Elsevier

The Lancet Oncology

Volume 22, Issue 8, August 2021, Pages 1126-1138
The Lancet Oncology

Articles
Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(21)00332-6Get rights and content

Summary

Background

Patients with radioiodine-refractory differentiated thyroid cancer (DTC) previously treated with vascular endothelial growth factor receptor (VEGFR)-targeted therapy have aggressive disease and no available standard of care. The aim of this study was to evaluate the tyrosine kinase inhibitor cabozantinib in this patient population.

Methods

In this global, randomised, double-blind, placebo-controlled, phase 3 trial, patients aged 16 years and older with radioiodine-refractory DTC (papillary or follicular and their variants) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to oral cabozantinib (60 mg once daily) or matching placebo, stratified by previous lenvatinib treatment and age. The randomisation scheme used stratified permuted blocks of block size six and an interactive voice–web response system; both patients and investigators were masked to study treatment. Patients must have received previous lenvatinib or sorafenib and progressed during or after treatment with up to two VEGFR tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib on disease progression confirmed by blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (confirmed response per Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) in the first 100 randomly assigned patients (objective response rate intention-to-treat [OITT] population) and progression-free survival (time to earlier of disease progression per RECIST version 1.1 or death) in all patients (intention-to-treat [ITT] population), both assessed by BIRC. This report presents the primary objective response rate analysis and a concurrent preplanned interim progression-free survival analysis. The study is registered with ClinicalTrials.gov, NCT03690388, and is no longer enrolling patients.

Findings

Between Feb 27, 2019, and Aug 18, 2020, 227 patients were assessed for eligibility, of whom 187 were enrolled from 164 clinics in 25 countries and randomly assigned to cabozantinib (n=125) or placebo (n=62). At data cutoff (Aug 19, 2020) for the primary objective response rate and interim progression-free survival analyses, median follow-up was 6·2 months (IQR 3·4–9·2) for the ITT population and 8·9 months (7·1–10·5) for the OITT population. An objective response in the OITT population was achieved in ten (15%; 99% CI 5·8–29·3) of 67 patients in the cabozantinib group versus 0 (0%; 0–14·8) of 33 in the placebo (p=0·028) but did not meet the prespecified significance level (α=0·01). At interim analysis, the primary endpoint of progression-free survival was met in the ITT population; cabozantinib showed significant improvement in progression-free survival over placebo: median not reached (96% CI 5·7–not estimable [NE]) versus 1·9 months (1·8–3·6); hazard ratio 0·22 (96% CI 0·13–0·36; p<0·0001). Grade 3 or 4 adverse events occurred in 71 (57%) of 125 patients receiving cabozantinib and 16 (26%) of 62 receiving placebo, the most frequent of which were palmar–plantar erythrodysaesthesia (13 [10%] vs 0), hypertension (11 [9%] vs 2 [3%]), and fatigue (ten [8%] vs 0). Serious treatment-related adverse events occurred in 20 (16%) of 125 patients in the cabozantinib group and one (2%) of 62 in the placebo group. There were no treatment-related deaths.

Interpretation

Our results show that cabozantinib significantly prolongs progression-free survival and might provide a new treatment option for patients with radioiodine-refractory DTC who have no available standard of care.

Funding

Exelixis.

Introduction

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.

Section snippets

Study design and participants

COSMIC-311 was a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Patients from 164 clinics in 25 countries (appendix pp 2–3) were eligible for enrolment if they were aged 16 years or older, had a confirmed diagnosis of DTC (papillary or follicular and their histological variants), had measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and were previously treated with or deemed ineligible for treatment with

Results

Patients were enrolled into the trial from Feb 27, 2019, to Aug 18, 2020. The data reported here are as of the data cutoff date of Aug 19, 2020, 6 months after the last patient in the OITT population was randomly assigned. Of 227 patients assessed for eligibility, 187 patients were enrolled and randomly assigned to cabozantinib (n=125) or to placebo (n=62). These patients comprise the ITT and safety populations, since all randomised patients received at least one dose of their assigned study

Discussion

In this trial, cabozantinib significantly prolonged progression-free survival in patients with progressive radioiodine-refractory DTC who had previously received a VEGFR-targeted therapy, with a significant reduction in the risk of disease progression or death. This clinically significant progression-free benefit with cabozantinib versus placebo was observed despite the relatively short median follow-up at the time of the interim progression-free survival analysis. The objective response rate

Data sharing

Individual participant data will not be made available.

Declaration of interests

MSB has an institutional funding grant from Exelixis, and has received consulting fees from Bayer, Lilly, LOXO, Eisai, Blueprint, and Kura outside of the submitted work. SIS is a consultant with Exelixis. JK is a consultant with Exelixis, and reports consulting with LOXO, Bayer Health Care, Sanofi-Genzyme, and Ipsen, and has acted as a sub-investigator for Eisai, outside of the submitted work. C-CL has received travel fees from BeiGene and Daiichi Sankyo, has had an advisory role with Blueprint

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