Articles

Cabozantinib for radioiodine-refractory differentiated

thyroid cancer (COSMIC-311): a randomised, double-blind,
placebo-controlled, phase 3 trial
Marcia S Brose, Bruce Robinson, Steven I Sherman, Jolanta Krajewska, Chia-Chi Lin, Fernanda Vaisman, Ana O Hoff, Erika Hitre, Daniel W Bowles,
Jorge Hernando, Leonardo Faoro, Kamalika Banerjee, Jennifer W Oliver, Bhumsuk Keam, Jaume Capdevila

Summary
Background Patients with radioiodine-refractory differentiated thyroid cancer (DTC) previously treated with vascular Lancet Oncol 2021
endothelial growth factor receptor (VEGFR)-targeted therapy have aggressive disease and no available standard of Published Online
care. The aim of this study was to evaluate the tyrosine kinase inhibitor cabozantinib in this patient population. July 5, 2021
https://doi.org/10.1016/
S1470-2045(21)00332-6
Methods In this global, randomised, double-blind, placebo-controlled, phase 3 trial, patients aged 16 years and older
Abramson Cancer Center,
with radioiodine-refractory DTC (papillary or follicular and their variants) and an Eastern Cooperative Oncology Group University of Pennsylvania,
performance status of 0 or 1 were randomly assigned (2:1) to oral cabozantinib (60 mg once daily) or matching placebo, Philadelphia, PA, USA
stratified by previous lenvatinib treatment and age. The randomisation scheme used stratified permuted blocks of block (Prof M S Brose MD); Sydney
Medical School, The University
size six and an interactive voice–web response system; both patients and investigators were masked to study treatment.
of Sydney, Sydney, NSW,
Patients must have received previous lenvatinib or sorafenib and progressed during or after treatment with up to two Australia (Prof B Robinson MD);
VEGFR tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib on disease Department of Endocrine
progression confirmed by blinded independent radiology committee (BIRC). The primary endpoints were objective Neoplasia and Hormonal
Disorders, University of Texas
response rate (confirmed response per Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) in the first
MD Anderson Cancer Center,
100 randomly assigned patients (objective response rate intention-to-treat [OITT] population) and progression-free Houston, TX, USA
survival (time to earlier of disease progression per RECIST version 1.1 or death) in all patients (intention-to-treat [ITT] (Prof S I Sherman MD);
population), both assessed by BIRC. This report presents the primary objective response rate analysis and a concurrent Department of Nuclear
Medicine and Endocrine
preplanned interim progression-free survival analysis. The study is registered with ClinicalTrials.gov, NCT03690388,
Oncology, Maria Sklodowska
and is no longer enrolling patients. Curie National Research
Institute of Oncology Gliwice
Findings Between Feb 27, 2019, and Aug 18, 2020, 227 patients were assessed for eligibility, of whom 187 were enrolled Branch, Gliwice, Poland
(J Krajewska MD); Department
from 164 clinics in 25 countries and randomly assigned to cabozantinib (n=125) or placebo (n=62). At data cutoff (Aug
of Oncology, National Taiwan
19, 2020) for the primary objective response rate and interim progression-free survival analyses, median follow-up University Hospital, Taipei,
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 Taiwan (Prof C-C Lin MD);
objective response in the OITT population was achieved in ten (15%; 99% CI 5·8–29·3) of 67 patients in the Instituto Nacional de Câncer,
Rio de Janeiro, Brazil
cabozantinib group versus 0 (0%; 0–14·8) of 33 in the placebo (p=0·028) but did not meet the prespecified significance (F Vaisman MD); Department of
level (α=0·01). At interim analysis, the primary endpoint of progression-free survival was met in the ITT population; Endocrinology, Instituto do
cabozantinib showed significant improvement in progression-free survival over placebo: median not reached (96% CI Câncer do Estado de São Paulo,
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 Universidade de São Paulo,
São Paulo, Brazil (A O Hoff MD);
adverse events occurred in 71 (57%) of 125 patients receiving cabozantinib and 16 (26%) of 62 receiving placebo, the Department of Medical
most frequent of which were palmar–plantar erythrodysaesthesia (13 [10%] vs 0), hypertension (11 [9%] vs 2 [3%]), and Oncology and Clinical
fatigue (ten [8%] vs 0). Serious treatment-related adverse events occurred in 20 (16%) of 125 patients in the cabozantinib Pharmacology “B”, Országos
group and one (2%) of 62 in the placebo group. There were no treatment-related deaths. Onkológiai Intézet, Budapest,
Hungary (E Hitre MD); Division
of Medical Oncology,
Interpretation Our results show that cabozantinib significantly prolongs progression-free survival and might provide Department of Medicine,
a new treatment option for patients with radioiodine-refractory DTC who have no available standard of care. University of Colorado
Anschutz Medical Campus,
Aurora, CO, USA
Funding Exelixis. (D W Bowles MD); Vall d’Hebron
University Hospital, Vall
Copyright © 2021 Elsevier Ltd. All rights reserved. d’Hebron Institute of Oncology,
Universitat Autònoma de
Barcelona, Barcelona, Spain
Introduction approach that can include active surveillance, surgery, (J Hernando MD, J Capdevila MD);
Differentiated thyroid cancer (DTC) accounts for and radioiodine therapy.4,5 The prognosis for patients is Exelixis, Alameda, CA, USA
90–95% of newly diagnosed thyroid cancers and relatively favourable,6 but up to 15% of patients develop (L Faoro MD, K Banerjee MSc,
J W Oliver MD); Department of
includes papillary (80%) and follicular (10–15%) radioiodine-refractory metastatic disease and have a
Internal Medicine, Seoul
carcinomas, and the less frequent Hürthle cell and poor prognosis.1,7 Treatment options for these patients National University Hospital,
poorly differentiated histologies (5–10%).1–3 Treatment include the tyrosine kinase inhibitors (TKIs) sorafenib Seoul, South Korea (B Keam MD)
strategies for DTC are multimodal, with a risk-adaptive and lenvatinib.8,9

www.thelancet.com/oncology Published online July 5, 2021, https://doi.org/10.1016/S1470-2045(21)00332-6 1

 Articles

Correspondence to:
Prof Marcia S Brose, Abramson
Cancer Center, University of
Pennsylvania, Philadelphia,
PA 19010, USA
marcia.brose@pennmedicine.
upenn.edu
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.8–10 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 pro­
See Online for appendix gression.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.14–21 MET and
AXL have also been implicated in resistance to vascular
endothelial growth factor (VEGF) pathway inhibition;22–24
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.25–27 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.28–30 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.
Methods
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 iodine-131.
Patients must have received previous treatment with
lenvatinib or sorafenib, and up to two previous VEGFR
TKIs were allowed. Patients must have had radiographic
progression per RECIST version 1.1 during or following
treatment with a VEGFR TKI. Patients were also required
to have an Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1, adequate organ and bone
marrow function, and must have been receiving thyroxine
replacement therapy with serum thyroid-stimulating
hormone concentrations below the lower cutoff of the
reference range or less than 0·50 mIU/L. Organ function
was assessed at screening through review of haematology,
chemistry, and urine laboratory results. Key exclusion
criteria included previous treatment with selective BRAF
inhibitors, concurrent treatment with oral anticoagulants
or platelet inhibitors (excluding low-dose aspirin and
low-dose low-molecular-weight heparins), presence of

2 www.thelancet.com/oncology Published online July 5, 2021, https://doi.org/10.1016/S1470-2045(21)00332-6


untreated brain metas­tases, and uncontrolled, significant
intercurrent illness. Additional eligibility criteria are listed
in the appendix (pp 4–8) and the study protocol (appendix).
The study protocol was approved by the institutional
review board or ethics committee at each centre and the
trial was done in accordance with Good Clinical Practice,
including the International Conference on Harmonisation
and the Declaration of Helsinki. All patients provided
written informed consent.
Randomisation and masking
Patients were randomly assigned (2:1) to receive
cabozantinib or matching placebo. The 2:1 randomisation
was selected to reduce the proportion of patients assigned
to placebo because these patients have no standard of
care. Randomisation was stratified by previous lenvatinib
treatment (yes vs no) and age (≤65 vs >65 years). The
randomisation scheme used stratified permuted blocks of
block size six and study treatment was centrally assigned
through an interactive voice–web response system.
Generation of the randomisation schedule was assigned
to a clinical research organisation who maintained an
unmasked team independent from the study. The live
schedule, generated by the clinical research organisation,
was uploaded to a secured server for the interactive
response technology vendor who was responsible for
interactive voice–web response services. Study personnel
did not have access to the live schedule, the master list of
blocks or block sizes, until authorised and documented
unmasking (April 16, 2021). Unique drug pack numbers
were preprinted onto each bottle or package and assigned
to the patient by the interactive voice–web response
system to ensure patients, investigators, site staff, and the
study sponsor remained masked to treatment assignment.
Investigators could request that patients be unmasked at
the time of radio­ graphic progression confirmed by
blinded independent radiology committee (BIRC).
Procedures
Patients self-administered 60 mg of cabozantinib tablets
or matching placebo tablets orally once per day. Both
groups also received best supportive care (analgesia,
antibiotics for infections, transfusions for anaemia,
nutritional support, and psychological support with
medication or counseling as appropriate). Adverse events
were managed with dose modification and supportive
care, which were allowed at any time per investigator
judgment. Dose interruptions, reductions, or both, were
recommended for treatment-related adverse events. Dose
modification was recommended for intolerable grade 2
adverse events and grade 3 or 4 adverse events. Dose
interruptions were allowed for up to 8 weeks, or longer
but only with sponsor approval, and the dose could be
reduced from 60 mg to 40 mg daily and then to 20 mg
daily. Patients continued to receive treatment until disease
progression was confirmed per RECIST version 1.1 or
until unacceptable toxicity. Other reasons for treatment
www.thelancet.com/oncology Published online July 5, 2021, https://doi.org/10.1016/S1470-2045(21)00332-6 3
Articles
discontinuation included patient decision, non-com­
pliance, or pregnancy. Patients who were unmasked at
radiographic progression and found to be in the placebo
group could cross over, if eligible, to receive open-label
cabozantinib. Patients in the cabozantinib group who had
radiographic progression could also transition to open-
label cabozantinib as long as they were deriving clinical
benefit in the opinion of the investigator.
Tumour response and progression were assessed by
MRI or CT at baseline, every 8 weeks after randomisation
for 12 months, and then every 12 weeks thereafter.
Images were evaluated per RECIST version 1.1 by the
investigators and BIRC. Serum thyroglobulin was
assessed at baseline, week 5, week 9, and then every
8 weeks. Quantification of serum thyroglobulin was done
by Covance Central Laboratory Services (Indianapolis,
IN, USA), and was established by chemiluminescence
immunoassay by means of IMMULITE 2000 (Siemens
Medical Solutions Diagnostics, Los Angeles, CA, USA).
Laboratory tests, including haematology, chemistry,
coagulation, urine, and thyroid function tests, were done
at baseline, every 2 weeks until week 9, and then every
4 weeks thereafter. Safety was assessed every 2 weeks
until week 9, then every 4 weeks thereafter, with a post-
treatment follow-up visit 30 days after treatment
discontinuation. Adverse events were assessed by
investigators with severity graded according to the
National Cancer Institute Common Terminology Criteria
for Adverse Events, version 5. Overall survival was
assessed every 12 weeks after the last post-treatment visit.
Outcomes
The multiple primary endpoints were objective response
rate in the first 100 randomly assigned patients (the
objective response rate intention-to-treat [OITT]
population) and progression-free survival in all randomly
assigned patients (the intention-to-treat [ITT] population),
both based on evaluations by BIRC. Meeting either of the
endpoints of objective response rate or progression-free
survival would indicate superiority of cabozantinib
treatment over placebo. Progression-free survival was
defined as time from randomisation to the earlier of either
radiographic progression per RECIST version 1.1 or death
from any cause, and objective response rate was defined
as the proportion of patients with a confirmed complete or
partial response per RECIST version 1.1 after a minimum
of 6 months of follow-up in the OITT population. Other
prespecified efficacy endpoints included overall survival
(defined as the time from randomisation to death from
any cause), duration of response (defined as the time from
first documentation of objective response that is
confirmed at least 28 days later to the earliest date of
disease progression or death from any cause), and changes
in serum thyroglobulin concentrations (defined as the
best percentage decrease in serum thyroglobulin concen­
trations on the basis of assessments at baseline, week 5
day 1, and week 9 day 1) and were evaluated in the OITT
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and ITT populations. The disease stabilisation rate was a

Objective response rate Intention-to-treat
intention-to-treat population prespecified supportive analysis and was defined as the
population proportion of patients achieving a confirmed response
Cabozantinib Placebo Cabozantinib Placebo (complete or partial) or stable disease with a duration of at
group group group group least 16 weeks. Safety and tolerability were evaluated in all
(n=67) (n=33) (n=125) (n=62) patients who received at least one dose of the trial regimen
Age, years 62 (56–71) 63 (55–71) 65 (56–72) 66 (56–72) (the safety population). Additional endpoints included the
≥65 years 32 (48%) 16 (48%) 63 (50%) 33 (53%) pharmacokinetics of cabozantinib, the association of
Sex biomarkers with outcomes, health-related quality of life,
Male 32 (48%) 12 (36%) 57 (46%) 28 (45%) and health-care utilisation; analyses of these endpoints are
Female 35 (52%) 21 (64%) 68 (54%) 34 (55%) in progress.
Geographical region
Europe 35 (52%) 14 (42%) 65 (52%) 32 (52%) Statistical analysis
Asia 6 (9%) 8 (24%) 16 (13%) 13 (21%) The study was designed to provide adequate power for
North America (USA and Canada) 8 (12%) 6 (18%) 13 (10%) 9 (15%) assessment of the two primary endpoints of objective
Rest of the world 18 (27%) 5 (15%) 31 (25%) 8 (13%) response rate and progression-free survival with an
Race* estimated sample size of 300 patients. Inflation of type 1
White 47 (70%) 20 (61%) 90 (72%) 41 (66%)
error associated with two primary endpoints was
Asian 10 (15%) 9 (27%) 20 (16%) 14 (23%)
controlled by a modified Bonferroni procedure, which
Black 1 (1%) 1 (3%) 1 (1%) 2 (3%)
involved a two-sided test of objective response rate at the
Other 3 (4%) 0 5 (4%) 1 (2%)
1% α level and of progression-free survival at the 4% α
level. This split was chosen to help minimise total sample
Not reported or missing 6 (9%) 3 (9%) 9 (7%) 4 (6%)
size, weighting progression-free survival because it is the
Eastern Cooperative Oncology Group performance status
determinant of the total sample size. The primary
0 33 (49%) 17 (52%) 59 (47%) 30 (48%)
objective of the study would be met if at least one null
1 34 (51%) 16 (48%) 66 (53%) 32 (52%)
hypothesis was rejected at its respective α level. Objective
Radioiodine therapy status†
response rates of 35% in the cabozantinib group and
Refractory 65 (97%) 33 (100%) 121 (97%) 62 (100%)
2% in the placebo group were assumed. We estimated that
Ineligible 3 (4%) 0 5 (4%) 0
100 patients in the OITT population would be adequate to
Previous sorafenib or lenvatinib
evaluate objective response rate alone by means of a two-
Sorafenib but no lenvatinib 26 (39%) 12 (36%) 46 (37%) 23 (37%)
sided Fisher’s exact test at a significance level of 0·01 with
Lenvatinib but no sorafenib 22 (33%) 13 (39%) 48 (38%) 26 (42%)
a power greater than 90%. The primary analysis of
Sorafenib and lenvatinib 19 (28%) 8 (24%) 31 (25%) 13 (21%) objective response rate in the OITT population was to be
Number of previous vascular endothelial growth factor receptor tyrosine kinase inhibitors done 6 months after the 100th patient had been randomly
1 46 (69%) 24 (73%) 91 (73%) 48 (77%) assigned. For progression-free survival, we estimated that
2 21 (31%) 9 (27%) 34 (27%) 14 (23%) 193 events observed in 300 patients in the ITT population
Thyroid stimulating hormone level, mIU/L 0·025 0·020 0·023 0·019 would provide 90% power to detect a hazard ratio (HR)
(0·01–0·06) (0·01–0·06) (0·01–0·06) (0·01–0·04)
of 0·61 by means of a two-sided log-rank test at a
Histological subtype‡
significance level of 0·04. Assuming an exponential
Papillary 39 (58%) 20 (61%) 67 (54%) 35 (56%)
distribution of progression-free survival, this corre­spon­
Follicular 30 (45%) 13 (39%) 62 (50%) 28 (45%)
ded to a hypo­thesised increase in median progression-free
Metastatic lesions§ 63 (94%) 32 (97%) 117 (94%) 60 (97%)
survival of 64% from 5·5 months to 9 months (HR 0·61).
Bone 35 (52%) 14 (42%) 62 (50%) 24 (39%) An interim analysis of progression-free survival was
Liver 15 (22%) 4 (12%) 27 (22%) 6 (10%) planned at the time of the primary analysis of objective
Lung 46 (69%) 26 (79%) 88 (70%) 49 (79%) response rate. Approximately 43% of the total progression-
Other 57 (85%) 28 (85%) 104 (83%) 56 (90%) free survival events were expected to have been observed
Time from diagnosis, years 7·8 6·2 7·6 8·1 in the ITT population at this time. Inflation of type 1 error
(5·9–11·1) (2·9–15·8) (4·8–11·1) (3·3–14·0)
arising from repeated analyses of progression-free survival
Time since last disease progression, months 1·9 1·6 1·9 1·9
(1·0–4·7) (0·9–4·4) (1·0–4·0) (0·8–3·7)
was controlled by a Lan-DeMets–O’Brien Fleming alpha
spending function, by means of the actual information
Data are median (IQR) or n (%). *More than one category could be self-reported by the patient. †One patient in the fraction at the time of the interim analysis. By means of
cabozantinib group was recorded as both refractory to and ineligible for radioiodine therapy. ‡Five patients in the
intention-to-treat population were noted as having both papillary and follicular histology. §Per investigator
the alpha re-allocation technique, the alpha spending
assessment. function used to establish the critical values for rejection
of the null hypothesis for progression-free survival was
Table 1: Baseline demographics and clinical characteristics
planned to be based on a total alpha of 5% or 4%,
conditional on whether the null hypothesis for objective
response rate was rejected or not rejected, respectively. An

4 www.thelancet.com/oncology Published online July 5, 2021, https://doi.org/10.1016/S1470-2045(21)00332-6

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Intention-to-treat population Objective response rate intention-to-treat population

227 patients were assessed for eligibility

40 did not meet eligibility criteria

187 randomly assigned First 100 patients randomly assigned

125 assigned to and received 62 assigned to and received placebo 67 assigned to and received 33 assigned to and received placebo
cabozantinib cabozantinib

36 discontinued masked 36 discontinued masked 30 discontinued masked 24 discontinued masked

cabozantinib placebo cabozantinib placebo
14 disease progression 29 disease progression 13 disease progression 19 disease progression
8 adverse event 1 adverse event 6 adverse event 1 adverse event
10 clinical deterioration 6 clinical deterioration 8 clinical deterioration 4 clinical deterioration
1 lack of clinical benefit 26 continued masked placebo 1 lack of clinical benefit 9 continued masked placebo
2 withdrew consent at data cutoff 1 withdrew consent at data cutoff
1 other reason 1 other reason
89 continued masked 37 continued masked
cabozantinib at data cutoff cabozantinib at data cutoff

2 transitioned to open-label 19 transitioned to open-label 2 transitioned to open-label 11 transitioned to open-label

cabozantinib cabozantinib cabozantinib cabozantinib
1 discontinued open-label 5 discontinued open-label 1 discontinued open-label 3 discontinued open-label
cabozantinib (clinical cabozantinib cabozantinib (clinical cabozantinib
deterioration) 1 disease progression deterioration) 1 disease progression
1 continued open-label 1 adverse event 1 continued open-label 1 adverse event
cabozantinib at data 3 clinical deterioration cabozantinib at data 1 clinical deterioration
cutoff 14 continued open-label cutoff 8 continued open-label
cabozantinib at data cabozantinib at data
cutoff cutoff

125 included in the efficacy and safety 62 included in the efficacy and safety 67 included in response analyses 33 included in response analyses
analyses analyses

Figure 1: Trial profile

alpha of 0·0008 for the interim analysis of progression-
free survival was assumed on the basis of a predicted 43%
information fraction at interim analysis of progression-
free survival done at the time of the objective response
rate analysis. However, at this analysis, the actual infor­
mation fraction was 38% for progression-free survival;
therefore, the alpha was adjusted to 0·00036 to reflect
the 38% information fraction. The trial was not designed
to control type 1 error for overall survival.
Efficacy was assessed in both the OITT and ITT
populations. Subgroup analyses of objective response
rate, progression-free survival, and overall survival were
prespecified with subgroups defined by previous
treatment with sorafenib, lenvatinib, or both; number of
previous VEGFR TKIs; age; sex; race; ECOG performance
status score; geographical region; previous treatment with
radioiodine; DTC histology; and metastatic site. Here we
have presented only the subgroup analysis of progression-
free survival. We do not show the subgroup analysis
for the objective response rate endpoint as it was not
significant and there were no responses in the placebo
group. As the overall survival was not a controlled
endpoint and the duration of follow-up was relatively
short, the subgroup analysis for this endpoint is also not
presented. Metastatic sites included liver and lung, the
most common sites for visceral metastasis in patients
with DTC, which were assessed as individual subgroups
and in aggregate to ensure a more robust subgroup
analysis. Objective response rate per RECIST 1.1 by BIRC
was compared using Fisher’s exact test at an alpha of 1%
for the OITT population. The 99% CI for objective
response rate was also estimated using an exact binomial
method. A prespecified non-inferential sensitivity analysis
for objective response rate per RECIST 1.1 by investigator
was done as well. Waterfall plots displaying maximum
percentage tumour reduction or minimum increase since
baseline in target lesions were generated as a supportive
analysis. The Kaplan-Meier method was used to estimate
the median follow-up times and associated 95% CIs for
all time-to-event endpoints, including duration of
response and progression-free survival. The Kaplan-Meier
survival estimates at pre-specified timepoints were

www.thelancet.com/oncology Published online July 5, 2021, https://doi.org/10.1016/S1470-2045(21)00332-6 5

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Objective response rate intention-to-treat Intention-to-treat population

population
Cabozantinib group Placebo group Cabozantinib group Placebo group
(n=67) (n=33) (n=125) (n=62)
Objective response rate, % 15% (99% CI 5·8–29·3) 0 (99% CI 0–14·8) 9% (95% CI 4·5–15·2) 0 (95% CI 0–5·8)
p value* 0·028 ·· 0·017 ··
Best overall confirmed response
Complete response 0 0 0 0
Partial response 10 (15%) 0 11 (9%) 0
Stable disease 46 (69%) 14 (42%) 76 (61%) 21 (34%)
≥16 weeks 30 (45%) 9 (27%) 43 (34%) 10 (16%)
Progressive disease 4 (6%) 18 (55%) 8 (6%) 31 (50%)
Not evaluable 1 (1%) 1 (3%) 2 (2%) 1 (2%)
No disease 1 (1%) 0 1 (1%) 0
Missing 5 (7%) 0 27 (22%) 9 (15%)
Disease stabilisation rate, %† 60% (95% CI 47·0–71·5) 27% (95% CI 13·3–45·5) 43% (95% CI 34·4–52·4) 16% (95% CI 8·0– 27·7)
Duration of response, median, months NR (95% CI 4·1–NE) NA NR (95% CI 4·1–NE) NA
Time to response, median (IQR), months 2·5 (1·8–3·6) NA 1·9 (1·8-3·6) NA

Data are n (%), unless otherwise indicated. Tumour response was assessed with Response Evaluation Criteria in Solid Tumours, version 1.1 by blinded independent radiology
committee. No disease=baseline disease was not detected by BIRC; all patients had measurable disease per investigator per eligibility criteria. Missing=missing baseline or
post-baseline assessment, or stable disease not meeting minimum criteria for interval from randomisation. Not evaluable=best overall response could not be evaluated with
available assessments (eg, due to image quality or lesion characteristics). NA=not applicable. NE=not estimable. NR=not reached. *Fisher’s exact text (unstratified); p value
compares the treatment groups. †Prespecified supportive analysis, complete or partial response or stable disease for ≥16 weeks.

Table 2: Response outcomes

also provided. Median time to response was estimated by
the arithmetic method. The primary endpoint of
progression-free survival used the 96% CI for inferential
purposes as the 1% alpha was spent in the analysis of the
other primary endpoint of objective response rate and
could not be reallocated to progression-free survival.
Hypothesis testing for progression-free-survival was done
with a stratified log-rank test. The HR was estimated by
means of a stratified Cox proportional hazards model. The
proportional hazards assumption was evaluated visually
and by means of the time by effect interaction test for the
treatment effect. No violation of the proportional hazards
assumption was found. Three sensitivity analyses of
progression-free survival were done to evaluate the effect
of inconsistent tumour assessment intervals between
groups, evaluation of progression by the investigator, and
the effect of missing tumour assessments. Only the
sensitivity analysis of progression-free survival by
investigator assessment is shown to establish consistency
with the BIRC assessment. Categorical and continuous
data were summarised with descriptive statistics. All
analyses were done with SAS version 9.4.
Safety and efficacy were monitored by an independent
data monitoring committee.
This trial is registered with ClinicalTrials.gov,
NCT03690388.
Role of the funding source
The funder of the study provided cabozantinib and
placebo and had a role in study design, data collection,
and data analysis. MSB, BR, SIS, and the steering
committee in collaboration with the funder designed the
trial. The authors and the funder were responsible for data
collection, data analysis, and data interpretation. The
funder also provided financial support for medical writing.
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
treatment. The first 100 randomly assigned patients
(67 in the cabozantinib group and 33 in the placebo
group) comprise the OITT population.
Baseline demographics and clinical characteristics are
shown in table 1. Median age was 66 years (IQR 56–72) in
the ITT population. Regarding previous therapy, 118 (63%)
of 187 patients had received previous lenvatinib,
113 (60%) patients had received previous sorafenib, and
44 (24%) patients had received both lenvatinib and
sorafenib. Most patients (142 [76%] had had disease
progression while receiving sorafenib or lenvatinib as their
most recent previous therapy (appendix p 9). The median
(IQR) number of previous systemic non-radiation anti-
cancer therapies was two (2–3) in both treatment groups.

6 www.thelancet.com/oncology Published online July 5, 2021, https://doi.org/10.1016/S1470-2045(21)00332-6

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A
40
30
Best percentage change from baseline in

20
target lesions (sum of diameters)

10
0
–10
–20
–30
* *
–40 *
* * *
–50 * *
–60 * *
–70

B
40
Best percentage change from baseline in

30
target lesions (sum of diameters)

20
10
0
–10
–20
–30
–40
–50
–60

Figure 2: Waterfall plot for maximum percentage tumour reduction from baseline in target lesions for individual patients (objective response rate
intention-to-treat population)
(A) Cabozantinib group. (B) Placebo group. Tumour response was assessed with Response Evaluation Criteria in Solid Tumours version 1.1 by blinded independent
radiology committee. The waterfall plots show the maximum percentage reduction or minimum increase from baseline in sum of diameters of target lesions before
progressive disease or initiation of any non-protocol anti-cancer medication. Only patients with at least one baseline and post-baseline assessment are shown. Of the
58 patients in the cabozantinib group and 31 in the placebo group with at least one-post baseline assessment, one patient in the cabozantinib group and
two patients in the placebo group did not have a qualifying sum of diameter for inclusion in the waterfall plot. *Confirmed partial response.

At data cutoff, 89 patients were continuing masked
cabozantinib treatment, and 26 were continuing masked
placebo treatment (figure 1). The most common reason
for treatment discontinuation was disease progression in
both treatment groups. Two patients in the cabozantinib
group and 19 in the placebo group had been unmasked at
radiographic progression per BIRC and transitioned to
receive open-label cabozantinib. 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.
In the OITT population, ten (15%) of 67 patients had
confirmed partial responses by BIRC in the cabozantinib
group, and there were no confirmed responses among
33 patients in the placebo group. The objective response
rate by BIRC was 15% (99% CI 5·8–29·3) in the
cabozantinib group versus 0% (0–14·8) in the placebo
group (p=0·028, table 2); this difference was not
significant (the observed p value >the critical p value
of 0·01). Median duration of response in the cabozantinib
group had not been reached at the data cutoff, with
nine of ten patients maintaining response at data cutoff
while one patient had disease progression. 44 (76%) of
58 patients with at least one post-baseline target lesion
assessment in the cabozantinib group had a reduction in
target lesions compared with nine (29%) of 31 patients in
the placebo group (figure 2). Response outcomes by
investigator assessment (appendix p 10) were generally
consistent with outcomes by BIRC.
At the data cutoff, 74 (38%) of 193 of the total progression-
free survival events had occurred. There were
31 progression-free survival events in the cabo­zantinib
group and 43 in the placebo group. Because the null
hypothesis for objective response rate was not rejected,
the critical p value for rejecting the null hypothesis for
progression-free survival at the interim analysis was
computed to be 0·00036, per the alpha spending function
at the 4% level for the 38% information fraction.
Interim analysis of progression-free survival by BIRC
in the ITT population showed a significant improvement
with cabozantinib versus placebo. Median progression-
free survival was not reached (96% CI 5·7–not estimable
[NE]) in the cabozantinib group compared with
1·9 months (1·8–3·6) in the placebo group (HR 0·22
[96% CI 0·13–0·36], p<0·0001), with progression-free
survival estimates of 57% (96% CI 43–69) versus 17%
(7–30) at 6 months (figure 3A), resulting in the rejection
of the null hypothesis for progression-free survival (the
observed p value <the critical p value of 0·00036).

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of −46% (IQR −70 to 0) in the cabozantinib group

A
100 Cabozantinib
and 14% (0 to 58) in the placebo group. 17 patients in the
90 Placebo cabozantinib group and ten patients in the placebo group
Progression-free survival (%)

80 HR 0·22 (96% Cl 0·13–0·36); p<0·0001 were not evaluable for change from baseline in serum
70 thyroglobulin.
60
50
Median duration of treatment exposure in the safety
40 population was 4·4 months (IQR 2·1–7·3) in the
30 cabozantinib group versus 2·3 months (1·6–5·6) in the
20
placebo group (appendix p 12). The median daily dose was
10
0 42·0 mg (IQR 32·2–54·5) with cabozantinib and 60·0 mg
0 3 6 9 12 15 18 (52·9–60·0) with placebo. Dose reductions to manage
Number at risk adverse events were required by 70 (56%) of 125 patients in
(number censored)
Cabozantinib 125 (0) 69 (45) 26 (69) 15 (79) 2 (92) 1 (93) 0 (94) the cabozantinib group and three (5%) of 62 in the placebo
Placebo 62 (0) 21 (11) 4 (17) 1 (18) 0 (19) 0 (19) 0 (19) group, and 28 (22%) of 125 and one (2%) of 62 patients
required a second dose reduction, respectively. The most
B
100 HR 0·54 (95% Cl 0·27–1·11)
common adverse events resulting in dose reduction of
90 cabozantinib included palmar-plantar erythrodysaes­thesia
80 (24 [19%] of 125), diarrhoea (13 [10%]), and fatigue (nine
Overall survival (%)

70 [7%]). In the placebo group, adverse events resulting in

60
50
40
30
20
10
0 group. Six (5%) of 125 patients in the cabozantinib group
0 3 6 9 12 15
Time since randomisation (months)
Number at risk
(number censored)
Cabozantinib 125 (0) 90 (31) 54 (58) 24 (84) 7 (101) 1 (107)
Placebo 62 (0) 42 (13) 24 (25) 9 (39) 0 (48) 0 (48)
Figure 3: Kaplan-Meier estimates of progression-free survival (A) and overall survival (B) in the intention-to-
treat population
Disease progression was assessed with the use of Response Criteria in Solid Tumours, version 1.1 by blinded
independent radiology committee. NE=not estimable. NR=not reached.
Progression-free survival outcomes by investigator
assessment were generally consistent with outcomes by
BIRC (appendix p 14). The progression-free survival
benefit was maintained across predefined subgroups
with reasonable sample sizes (appendix p 15).
At data cutoff, there were 17 (14%) deaths among
125 patients in the cabozantinib group and 14 (23%)
deaths among 62 patients in the placebo group. Median
overall survival was not reached (95% CI NE–NE) in
either treatment group (HR 0·54; 95% CI 0·27–1·11),
with overall survival estimates of 85% (95% CI 75·0–91·0)
in the cabozantinib group versus 73% (58·4–83·7) in the
placebo group at 6 months (figure 3B). The number of
patients who used subsequent systemic anticancer
therapy was three (2%) of 125 in the cabozantinib group
and four (6%) of 62 in the placebo group; this does not
include the 19 patients (31%) in the placebo group who
crossed over to open-label cabozantinib (appendix p 11).
The prespecified endpoint of disease stabilisation rate
is shown in table 2. In addition, 78 (62%) of 125 patients
in the cabozantinib group versus 12 (19%) of 62 in the
placebo group had a decrease in serum thyroglobulin
concentrations in the ITT population (appendix p 16),
with a median best percentage change from baseline
dose reduction included fatigue, dyspnoea, dysphagia, and
pruritus (one [2%] of 62 for each). The median time to the
first dose reduction was 57 days (IQR 35–90) in the
cabozantinib group and 85 days (30–153) in the placebo
18 and no patients in the placebo group discontinued
treatment due to treatment-emergent adverse events
unrelated to DTC. Treatment-related adverse events
0 (108)
0 (48) leading to discontinuation of cabozantinib included fatigue
(n=2), arthralgia (n=1), diarrhoea (n=1), hypercalcaemia
(n=1), hypertension (n=1), large-intestine perforation (n=1),
increased liver function test (n=1), myalgia (n=1), and renal
impairment (n=1); one patient could have more than one
treatment-related adverse event.
Adverse events of any causality and any grade occurred
in 117 (94%) of 125 patients in the cabozantinib group
and 58 (93%) of 62 in the placebo group, grade 3 or 4
adverse events occurred in 71 (57%) of 125 and 16 (26%)
of 62, and grade 4 adverse events occurred in seven (6%)
of 125 and two (3%) of 62 (table 3). The most common
grade 3 or 4 adverse events included palmar-plantar
erythrodysaesthesia (13 [10%] of 125 with cabozantinib
vs 0% with placebo), hypertension (11 [9%] vs two [3%]),
fatigue (ten [8%] vs 0%), diarrhoea (nine [7%] vs 0%),
and hypocalcaemia (nine [7%] vs 1 [2%]). Serious
treatment-related adverse events occurred in 20 (16%)
patients in the cabozantinib group and one (2%)
patients in the placebo group (appendix p 13).
A total of 16 deaths occurred through to 30 days after the
last dose: nine (7%) of 125 in the cabozantinib group and
seven (11%) of 62 in the placebo group. None of these
grade 5 events were considered treatment related. In the
cabozantinib group, five patients died from disease
progression or thyroid cancer. The other four patients had
the following grade 5 adverse events leading to death:
arterial haemorrhage, cardiorespiratory arrest, pneu­
monia, and pulmonary embolism (one patient for each).
In the placebo group, four patients died from disease

8 www.thelancet.com/oncology Published online July 5, 2021, https://doi.org/10.1016/S1470-2045(21)00332-6

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Cabozantinib group (n=125) Placebo group (n=62)

Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5
Any event 37 (30%) 64 (51%) 7 (6%) 9 (7%) 35 (56%) 14 (23%) 2 (3%) 7 (11%)
Diarrhoea 55 (44%) 9 (7%) 0 0 2 (3%) 0 0 0
Palmar-plantar erythrodysaesthesia 44 (35%) 13 (10%) 0 0 0 0 0 0
syndrome
Alanine aminotransferase increased 29 (23%) 1 (1%) 0 0 1 (2%) 0 0 0
Aspartate aminotransferase increased 29 (23%) 0 0 0 1 (2%) 0 0 0
Nausea 26 (21%) 4 (3%) 0 0 1 (2%) 0 0 0
Decreased appetite 25 (20%) 4 (3%) 0 0 10 (16%) 0 0 0
Hypertension 24 (19%) 10 (8%) 1 (1%) 0 1 (2%) 2 (3%) 0 0
Fatigue 24 (19%) 10 (8%) 0 0 5 (8%) 0 0 0
Weight decreased 22 (18%) 1 (1%) 0 0 3 (5%) 0 0 0
Hypocalcaemia 20 (16%) 6 (5%) 3 (2%) 0 0 1 (2%) 0 0
Proteinuria 18 (14%) 1 (1%) 0 0 2 (3%) 0 0 0
Vomiting 17 (14%) 1 (1%) 0 0 5 (8%) 0 0 0
Asthenia 16 (13%) 3 (2%) 0 0 9 (15%) 0 0 0
Dyspnoea 15 (12%) 4 (3%) 0 0 9 (15%) 1 (2%) 1 (2%) 0
Mucosal inflammation 14 (11%) 3 (2%) 0 0 0 0 0 0
Hypomagnesaemia 14 (11%) 1 (1%) 0 0 3 (5%) 0 0 0
Stomatitis 13 (10%) 3 (2%) 0 0 2 (3%) 0 0 0
Constipation 13 (10%) 0 0 0 5 (8%) 0 0 0
Dysphonia 13 (10%) 0 0 0 1 (2%) 0 0 0
Dry mouth 11 (9%) 1 (1%) 0 0 1 (2%) 0 0 0
Headache 10 (8%) 2 (2%) 0 0 1 (2%) 0 0 0
Arthralgia 9 (7%) 2 (2%) 0 0 4 (6%) 0 0 0
Abdominal pain 8 (6%) 2 (2%) 0 0 2 (3%) 0 0 0
Blood alkaline phosphatase increased 9 (7%) 1 (1%) 0 0 2 (3%) 0 0 0
Hypokalaemia 9 (7%) 1 (1%) 0 0 1 (2%) 0 0 0
Anaemia 5 (4%) 2 (2%) 0 0 8 (13%) 0 0 0
Pain in extremity 7 (6%) 1 (1%) 0 0 3 (5%) 0 0 0
Back pain 6 (5%) 1 (1%) 0 0 3 (5%) 0 0 0
Cough 6 (5%) 0 0 0 12 (19%) 0 0 0
Neutrophil count decreased 5 (4%) 2 (2%) 0 0 1 (2%) 0 0 0
Gamma-glutamyltransferase increased 4 (3%) 1 (1%) 1 (1%) 0 2 (3%) 0 0 0
Leukopenia 5 (4%) 1 (1%) 0 0 0 0 0 0
Pain 5 (4%) 1 (1%) 0 0 3 (5%) 1 (2%) 0 0
Pulmonary embolism 2 (2%) 3 (2%) 0 1 (1%) 0 0 0 0
Amylase increased 4 (3%) 1 (1%) 0 0 0 1 (2%) 0 0
Chest pain 3 (2%) 2 (2%) 0 0 2 (3%) 0 0 0
Dysphagia 4 (3%) 1 (1%) 0 0 1 (2%) 0 0 0
Hair colour changes 4 (3%) 1 (1%) 0 0 0 0 0 0
Neutropenia 4 (3%) 1 (1%) 0 0 0 0 0 0
Pleural effusion 1 (1%) 4 (3%) 0 0 2 (3%) 1 (2%) 1 (2%) 0
Pneumonia 2 (2%) 1 (1%) 0 1 (1%) 2 (3%) 0 0 0
Hyponatraemia 3 (2%) 1 (1%) 0 0 2 (3%) 1 (2%) 0 0
Insomnia 4 (3%) 0 0 0 0 1 (2%) 0 0
Musculoskeletal pain 3 (2%) 1 (1%) 0 0 1 (2%) 1 (2%) 0 0
Neck pain 3 (2%) 1 (1%) 0 0 1 (2%) 1 (2%) 0 0
Pruritus 4 (3%) 0 0 0 2 (3%) 1 (2%) 0 0
Skin ulcer 2 (2%) 2 (2%) 0 0 0 0 0 0
White blood cell count decreased 3 (2%) 1 (1%) 0 0 0 0 0 0
Confusional state 2 (2%) 1 (1%) 0 0 0 0 0 0
(Table 3 continues on next page)

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Cabozantinib group (n=125) Placebo group (n=62)

Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5
(Continued from previous page)
Deep vein thrombosis 2 (2%) 1 (1%) 0 0 0 0 0 0
Dehydration 1 (1%) 2 (2%) 0 0 0 0 0 0
Disease progression 0 1 (1%) 0 2 (2%) 0 0 0 2 (3%)
Fall 3 (2%) 0 0 0 1 (2%) 1 (2%) 0 0
Electrolyte imbalance 1 (1%) 1 (1%) 0 0 0 0 0 0
Gastro-oesophageal reflux disease 1 (1%) 1 (1%) 0 0 2 (3%) 0 0 0
General physical health deterioration 0 2 (2%) 0 0 0 0 0 1 (2%)
Haemoptysis 1 (1%) 1 (1%) 0 0 1 (2%) 0 0 0
Hypoalbuminaemia 1 (1%) 1 (1%) 0 0 1 (2%) 0 0 0
Painful respiration 1 (1%) 1 (1%) 0 0 0 0 0 0
Blood magnesium decreased 1 (1%) 1 (1%) 0 0 0 0 0 0
Haematoma 0 1 (1%) 0 0 0 0 0 0
Hypercalcaemia 0 0 1 (1%) 0 2 (3%) 2 (3%) 0 0
Hypertensive crisis 0 1 (1%) 0 0 0 0 0 0
Intestinal obstruction 0 1 (1%) 0 0 0 0 0 0
Jaundice cholestatic 0 1 (1%) 0 0 0 0 0 0
Large-intestine perforation 0 0 1 (1%) 0 0 0 0 0
Laryngeal necrosis 0 1 (1%) 0 0 0 0 0 0
Lung disorder 0 1 (1%) 0 0 0 0 0 0
Oesophageal stenosis 0 1 (1%) 0 0 0 0 0 0
Osteonecrosis of jaw 0 1 (1%) 0 0 1 (2%) 0 0 0
Pathological fracture 0 1 (1%) 0 0 0 0 0 0
Spinal cord compression 0 1 (1%) 0 0 0 1 (2%) 0 0
Acute kidney injury 0 1 (1%) 0 0 0 0 0 0
Anal abscess 0 1 (1%) 0 0 0 0 0 0
Aptyalism 0 1 (1%) 0 0 0 0 0 0
Arterial haemorrhage 0 0 0 1 (1%) 0 0 0 0
Arthropod bite 0 1 (1%) 0 0 0 0 0 0
Atrial fibrillation 0 1 (1%) 0 0 0 0 0 0
Bone lesion 0 1 (1%) 0 0 0 0 0 0
Cancer pain 0 1 (1%) 0 0 0 0 0 0
Cardiac arrest 0 0 0 1 (1%)† 0 0 0 1 (2%)
Cardio-respiratory arrest 0 0 0 1 (1%) 0 0 0 0
Cholangitis 0 1 (1%) 0 0 0 0 0 0
Cholangitis acute 0 1 (1%) 0 0 0 0 0 0
Cholelithiasis 0 1 (1%) 0 0 0 0 0 0
COVID-19 0 1 (1%) 0 0 1 (2%) 0 0 0
Ejection fraction decreased 0 1 (1%) 0 0 0 0 0 0
Radicular pain 0 1 (1%) 0 0 0 0 0 0
Rectal abscess 0 1 (1%) 0 0 0 0 0 0
Renal impairment 0 1 (1%) 0 0 0 0 0 0
Spinal fracture 1 (1%) 0 0 0 0 1 (2%) 0 0
Syncope 0 1 (1%) 0 0 0 0 0 0
Thyroid cancer 0 0 0 1 (1%) 0 0 0 1 (2%)
Thyroid cancer metastatic 0 0 0 1 (1%) 0 0 0 0
Tumour pain 1 (1%) 0 0 0 2 (3%) 1 (2%) 0 0
Urine output decreased 0 1 (1%) 0 0 0 0 0 0
Wound dehiscence 0 1 (1%) 0 0 0 0 0 0
Wound infection 0 1 (1%) 0 0 0 0 0 0
(Table 3 continues on next page)

10 www.thelancet.com/oncology Published online July 5, 2021, https://doi.org/10.1016/S1470-2045(21)00332-6


Cabozantinib group (n=125)
Grade 1–2 Grade 3
(Continued from previous page)
Carotid artery stenosis 0 0
Hydrothorax 0 0
Lower respiratory tract infection 0 0
Pain in jaw 0 0
Renal failure 0 0
Cerebrovascular accident 0 0
Poorly differentiated thyroid carcinoma 0 0
Data are n (%). Patients are counted at the worst toxicity grade overall and at each preferred term. *Adverse events, regardless of causality, that were reported in at least 10%
of patients in either treatment group or any event of grade 3 or worse. Severity was graded according to National Cancer Institute Common Terminology Criteria for Adverse
Events, version 5.0. †Event associated with disease progression.
Table 3: Adverse events (safety population)*
progression or thyroid cancer. The other three patients
had the following grade 5 events leading to death: cardiac
arrest, cerebrovascular accident, and general physical
health deterioration (one patient for each).
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
favoured cabozantinib over placebo in the OITT
population, but the difference between the treatment
groups was not significant. Although the rate of
confirmed responses was lower than the rate assumed
for the statistical design of the study, 44 (76%) of
58 patients in the cabozantinib group had a reduction in
target lesion compared with nine (29%) of 31 in the
placebo group. The increased rate of disease stabilisation
with cabozantinib treatment versus placebo (54 [43%] of
125 vs 10 [16%] of 62] for the intention-to-treat population)
probably contributed to the significant progression-free
survival benefit. Analysis of overall survival in the ITT
population also favoured cabo­zantinib, but this was not a
controlled endpoint and survival data are limited by the
duration of follow-up, sample size, and crossover of
patients from placebo to open-label cabozantinib. The
safety profile of cabozantinib was manageable and
predictable, with the types of adverse events recorded
consistent with previous reports.26,27
The significant progression-free survival benefit
associated with a short follow-up time might indicate
that cabozantinib imparted disease stabilisation in a
patient population who would have otherwise had rapid
disease progression. The short median progression-free
survival (1·9 months) for the placebo group indicates the
www.thelancet.com/oncology Published online July 5, 2021, https://doi.org/10.1016/S1470-2045(21)00332-6 11
Articles
Placebo group (n=62)
Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5
0 0 0 1 (2%) 0 0
0 0 0 1 (2%) 0 0
0 0 0 1 (2%) 0 0
0 0 1 (2%) 1 (2%) 0 0
1 (1%) 0 0 0 0 0
0 0 0 0 0 1 (2%)
0 0 0 0 0 1 (2%)
aggres­ sive nature of the disease in the overall study
population following progression on at least one VEGFR
TKI, a group that has not previously been studied. In this
regard, it should be noted that the study population of
COSMIC-311 was pretreated. Eligibility criteria required
previous treatment with sorafenib or lenvatinib and
allowed up to two previous VEGFR TKIs. The median
number of previous systemic (non-radiation) treatment
regimens was two, with 44 (24%) of 187 patients having
received previous therapy with both sorafenib and
lenvatinib. Most patients had progressed on sorafenib
or lenvatinib as their most recent previous therapy.
The progression-free survival benefit achieved with
cabozantinib was maintained across prespecified
subgroups with reasonable sample sizes with the HRs
consistent with that of the overall study population.
These data indicate that cabozantinib provided a clinically
meaningful improve­ ment in progression-free survival
for all pretreated patients, irrespective of previous
treatment with sorafenib or lenvatinib and up to two
previous VEGFR TKIs.
At the time of study design, few data were available
to guide estimates of objective response rate and
progression-free survival for the statistical plan. An
objective response rate of 35% with cabozantinib had
been assumed on the basis of previous phase 1 and 2
studies of cabozantinib in radioiodine-refractory DTC.28–30
However, those were relatively small studies in both the
first-line and second-line settings. Observational studies
have reported an objective response rate of 15–20% with
second-line VEGFR TKIs,31,32 consistent with the findings
in this current study. The objective response rate might
be affected by the amount of time that has passed
following progression from the most recent VEGFR TKI,
with longer periods resulting in new vessel growth,
which is more likely to respond to reintroduction of
VEGFR and other kinase inhibition. For the ITT
population, the median time to randomisation since the
last disease progression was 1·9 months (IQR 1·0–4·0)
in the cabozantinib group and 1·9 months (0·8–3·7) in
 Articles
the placebo group. The median progression-free survival
of 1·9 months in the placebo group was shorter than the
5·5 months that had been assumed for placebo in the
study design. This estimate was based on the phase 3
DECISION study of first-line sorafenib, which enrolled
patients with radioiodine-refractory DTC who had not
received previous systemic therapy; the median
progression-free survival in the placebo group for the
DECISION study was 5·8 months.8 Notably, the median
progression-free survival for the placebo group was
much shorter (3·6 months vs 5·8 months) in the
subgroup of second-line patients from the phase 3
SELECT study of lenvatinib.9 Taken together, these data,
along with reports from other studies,31,32 indicate that
DTC can progress rapidly after treatment with VEGFR-
targeted therapy.
Stable disease as best overall response and the
reduction of target lesions in some patients assigned
to the placebo probably reflect variability in tumour
assessment or the natural history of DTC. The DECISION
and SELECT studies also reported tumour shrinkage in
patients receiving placebo, as well as partial responses
and stable disease as best response.8,9 We also note that
there were no confirmed responses in the placebo group
of the current study and that the waterfall plot presents
data only on target lesions. Additionally, the short
progression-free survival in the placebo group indicates
that this variability was short-lived. Given the HR of 0·22
for progression-free survival, any placebo effect was
probably minimal.
Potential shortcomings of our study include the
short follow-up because of the early rejection of the
null hypothesis at the planned interim analysis for
progression-free survival. As a result, a full characteri­
sation of the duration of benefit for progression-
free survival and duration of objective response rate is
curtailed at this time. Supportive analyses of progression-
free survival with additional follow-up will be done.
Although subgroup analyses supported cabozantinib
across the various predefined subsets of patients, some
of the subgroups had relatively small patient numbers.
Additionally, interpretation of the overall survival data is
limited by the short duration of follow-up, sample size,
and crossover of patients from placebo to open-label
cabozantinib. However, the early rejection of the null
hypothesis for progression-free survival in a planned
interim analysis is noteworthy in a patient population
with few treatment options.
Patients with radioiodine-refractory DTC who have
progressed during or following treatment with VEGFR-
targeted therapy have few treatment options, a poor
prognosis, and a high unmet medical need.11,12 Approved
systemic treatments for patients with radioiodine-
refractory disease include lenvatinib and sorafenib.8,9 Other
treatment options include select VEGFR-targeted TKIs,
cytotoxic chemotherapy, or palliative care.11 Larotrectinib,
entrectinib, selpercatinib, and pralsetinib are also available,
12 www.thelancet.com/oncology Published online July 5, 2021, https://doi.org/10.1016/S1470-2045(21)00332-6
but these require the presence of actionable mutations,
and pembrolizumab is an option for patients with high
tumour mutational burden. There is little evidence of
treatment efficacy in patients with radioiodine-refractory
DTC who have been previously treated with lenvatinib,
sorafenib, or both, and there is no standard of care.11 To our
knowledge, COSMIC-311 is the first randomised phase 3
study to evaluate a VEGFR-targeted TKI in patients who
had received previous lenvatinib or sorafenib and up to
two previous VEGFR TKIs.
Cabozantinib has now been approved for several types
of advanced solid tumours including in patients who
have received previous VEGFR-targeted therapy, and in
the phase 3 trial of patients with medullary thyroid
cancer, the progression-free survival benefit associated
with cabozantinib was maintained in the subgroup
previously treated with a VEGFR TKI.25–27 Preclinical
studies indicate that increased signalling via MET and
AXL, targets of cabozantinib, can be associated with
resistance to VEGF pathway inhibition.22,33,34 The results
reported here add to the body of evidence supporting the
efficacy of cabozantinib in patients previously treated
with a VEGFR-targeted therapy in part by inhibiting
these potential resistance pathways.
In conclusion, treatment with cabozantinib signifi­
cantly prolonged progression-free survival compared
with placebo in patients with progressive, radioiodine-
refractory DTC previously treated with VEGFR-targeted
therapy. The safety profile was manageable and
consistent with the known safety profile of cabozantinib.
These findings support cabozantinib as a new treatment
option in patients with previously treated radioiodine-
refractory DTC for whom there is no standard of care
and a high unmet medical need.
Contributors
MSB, BR, SIS, LF, BK, and JWO contributed to the study conception and
design. MSB, BR, SIS, JK, C-CL, FV, AOH, EH, DWB, JH, LF, JWO, BK,
and JC contributed to data acquisition. LF, KB, and JWO provided data
analyses. All authors contributed to the interpretation of data. MSB
wrote the first draft of the manuscript with assistance from LF, KB, and
JWO in collaboration with Exelixis and medical writing support, funded
by Exelixis. LF, KB, and JWO verified the underlying data. All authors
reviewed and approved the final manuscript. All authors had full access
to the full dataset and approved the final manuscript for submission.
The corresponding author had full access to all the data and the final
responsibility for the decision to submit for publication.
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 Medicines, Boehringer-Ingelheim, Bristol
Myers Squibb, Daiichi Sankyo, Novartis, and has received honorarium
from Eli Lilly, Novartis, and Roche, all outside of the submitted work.
AOH is a consultant with Exelixis, and reports consulting and lecture
fees with Bayer and consulting with Eli Lilly, outside of the submitted
work. JH reports personal fees from Ipsen, Eisai, Novartis, Angelini
Pharma, AAA, Pfizer, and Roche, outside of the submitted work. LF is an
employee and stockholder of Exelixis. KB is an employee and stockholder

of Exelixis. JWO is an employee and stockholder of Exelixis. BK has
received grants from Ono Pharmaceutical, MSD Oncology, AstraZeneca
and has received personal fees from MSD Oncology, AstraZeneca,
Genexin, Handok, and CBS Bio, all outside of the submitted work. JC has
received grants from Bayer, Eisai, Ipsen, AstraZeneca, Roche, and
Adacap, and personal fees from Lilly, Bayer, Eisai, Exelixis, Pfizer, Ipsen,
Novartis, Adacap, Merck, and Sanofi, all during the conduct of this study;
and grants from Bayer, Eisai, Roche, Ipsen, and personal fees from Bayer,
Eisai, Exelixis, Sanofi, Lilly, and Ipsen, outside of the submitted work.
BR, FV, EH, and DWB declare no competing interests.
Data sharing
Individual participant data will not be made available.
Acknowledgments
The study was sponsored by Exelixis (Alameda, CA, USA). We thank the
patients, their families, the investigators, and site staff. We thank
Suvajit Sen, PhD (Exelixis, Alameda, CA, USA), for critical review of the
manuscript. Editorial and writing assistance was provided by
Michael Raffin and Alexus Rivas, PharmD (Fishawack Communications,
a part of Fishawack Health, Conshohocken, PA, USA), and was funded
by Exelixis.
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