nuevos tratamientos dirigidos en carcinoma medular de tiroides · carcinoma medular y anaplásico...

Carcinoma medular

y anaplásico de tiroides

Dr. Javier Martínez Trufero,

Hospital Universitario Miguel Servet,

Zaragoza

GRUPO ESPAÑOL DE TRATAMIENTO

DE TUMORES DE CABEZA Y CUELLO

Thyroid Cancer: Clinical Pathology

American Cancer Society. www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_thyroid_cancer_43.asp. Carling T and Uldesman R. Cancer of the Endocrine System.: Section 2: Thyroid Cancer. Principles of Clinical Oncology. 7th edition. Lippincott Williams and Wilkins. 2005.

Parafollicular cells

(3-5%)

Follicular cells (90-95%)

Differentiated

Anaplastic(2%)

Poorly differentiated ?

Medullary

Papillary

Follicular

Hurtle Cell

Sporadic (75%)

Familial (25%)

Mutation profile in MTC

Somatic RET mutations in sporadic MTC

Elisei R. J Clin Endocrinol Metab. 2008 Mar; 93(3):682-7.

MTC management

• Main treatment: total thyroidectomy +/- lymphadenectomy

• No role for Radioactive Iodine Therapy or Thyroid Hormone Suppression.

• Somatostatin analogues: symptomatic treatment of diarrhoea.

• Radiotherapy: – Not well established role. – Potential useful in adjuvant setting and palliative

treatment of bone metastases.

• Chemotherapy: very limited data. • New TKIs (Targeted therapy).

Chemotherapy in MTC

Schlumberger M. Eur Thyroid J 2012;1:5–14

N Partial

response Stable

disease Progressive

disease

Doxorrubicin 41 17 21 56

Doxo-Cisplatin 43 26 30 44

DTIC-5FU 5 60 20 20

Ciclofosfamide-Vincristine-DTIC

7 28 28 42

Streptozocin-5FU alternating DTIC-5FU

20 15 55 30

Cellular Signaling Pathway Alterations for Medullary Thyroid Carcinoma

Multikinase inhibitors related to MTC Drug In vitro IC50 (nm)

VEGFR1 VEGFR2 VEGFR3 RET PDGFRβ

RAF Other

Sorafenib - 90 20 49 58 6

Vandetanib 1600 40 110 100 - EGFR 500

Cabozantinib

(XL 184) - 0.035 - 4.5 - C-MET 1.8

Sunitinib - 4 - 100 39 -

Axitinib 1.2 0.16 0.29 1.2 -

Motesanib 2 3 6 59

Lenvatinib 22 4 5.2 39 FGFR1

22

Pazopanib 10 30 47 84 FGFR1

14

Adapted from Sherman, J Clin Endocrinol Metab, 2009, p 1494

VANDETANIB

Vandetanib (Zactima ®) targets the RET, EGF and VEGF receptors

Degrauwe et al. Clinical Medicine Insights: Oncology 2012:6

Phase II Trials Vandetanib in MTC

20% PR. 53% SD ≥ 24 weeks,DCR 73% . Decrease in CEA and calcitonin levels > 50% (lasting >4 weeks in >80% patients)

300mg/d N:30p

Robinson BG. J Clin Endocrinol Metab. 2010 Wells SA. J Clin Oncol Jan 11, 2010

16% PR. 53% SD ≥ 24 weeks,DCR 68 % . Decrease in CEA and calcitonin levels > 50% (lasting >4 weeks in 21% patients)

100 mg /d N:19p

Wells SA. J Clin Oncol Jan 11, 2012

ZETA STUDY:PFS and OS results

mPFS: 19.3 vs 30.5 months* HR: 0.46, p<0.001

Wells SA, et al. J Clin Oncol 2012


ZETA STUDY: PFS subgroups

End point Vandetanib Placebo HR p

Overal response rate (%)

45 13

5.48 (2.99 -

10.79)

<0.001

Disease control rate (%)

87 71

2.64 (1.48 - 4.69)

0.001

Calcitonin response

(%) 69 3

72.9 (26.2-303.2)

<0.001

CEA response

(%) 52 2

52.0 (16.0 -

320.3)

0.001

ZETA STUDY: efficacy end points


ZETA STUDY:toxicity


CABOZANTINIB (XL184)

MET signalling pathway

Peters, S. & Adjei, A. A. (2012) MET: a promising anticancer therapeutic target Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2012.71

MET activation is a common feature of human tumors

MET activation drives survival, invasion and metastasis MET and VEGFRs cooperate to promote tumor angiogenesis Selective MET inhibitors have shown limited clinical utility to date

MET up-regulation occurs as a response to diverse therapies

VEGF-pathway inhibition, androgen ablation, radiotherapy Promotes resistance and “escape” – increased tumor invasiveness and metastasis

Simultaneous inhibition of MET and VEGFRs provides

Broad anti-tumor activity via impact on tumor and stroma Blockade of a key mechanism of evasive resistance Clear differentiation from VEGF pathway inhibition – may overcome current “ceiling” on the efficacy of anti-angiogenic therapy

Cabozantinib Phase I trial. • Phase I-II trial of cabozantinib .

• Maximum tolerated dose (MTD: 175 mg per day).

• 85 patients were treated; 37 of these had MTC.

• Responses: 10p PR was confirmed, 25p tumor shrinkage <30 % or SD > 6 months. 3p confirmed response had been pretreated with vandetanib or sorafenib that also target RET and VEGFR.

• There was no correlation between mutations and clinical response.

• In a subset of MTC patients (n = 15) analyzed for MET mutations in the tumor DNA, no mutations were detected and copy number gain was only assessed in a few samples and in three patients found to be increased.

EXAM – Trial design

Treatment until progression

or unacceptable adverse events

Locally advanced

or metastatic

MTC with

documented

RECIST

progression

(N=330)

Cabozantinib 140 mg

Placebo

2:1 Randomisation

PR

OG

RE

SS

ION

Survival

follow-up

No Cross-Over

No Un-

blinding

Key eligibility criteria

Locally advanced or metastatic MTC with radiographic progressive disease within 14 months per mRECIST

Key study endpoints

Primary: Progression Free Survival (PFS) per mRECIST determined by independent radiology committee (IRC)

Secondary: response rate per mRECIST and overall survival (OS)

mRECIST: modified Response Evaluation Criteria in Solid Tumours Elisei R et al. JCO 2013 vol 31. no 29; 3639-3646

EXAM – Primary endpoint:

Progression Free Survival per IRC

Elisei R et al. JCO 2013 vol 31. no 29; 3639-3646

Prior TKI exposure: 20 vs 22%

EXAM – PFS subgroups


Hazard Ratio and 95% CI

Overall Survival in interim analysis

(75% of events)


HR de 0,53, p=0,0179

Overall Survival in RET mutation

M918T


Effect of RET mutation status on PFS

Median PFS

Cabozantinib 60 weeks

Placebo 20 weeks

HR (95%CI) = 0.23 (0.14, 0.38)

Median PFS

Cabozantinib 25 weeks

Placebo 23 weeks

Hazards not proportional

Sherman et al. European Thyroid Journal OP1 Topic Highlights, 2013; September

RAS mutation-positive patients show prolonged PFS on cabozantinib


Total patients analysed 85

Patients with RAS mutations

16

HRAS G13 3

KRAS G12 5

KRAS Q61 6

NRAS G12 1

HRAS G13, NRAS G12/A18 1

Patients with no RAS mutation

69

Residual clinical activity in patients lacking RET and RAS mutation


EXAM – Most frequent adverse events (>25% incidence)

Cabozantinib (N=214) Placebo (N=109)

Median Duration of Exposure

6.7 months

3.4 months

Adverse Eventa All Grades n (%)

Grade ≥ 3 n (%)

All Grades n (%) Grade ≥ 3 n (%)

Diarrhoea 135 (63) 34 (16) 36 (33) 2 (2)

Hand foot skin reaction 107 (50) 27 (13) 2 (2) -

Decreased weight 102 (48) 10 (5) 11 (10) -

Decreased appetite 98 (46) 10 (5) 17 (16) 1 (1)

Nausea 92 (43) 3 (1) 23 (21) -

Fatigue 87 (41) 20 (9) 31 (28) 3 (3)

Dysgeusia 73 (34) 1 (0.5) 6 (6) -

Hair colour changes 72 (34) 1 (0.5) 1 (1) -

Hypertensionb 70 (33) 18 (8) 5 (5) 1 (1)

Stomatitis 62 (29) 4 (2) 3 (3) -

Constipation 57 (27) - 6 (6) -


Wells, S., et al. J Clin Oncol 2012; 30: 134-141 Elisei, R., et al.. J Clin Oncol 2013; 31 Cabozantinib. Summary of product characteristic. 2014

Links TP. Eur J Endocrinol June 1, 2015

Other TKIs in MTC

PAZOPANIB

ORR: 14.3% DCR: 71% mPFS: 9.4 m mOS: 19.9 m

Bible KC. J Clin Endocrinol Metab. 2014 May;99(5):1687-93

SUNITINIB

ORR: 35% DCR:92% mPFS: 12.2 m mOS: NA

MOTESANIB

ORR: 2% DCR:93% mPFS: 12 m mOS: NA

ORR: 10% DCR:90% mPFS: 17.9 m mOS: NA

SORAFENIB

Other TKIs in MTC

AXITINIB

ORR: 18% DCR:45%

LENVATINIB

ORR: 36% DCR:70% mPFS: 9 m mOS: 16.6 m

Other TKIs in MTC

Bible KC. J Clin Endocrinol Metab. 2014 May;99(5):1687-93

Other potential targets in MTC

• New RET inhibitors: ponatinib, AST487. • mTOR inhibitors: everolimus, NVP BEZ235 • Other TKI: nindetanib, sulfatinib, AMG706. • Anti HSP90: nelfinavir • JAK/STAT pathway inhibitors: AZD1480. • Chemotherapy: Irinotecan. • Somatostatin analogues • Radiolabeled molecules: LU 177. • Vaccines.

CONCLUSIONS MTC

• MTC : rare tumor with wide range of potential targets.

• Advanced disease: very limited efficacy of classic chemotherapy.

• Two recently approved and available new drugs:

• Remarkable disease control rate with both.

• Long term survival benefit.

• Not cross resistance. Response in previous treated patients.

• Potential sequential use.

• Limiting toxicities:

• Vandetanib: diarrhea , HT, prolonged QT.

• Cabozantinib: diarrhea, PPS.

• Up front treatment:

• Approved TKIs as main option.

• Select appropriately patient and moment to start treatment

• Resistance: • Clinical trials

• Off- label use of other TKIs

• Rare; < 5% of thyroid carcinomas

• Highly malignant and generally fatal < 1yr.

• Elderly 65 yrs; females slightly > males

• Rapidly enlarging bulky neck mass

• Dysphagia, dyspnoea, hoarseness

ANAPLASTIC THYROID CANCER (ATC)

ANAPLASTIC THYROID CANCER (ATC):

PROGNOSIS

Elisei R, Molinaro E. et al. JCEM 2010.

ATC: Median survival of 4 to 5 months at time of diagnosis

Am J Pathol 2002;161:1549-1556

Comparison of Clinical Characteristics of Well-, Poorly-Differentiated, and ATC: MSKCC Experience

Follow up:43 months

ENFERMEDAD LOCALIZADA RESECABLE

ENFERMEDAD METASTÁSICA

ALGORITMO TERAPEUTICO CAT

ENFERMEDAD LOCALIZADA IRRESECABLE

CIRUGIA RADIOTERAPIA +/-

QT RADIOSENS.

QT PALIATIVA NUEVOS AGENTES

RADIOTERAPIA ADYUVANTE

Smallridge RC, et al. Thyroid 2012

Cabanillas ME, J Oncol Pract. 2016 Jun;12(6):511-8.

New potential treatments in ATC

• Antivascular disrupting agents: Fosbretabulin. • TKI: Lenvatinib • BRAF inhibitors: Vemurafenib • mTOR inhibitors • ALK inhibitors.

Sosa JA, et al. Thyroid 2014;24(2):232-40 Dark GG, et al. Cancer Res 1997;57: 1829–1834

Mooney CJ, et al. Thyroid 2009

Phase II Trial of Fosbretabulin in Advanced Anaplastic Thyroid Carcinoma

Sosa JA, et al. Thyroid 2014;24(2):232-40

Phase II Trial of Fosbretabulin in Advanced Anaplastic Thyroid Carcinoma

80 pts recruited from 180 planned

*Anaplastic thyroid cancer confirmed by independent pathologic review. †Patients with partial response as best overall response.

Phase II Trial of Lenvatinib in Advanced DTC, MTC and ATC

Outcome ATC

(n = 17) RR-DTC (n = 25)

MTC (n = 9)

Progression-free survival

Median (95% CI), months

7.4 (1.7–12.9)

25.8 (18.4–NE)

9.2 (1.8–NE)

Overall survival Median (95% CI), months

10.6 (3.8–19.8)

31.8 (31.8–NE)

12.1 (3.8–NE)

Best overall response, n (%) Complete response Partial response Stable disease* Progressive disease NE

0

4 (23.5) 12 (70.6)

1 (5.9) 0

0

17 (68.0) 8 (32.0)

0 0

0

2 (22.2) 7 (77.8)

0 0

Objective response rate, n (%)† 4 (23.5) 17 (68.0) 2 (22.2)

Disease control rate, n (%)† 16 (94.1) 25 (100.0) 9 (100.0)

Clinical benefit rate, n (%)‡ 12 (70.6) 21 (84.0) 7 (77.8)

Takahashi S. ASCO 2016

Time to Response and Durability of Response For Patients With ATC Treated With Lenvatinib

48

AE, adverse event; ATC, anaplastic thyroid cancer; PD, progressive disease.


Computed Tomography Scans of a Representative Patient With ATC at Baseline and

During Treatment With Lenvatinib

49

ATC, anaplastic thyroid cancer.


Vemurafenib in Multiple Nonmelanoma Cancers

with BRAF V600 Mutations

Hyman DM; et al. N Engl J Med 2015

Wagle N, et al. N Engl J Med 2014;371:1426-33

Response and Acquired Resistance to Everolimus in

Anaplastic Thyroid Cancer (TSC2 mutation)

Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of

thyroid cancer: ATC as an ALKOMA

Kelly LM, et al. PNAS 2014

Remarkable Response to Crizotinib in Woman With

ALK–Rearranged Anaplastic Thyroid Carcinoma

Godbert Y, et al. J Clin Oncol 2015

ATC: CONCLUSIONS

• ATC : multiple challenges

• Extremely rare tumor

• Fatal prognosis: median OS 3-4 m

• Lack evidence

• Very limited research

• Oncologic emergency !!

• First approach: surgery and /or CT-RT

• Promising agent: lenvatinib

• New Potential targets :

• Vascular disruptors

• B-RAF

• m-TOR

• ALK

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