Cáncer de Tiroides: Novedades Terapéuticas · Cáncer de Tiroides: Novedades Terapéuticas ....

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

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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

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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

jacapdevila@vhebron.net jcapdevila@vhio.net

GRACIAS POR VUESTRA ATENCIÓN