET fusion proteins are oncogenic drivers in a subset of patients with papillary thyroid cancer.20, 21 Cabozantinib has shown clinical benefit in patients with solid tumours previously treated with VEGFR-targeted therapy, including renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer.25, 26, 27 Phase 1 and 2 studies have shown the clinical activity of cabozantinib in patients with radioiodine-refractory DTC, including those previously treated with VEGFR-targeted therapy.28, 29, 30 Here, we report the primary analysis of objective response rate and interim analysis of progression-free survival from COSMIC-311, a phase 3 trial that evaluated the efficacy and safety of cabozantinib in patients with previously treated radioiodine-refractory DTC.