Recent progress of targeted kinase inhibitors in thyroid cancer

Recent progress of targeted kinase inhibitors in thyroid cancer

A/Prof Rory Clifton-Bligh

Kolling Institute of Medical Research, University of Sydney

Department of EndocrinologyRoyal North Shore Hospital, St Leonards, NSW

Royal North Shore Hospital

10th Asia and Oceania Thyroid Association Congress, Bali 23rd October 2012

Overview

Scope of problem for thyroid cancer Molecular targets for thyroid cancer Data Success of kinase inhibitors in other

cancers Pharmacogenomics Conclusions

Thyroid cancer subtypes

…10-year mortality

DTC

85%cured with treatment

15% recurrent/metastatic disease

7%

15%25% 35% 100%

~1/3 controlled by I-131, T4 and/or local Rx

Tuttle et al J Natl Compr Canc Netw 2010;8:1228-1274

“Unmet need”

Metastatic Disease: existing therapies

Regional LNs-surgery

Brain-Surgery-XRT-RAI

Lung-RAI

Bone-RAI-XRT-Bisphosphonates

Challenge in designing clinical trials in DTC: (sometimes) indolent natural history

Leboulleux et al Lancet Oncol 2012;13:897–905

Waterfall plot of best percentage change in target lesion size from baseline, placebo group from Vandetanib trial in DTC, phase II

!

Growth signalling: targets for new drugs

Somatic mutations in papillary thyroid cancer: BRAF 30-70% RAS 0-20% RET/PTC 20-50%

PI3-kinase pathway also involved (PIK3CA copy number gain and mutation; PTEN): FTC 55% PTC 24% ATC 58%

Cell proliferationDifferentiation

Gild et al Nat Rev Endocrinol 2011; Hou et al Clin Cancer Res 2007;13:1161-70.

PI3KBRAF

RAS

RETRET/PTC

Adapted from Brose et al BMC Cancer 2011;11:349

Growth signalling: targets for new drugs

Tumor endothelial cell

DTC tumor cell

PDGF-βVEGF

VEGFR-2PDGFR-β

PI3KBRAF

RAS

RETRET/PTC

Rationale for targeting growth factor signalling cascades in thyroid cancer- Preclinical studies

conditional expression of BRAFV600E in adult mice causes PTC

Treatment with MEK inhibitor resulted in partial tumor regression

Charles et al Cancer Res 2011;71:3863-71

Rationale for targeting growth factor signalling cascades in thyroid cancer- Clinical data

Medullary thyroid cancer in MEN2: RET genotype/activity determines biological

aggressiveness

Papillary thyroid cancer: BRAFV600E connotes risk of death

Cote et al., 2003 N Engl J Med 2003;349: 1566-1569

BRAFV600E and immunohistochemistrymouse monoclonal antibody, clone VE1 (Capper and von Deimling)

Bullock et al Endocr Rel Cancer 2012

58%

BRAFV600E positive by IHC positive by sequencing

BRAFV600E positive by IHCnegative by sequencing

10%(32% negative for both IHC and sequencing)

Kinase inhibitors

mimicking ATP within catalytic sites

pseudosubstrate

alteration of kinase stability

Wan et al Cell 2004;116:855-867

sorafenib

BRAF kinase

Phase Drug n CR(%) PR(%) SD(%)Medullary thyroid cancerCohen et al 2 Axitinib 11 0 18 27Schlumberger et al 2 Motesanib 91 0 2 48Wells et al 2 Vandetanib 30 0 20 53Robinson et al 2 Vandetanib 19 0 16 53Kuzrock et al 1 Cabozantinib 37 0 29 41Ahmed et al 2 Sorafenib 15 0 25 naLam et al 2 Sorafenib 16 0 6 50Hong et al 1 Sor’+tipifarnib 13 0 38 31Carr et al 2 Sunitinib 7 0 50 na

Differentiated thyroid cancerCohen et al 2 Axitinib 45 0 31 42Sherman et al 2 Motesanib 93 0 14 35Gupta-Abramson et al 2 Sorafenib 30 0 23 53Kloos et al 2 Sorafenib 41 0 15 56Ahmed et al 2 Sorafenib 19 0 18 73Carr et al 2 Sunitinib 28 3 28 37Hong et al 1 Sor’+tipifarnib 22 0 4.5 36Bible et al 2 Pazopanib 39 0 49 nr

Data from randomized, placebo-controlled studies

Typical inclusion criteria

Measurable disease at least one measurable lesion as measured

by CT or MRI Disease progression (RECIST)

(RAI-refractory disease: for DTC trials)

Medullary Thyroid Cancer

Vandetanib

Cabozantinib

Vandetanib

RET, VEGF receptor, and EGFR tyrosine kinases

MTC: approved for patients with unresectable locally advanced or metastatic disease (US, Canada, Europe)

Vandetanib in MTC: phase IIIVandetanibn = 231

Placebon = 100

HR/OR p value

1°endpoint

Progression free survival

30.5 mo 19.3 mo 0.46(0.31-0.69)

0.0001

2°endpoints

Objective 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 rate

69% 3% 72.9(26.2-303.2)

<0.001

CEA response rate

52% 2% 52.0(16.0-320.3)

<0.001

Wells et al J Clin Oncol 2012;30:134-141

Vandetanib in MTC: phase III- PFS


Vandetanib in MTC: phase III- OS


Overall survival data immature (HR 0.89; 0.48-1.65)A final survival analysis planned when 50% pts dead

Side-effects: vandetanib Diarrhoea (16%) Palmar-plantar erythrodysethesia (13%) Hypertension (8%) Prolonged QT Headache Nausea Leukopenia Discontinued therapy because of AE:

Vandetanib 12% Placebo 3%


Cabozantinib (XL184) in MTC: phase III

MET, VEGFR2, RET EXAM trial, international multicentre 330 pts, median age 55 y

Cabozantinib n = 219 Placebo n = 111

PFS: Cabo Placebo

11.2 mo 4.0 mo

(HR 0.28, 0.19-0.4, p < 0.0001)

ORR: 28% 0% (p, ns)

Schoffski et al J Clin Oncol 2012;30: suppl abstr 5508

Side-effects: cabozantinib

Diarrhoea (16%) Palmar-plantar erythrodysethesia (13%) Hypertension (8%)

Differentiated thyroid cancer

Vandetanib

(Lenvatinib)

(Sorafenib)

Vandetanib in DTC: phase II 16 medical centres in Belgium, Denmark, France, Norway,

Spain, Sweden, and Switzerland

Vandetanibn = 72

Placebon = 73

HR/OR p value

1°endpoint

Progression free survival

11.1 mo 5.9 mo 0.63(0.54-0.74)

0.008

2°endpoints

Objective response rate

8% 5% 1.57 (0.42-5.81)

0.501

Disease control rate

57% 42% 1.79(0.93-3.46)

0.082


Vandetanib in DTC: phase II - PFS


Pro

gre

ssio

n-fr

ee

su

rviv

al

Vandetanib in DTC: phase II - OS


(crossover from placebo to vandetanib allowed,confouding assessment of the effects of treatment on overall survival)

Two patients in the vandetanib group and one in the placebo group died from “treatment-related” serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group)

Vandetanib in DTC: phase II - OS


Lenvatinib (E7080)

VEGFR1-3, FGFR1-4, RET, KIT, PDGFRβ Phase II

RAI-refractory DTC (papillary, follicular or Hurthle Cell) and disease progression demonstrated by RECIST during the prior 12 months

58 pts: PR 50% (CI, 37-63%)

35% required dose reduction for management of toxicity, and 23% were withdrawn

Sherman et al, J Clin Oncol 29: 2011 (suppl; abstr 5503)

Sorafenib

Phase III trial ongoing (DECISION) Phase II: four trials including 168 patients

with thyroid cancer treated with sorafenib Median progression-free survival (PFS)

ranged from 58-84 weeks Partial responses in up to 25% Disease control rates (SD+PR) 59-100% Dose reductions due to AEs (mostly grade I-

II) in 62%

Brose et al BMC Cancer 2011;11:349

Thyroid dysfunction in patients on kinase inhibitors

Elevated TSH/requirement for higher Thyroxine dose in Thyroid cancer patients: 49-78% of patients receiving vandetanib

Hypothyroidism in patients with intact thyroid (eg renal cell cancer) In 36-85% pts treated with sunitinib In 18-68% pts treated with sorafenib

Torino et al Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxiceffect of targeted therapy. Nat Rev Clin Oncol 2009;6:219–28.

Other kinase inhibitors

Dabrafenib selective for mutant BRAF

Motesanib Axitinib Pazopanib Sunitinib

Combinations

Receptor tyrosine kinase + MEK inhibitor dabrafenib + MEKi

RAI + MEK inhibitor Selumetinib (AZD6244)*

TKI + mTOR inhibitor Temsirolimus + sorafenib*

BRAF

mTOR

*Ho et al J Clin Oncol 2012;30:suppl abstr 5509Sherman E et al J Clin Oncol 2012;30:suppl abstract 5514

MEK

I-131

Kinase inhibitors in other malignancies

Kinase inhibitors: haematologic malignancies

CML: BCR-ABL

Imatinib Nilotinib Dasatinib

complete response for up to 8 years in 85% of patients

Hairy cell leukaemia: BRAFV600E

Vemurafenib

Kinase inhibitors: melanoma

Chapman et al N Engl J Med 2011;364:2507-16 Flaherty et al N Engl J Med 2012;367:107-114

BRAF inhibitor MEK inhibitor

Kinase inhibitor combinations to overcome resistance: melanoma

Flaherty et al N Engl J Med 2012;doi: 10.1056

dabrafenib

dabrafenib+trametinib

Pharmacogenomics

BRAFV600E mutation: pharmacogenomics

In vitro experience suggests that thyroid cell lines containing mutant BRAF cell lines are more sensitive to BRAF or MEK inhibitors

?no clinical evidence for pharmacogenomic effects in thyroid cancer:

Motesanib (Phase 2, 93 pts)DCRBRAF+ 60% (6/10)BRAF- 33% (5/15)

Clear evidence from hairy cell leukemia and melanoma that response to BRAF-targeted therapy is strongly associated with tumor genotype

Leboeuf et al JCEM 2008;93:2194 Sherman et al N Engl J Med 2008;359:31

ns

RET mutation: pharmacogenomics

In subgroup analysis, suggestion of higher response rate to vandetanib in sporadic tumors with M918T mutation

in vitro, Vandetanib does not inhibit the V804 mutations in RET


Conclusions Thyroid cancer mortality is related to:

Well-defined activation of growth factor signalling pathways Loss of iodine uptake (DTC)

These signalling pathways are targets for several drugs in clinical use or development Many pts require dose reduction or drug withdrawal to

manage toxicity Some treatment-related deaths reported

Vandetanib has FDA approval for use in MTC Balance of risks vs benefits needs to be carefully

addressed in phase III trials Need greater definition of those pts who will have survival

benefit from treatment

Thyroid Group at RNSH, Sydney

Endocrine SurgeonsEndocrinologists

PathologistScientists

Bruce Robinson Stan Sihdu Mark SywakDiana Learoyd

Dindy Benn Anne-Louise Richardson

Anthony Gill

Leigh Delbridge

MartynBullock

Rory Clifton-Bligh

JulianIp

JimmyLee

JustinGundara

PhD students

and Matti Gild

Documents

Recent progress of targeted kinase inhibitors in thyroid cancer