2. Introduction
• DTC usually associated with genetic alterations in
signaling pathways, which are responsible for cell
growth and transformation
• Of these, the RET proto-oncogene rearrangements
result in constitutive activation tyrosine kinase
pathways in thyroid epithelial cells
• DTCs frequently show abnormal activation of Ras-Raf
pathways by the mutation of Ras and BRAF proteins
(35 – 70%)
4. • Patients with 131I-refractory metastases in
differentiated thyroid cancer carry a poor
prognosis owing to dedifferentiation of these
tissues
• Redifferentiation therapy is a potential
alternative for RAI-refractory disease.
• Redifferentiating agents could potentially
reactivate the RAI uptake ability of DTC
5. Sorafenib:
• an orally administered multi kinase inhibitor
• Inhibits VEGFR-1, VEGFR-2, and VEGFR-3,
RET(including RET/PTC), RAF (including
BRAFV600E), and PDGFR β
8. The DECISION Trial
• A multicentre, randomised, double-blind, placebo-controlled,
phase 3 trial
• First and the only phase 3 clinical trial to validate the
use of a multi kinase inhibitor in RAI resistant DTC
• Done in 77 centers spread across 18 countries
• Funding by Bayer and Onyx pharmaceuticals which
sponsored this trial to evaluate Sorafenib under the
trade name Nexavar
9. Inclusion Criteria
• Age 18 years or older
• Locally advanced or metastatic 131I-refractory
DTC that had progressed within the past 14
months as per RECIST
• At least one measurable lesion by CT or MRI
according to RECIST
• ECOG performance status 0–2
• Adequate bone marrow, liver, and renal function
• Serum TSH < 0·5 mIU/L
10. Definition
131I-refractory DTC was defined as follows:
• presence of at least one target lesion without iodine
uptake;
• patients whose tumours had iodine uptake and either
progressed after one radioactive iodine treatment
within the past 16 months, or progressed after two
radioactive iodine treatments within 16 months of
each other (with the last such treatment administered
more than 16 months ago)
• received cumulative radioactive iodine activity of at
least 600 mCi
11. Exclusion Criteria
• Patients who had received previous targeted
therapy, thalidomide, or chemotherapy for
thyroid cancer were excluded
• however, low-dose chemotherapy for
radiosensitisation was allowed
12. The study used IVRS to randomly allocate
patients in a 1:1 ratio to 2 groups:
• Group 1: Tab Sorafenib 400 mg bid (taken 12 h
apart without food, at least 1 h before or 2 h
after a meal)
• Group 2:matching placebo twice daily
13. Patients, investigators, and the study sponsor were
masked to treatment assignment through the use
of unique drug pack numbers that were
preprinted onto each bottle or package and
assigned to the patient by the IVRS
Randomisation was stratified by
• age (<60 vs≥60 years)
• geographical region (North America vs Europe vs
Asia)
14. Drug dosage management
• Interruption in case of
• Sequential reduction and reescalation adverse events
• Treatment continued until progression, unacceptable
toxicity, noncompliance, or withdrawal of consent
• In the event of protocol-defined progression, treatment
could be unmasked and patients from both groups could
begin open-label sorafenib
• They could continue on sorafenib until treatment was no
longer beneficial, based on investigator judgment
15. Outcomes
Primary end-point:
• PFS
• assessed every 8 weeks by central independent blinded
review with use of modified RECIST criteria
Secondary end-points:
• OS
• TTP
• Objective response rate (CR/PR)
• Disease control rate (CR/PR + SD ≥ 4 wks)
• Duration of response
16.
17.
18.
19.
20. Statistics
• With the assumption of a one-sided α of 0·01,
90% power, and a 55·5% increase in median PFS
in the sorafenib group compared with placebo,
267 progression-free survival events were needed
from 420 enrolled and randomised patients
• PFS, OS and TTP assessed using log rank test
• P values for 0.01 (PFS) and 0.025 (TTP and OS)
• Hazard ratios and 95% confidence levels using
Cox proportional hazards model
21. Exploratory Biomarker Analyses
• The study gathered archival formalin-fixed, paraffin-embedded
biopsies from the primary tumour or metastatic
sites from patients who gave consent
• Extracted DNA tested for BRAF and RAS (including NRAS,
HRAS, and KRAS) mutations
• Serum thyroglobulin measured at baseline and on day 1 of
each treatment cycle
• Univariate and multivariate Cox proportional hazards
models used to study the association between biomarkers
and PFS
22. Results
• 419 patients from 77 centers in 18 countries randomly
allocated from Nov 2009 to Aug 2011
• The study met its primary endpoint and showed a
significant improvement in median PFS for sorafenib
(10.8 mth) compared with placebo (5.8 mth)
• [HR 0·59, 95% CI 0·45–0·76; p<0·0001]
• 41% reduction in the risk of progression or death
during the double-blind period
28. Sorafenib and Serum Tg
• Median thyroglobulin increased gradually in
patients given placebo, and initially decreased in
patients in the sorafenib group, which suggests
that changes might represent disease progression
• PR: had the greatest decrease in median
thyroglobulin concentrations
• SD: remained nearer to baseline
• PD: initially dropped and then rose
29.
30.
31. Exploratory Biomarker Analysis
• Patient subset with BRAF mutations did better
on sorafenib than with wild-type BRAF (20·5
vs9·4 months; HR 0·46; p=0·02)
• Seems related to the higher predominance of
BRAF mutations in patients with PTC and the
overall better outcome of patients with PTC
32. • Multivariate analysis indicated that only histology
(papillary vs poorly differentiated), age, and sorafenib
treatment, but not BRAF or RAS mutation status, were
independently prognostic for PFS benefit
• Sorafenib improved PFS irrespective of BRAF or RAS
mutation status
• These findings suggested that presence of these
mutations neither independently prognostic nor
predictive of sorafenib benefit with regards to PFS
prolongation
33. Sorafenib: Adverse Events
• Adverse events were generally consistent with
the known safety profile of sorafenib
• Hand–foot skin reaction, alopecia, diarrhoea,
hypertension, squamous cell carcinoma of the
skin, and hypocalcaemia
34.
35. • The number of deaths in the double-blind part
of the study was low in both the groups
• Most causes of death related to underlying
disease
• One death in each group attributed to the
study drug
36. Discussion
• The study met its primary endpoint, with a
significant and clinically relevant 5-month
improvement in median PFS with sorafenib
• Survival benefit was recorded in all
prespecified subgroups, including age, sex,
geographical region, histology, sites of
metastases, and tumour burden
37. • Overall response rate was modest in the sorafenib group
• Target lesions shrank in most patients who were given
sorafenib
• Sorafenib increased the disease control rate and prolonged
TTP
• Median OS was not reached in either group and overall
survival did not differ significantly between groups at data
cutoff
