Upload
others
View
0
Download
0
Embed Size (px)
Citation preview
Cáncer de Tiroides: Novedades Terapéuticas
Jaume Capdevila, MD, PhD GI and Endocrine Tumor Unit Vall d’Hebron University Hospital
Vall Hebron Institute of Oncology (VHIO)
Thyroid Cancer: Cell Type and Histology
Follicular cells
Anaplastic Differentiated
Papillary Hürthle cell Follicular
Medullary thyroid carcinoma (MTC)
Parafollicular cells
(3-5%)
(90-95%)
Thyroid Cancer: Cell Type and Histology
Follicular cells
Anaplastic Differentiated
Papillary Hürthle cell Follicular
Medullary thyroid carcinoma (MTC)
Parafollicular cells
(3-5%)
(90-95%)
DECISION: Study Design
• Locally advanced or metastatic, RAI-refractory DTC
• Progression (RECIST) within the previous 14 months
• No prior chemotherapy, targeted therapy, or thalidomide
417 patients randomized from November 2009 to August 2011
• Stratified by: – Geographical region (North America or Europe or Asia) – Age (<60 or ≥60 years)
• Progression assessed by independent central review every 8 weeks
• At progression
– Patients on placebo allowed to cross over at the investigator’s discretion
– Patients on sorafenib allowed to continue on open-label sorafenib at the investigator’s discretion
Sorafenib 400 mg orally twice daily
Placebo Orally twice daily
Randomization 1:1 Primary endpoint
Secondary endpoints • Overall survival • Response rate • Safety • Time to progression • Disease control rate • Duration of response • Sorafenib exposure (AUC0-12)
• Progression-free survival
Brose M, et al. Lancet 2014
DECISION: Progression-free Survival (by Independent Central Review)
Brose M, et al. Lancet 2014
n Median PFS,
days (months) Sorafenib 207 329 (10.8)
Placebo 210 175 (5.8)
PFS
Prob
abili
ty (%
)
Days From Randomization 0 100 200 300 400 500 600 700 800
0
10
20
40
60
80
100
30
50
70
90
HR, 0.59; 95% CI, 0.45-0.76; P<0.0001
Brose M, et al. Lancet 2014
Reduction in Tumor Size with Sorafenib Treatment
Response Rate: 12%
Study 303 (SELECT): Study Schema
Patients with DTC (N = 392) • IRR evidence of
progression within previous 13 months
• 131I-refractory
disease • Measurable
disease • Up to 1 prior
VEGF or VEGFR-targeted therapy
Placebo (n = 131) 24 mg daily PO
Lenvatinib (n = 261) 24 mg daily PO
Stratification • Geographic
region (Europe, N. America, Other)
• Prior VEGF/ VEGFR-targeted therapy (0,1)
• Age (≤ 65 years, > 65 years)
Treatment until disease progression
confirmed by IRR (RECIST v1.1)
Lenvatinib (Optional, open-label)
Ran
dom
izat
ion
2:1
DTC, differentiated thyroid cancer; 131I, radioiodine; IRR, independent radiologic review, ORR, objective response rate; OS, overall survival; PO, by mouth; RECIST, response evaluation criteria in solid tumors.
Primary endpoint • PFS
Secondary endpoints
• ORR • OS • Safety
Schlumberger M, et al. N Engl J Med 2015
Primary Endpoint: Kaplan-Meier Estimate of PFS
Placebo vs Lenvatinib HR = 0.20 (95% CI 0.15–0.27), P < 0.001 3.6 mo (2.2–3.7) vs 18.3 mo (15.1–NA)
Schlumberger M, et al. N Engl J Med 2015
Median tumor shrinkage for
responders (range): -52%
(-100%, -30%) RR: 65%
Schlumberger M, et al. N Engl J Med 2015
Reduction in Tumor Size with LenvatinibTreatment
Genetics of Thyroid Cancer
TCGA. Cell 2014
Phase II study of Dabrafenib +/- Trametinib in BRAF V600E mutant or BRAF fusion PTC
Shah MH, et al. ASCO 2017
Primary endpoint: objective response (PR+MR)
Shah MH, et al. ASCO 2017
Best Objective Response
50 pts with BRAF V600E mutation 3 pts with BRAF fusion 75% first-line
Shah MH, et al. ASCO 2017
Primary Endpoint: Objective Response
45%
20-29%
37%
Altered proteins contain new epitopes for immune recognition, providing a common denominator for cancer immunotherapy
Rha
bdoi
d tu
mou
r
Ewin
g sa
rcom
a
Thyr
oid
Acut
e m
yelo
id
leuk
aem
ia
Med
ullo
blas
tom
a
Car
cino
id
Neu
robl
asto
ma
Pros
tatre
C
hron
ic
lym
phoc
ytic
le
ukae
mia
Lo
w-g
rade
glio
ma
Brea
st
Panc
reas
Mul
tiple
mye
lom
a
Kidn
ey c
lear
cel
l
Kidn
ey
papi
llary
cel
l O
varia
n
Glio
blas
tom
a m
ultif
orm
e
Cer
vica
l D
iffus
e la
rge
B-ce
ll ly
mph
oma
Hea
d an
d ne
ck
Col
orec
tal
Esop
hage
al
aden
ocar
cino
ma
Stom
ach
Blad
der
Lung
ade
no-
carc
inom
a Lu
ng s
quam
ous
cell
carc
inom
a
Mel
anom
a 0.01
0.1
1
10
100
1000
Som
atic
mut
atio
n fre
quen
cy (/
Mb)
22 20 52 134 26 23 81 227 91 57 121 13 63 214 11 394 219 20 49 181 231 76 88 35 335 179 121
C→T C→A C→G T→C T→A T→G
Lawrence Nature 2013
No at Risk
Frequency of genetic somatic mutations in cancer
Mehnert ASCO 2016
PEMBROLIZUMAB (200 mg i.v. every 3 weeks)
PD-L1 ≥1% + PTC & FTC 73% pretreated 41% ≥ 2 prior lines
Primary endpoint: Overall objective response rate Main secondary endpoints:
− Duration of response − relationship between PFS and tumor PD-L1 expression and GEP score − Safety − Progression free survival − Overall survival
Pembrolizumab in Thyroid Cancer
• 51 screenings for PD-L1 expression (22C3 moAb Merck) • 36 (71%) positive ≥1% in tumor and/or stromal cells • 22 received pembrolizumab
Mehnert ASCO 2016
Pembrolizumab in Thyroid Cancer
Mehnert ASCO 2016
mPFS: 6.8 months
Mehnert ASCO 2016
Pembrolizumab in Thyroid Cancer
Combination Targeted Therapy with Pembrolizumab and Lenvatinib in Progressive, Radioiodine-resistant Differentiated Thyroid Cancers
Previous VEGFR active multikinase inhibitor (except lenvatinib) – will stratify between both arms of primary study Patients who have been previously treated with non-VEGFR active kinase inhibitors other than lenvatinib (examples – dabrafenib, vemurafenib, selumetinib) will be eligible for substudy 1. Patients who have been previously treated with lenvatinib and have RECIST progression will be eligible for substudy 2
LENVATINIB (24 mg PO daily) and PEMBROLIZUMAB (200 mg
i.v. every 3 weeks)
Thyroid Cancer: Cell Type and Histology
Follicular cells
Anaplastic Differentiated
Papillary Hürthle cell Follicular
Medullary thyroid carcinoma (MTC)
Parafollicular cells
(3-5%)
(90-95%)
MOLECULAR PATHOGENESIS OF MTC: PROTO-ONCOGENE RET
Eng C et al. Cancer Res 1996 Huang SC et al. Cancer Res 2000
Lodish MB et al. Expert Rev Anticancer Ther 2008 Menacho et al. Cancer Res 2005
•Stimulation of downstream signalling pathways leads to aberrant cell proliferation, growth and neoangiogenesis
•Main signalling pathways involved in RET activation include RAS/ERK, PI3K, PLCΥ, SRC, STAT3 and JNK
•Hereditary syndromes accumulate mutations in different receptor domains
RET
MEN 2A FMTC
MEN 2B
FMTC Val 804 M/L
Met 918 Thr
Glu 768 Asp Leu 790 Phe Tyr 791 Phe
Ala 883 Phe
Cys 634
Cys 611 Cys 618 Cys 620 Cys 630
Ser 891 Ala
Cys 609
MOLECULAR PATHOGENESIS OF MTC: BEYOND RET MUTATIONS
Moura MM, et al. Endocr Relat Cancer 2015
VANDETANIB PIVOTAL PHASE III TRIAL: THE ZETA STUDY
Vandetanib 300 mg/d
n = 231
Placebo n = 100
Multiphasic CT or MRI performed every 12 weeks
Treatment until disease progression
Crossover allowed at time of PD
2:1
Randomization: December 2006 to November 2007
Primary Endpoint: • PFS
R A N D O M I Z E
Secondary Endpoints: • OS • ORR • DCR • Biochemical response (calcitonin/CEA) • Time to worsening of pain
Patients with locally advanced or metastatic MTC, N=331 • RET mutation positive or negative • Prior antitumour
therapy allowed • WHO PS ≤2
Stratified by: • RET mutation status • Hereditary vs Sporadic • Previous calcitonin and CEA • Prior therapies • Response to prior therapies
Wells SA, et al. J Clin Oncol 2012
VANDETANIB SIGNIFICANTLY PROLONGED PFS VS PLACEBO
Wells SA, et al. J Clin Oncol 2012
Prog
ress
ion-
free
su
rviv
al (p
ropo
rtio
n)
1.0
0.8
0.6
0.4
0.2
0 0 6 12 18 24 30 36
Number at risk VANDETANIB 300 mg 231 196 169 140 40 1 0 Placebo 100 71 57 45 13 0 0
VANDETANIB 300 mg Placebo
Time (months)
Median PFS: VANDETANIB: 30.5* months (modelled) Placebo: 19.3 months
Hazard ratio = 0.46 (95% CI: 0.31 to 0.69); P<0.001
*Not yet reached; predicted using a Weibull model. Weibull W. J Appl Mech Trans 1951;18:293–297
VANDETANIB SIGNIFICANTLY INCREASED OBJECTIVE RESPONSE RATE VERSUS PLACEBO
Wells SA, et al. J Clin Oncol 2012
• Odds ratio = 5.48 (95% CI: 2.99 to 10.79); P<0.001 • All responses were partial • Responses were durable in patients receiving Vandetanib
– Median duration of response had not been reached after 24 months of follow-up
12 of these 13 responses occurred while patients were subsequently receiving open-label
VANDETANIB
Patie
nts (
%)
VANDETANIB (n=231) Placebo (n=100)
• Phase III randomized, placebo-controlled, double-blind trial
Primary Endpoint • PFS
Cabozantinib 140 mg Continuous daily dosing
Placebo
* Recruitment completed in January 2011
Secondary Endpoints • OS • ORR • TTR • Safety • PK and PD data
R A N D O M I Z E
2:1
Locally advanced or metastatic MTC patients (n=330)
• Disease progression in past 14 months
• Not amenable to curative treatment
• No limit on prior therapy, including other TKIs
• WHO PS ≤2
CABOZANTINIB: EXAM PHASE III STUDY
Elisei R, et al. J Clin Oncol 2013
EXAM: PROGRESSION-FREE SURVIVAL BY IRC (PRIMARY ENDPOINT)
Elisei R, et al. J Clin Oncol 2013
Progression-Free Survival per IRC (months)
Cabozantinib Placebo
Median PFS (months) 11.2 4
1 year PFS 47.3% 7.2%
HR (95% CI) 0.28 (0.19, 0.40)
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Pro
babi
lity
of S
urvi
val
p<0.0001
TUMOR RESPONSE RATE
Elisei R, et al. J Clin Oncol 2013
Cabozantinib demonstrated a tumor response rate of 28% with a duration of 14.6 months in patients with progressive MTC
Cabozantinib
Cabozantinib
Lenvatinib in MTC
Schlumberger M, et al. Clin Cancer Res 2016
RR: 36%
mPFS: 9m
Pazopanib in MTC
Bible KC, et al. J Clin Endocrinol Metabol 2016
RR: 14%
Thyroid Cancer: Cell Type and Histology
Follicular cells
Anaplastic Differentiated
Papillary Hürthle cell Follicular
Medullary thyroid carcinoma (MTC)
Parafollicular cells
(3-5%)
(90-95%)
Is there Room for Precision Medicine in ATC? Results from the Whole-Exome Sequencing
Kuntsman JW. Hum Mol Genetics 2015
Efficacy of Dabrafenib and Trametinib in pts with BRAF V600E mutated ATC
Subbiah V, et al. ASCO 2017
Subbiah V, et al. ASCO 2017
Response Rate
RR: 70%
Subbiah V, et al. ASCO 2017
Treatment duration and TTF
Overall Survival estimation at 12 months: 80%
Activity of Lenvatinib in ATC patients
Takahashi S, et al. ESMO 2014
Is ATC a better candidate for Immunotherapy?
PDR001 (anti-PD-1) Nov 2016 Jan 2017
Take Home Messages
Both RAI-R DTC and MTC have two approved MKIs based on phase III data: sorafenib-lenvatinib & vandetanib-cabozantinib
Stronger drug development in DTC than MTC, focusing on targeted therapies against BRAF aberrant tumors and immunotherapy
ATC is a real orphan disease. Better characterization of molecular alterations could select better responders to targeted agents or immunotherapy
Phase III are feasible in DTC and MTC even their low incidence. Strong data on ATC coming from phase II studies should be enough for drug approval in this aggressive tumor
[email protected] [email protected]
GRACIAS POR VUESTRA ATENCIÓN