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
Wells et al J Clin Oncol 2012;30:134-141
Vandetanib in MTC: phase III- OS
Wells et al J Clin Oncol 2012;30:134-141
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%
Wells et al J Clin Oncol 2012;30:134-141
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
Leboulleux et al Lancet Oncol 2012;13:897–905
Vandetanib in DTC: phase II - PFS
Leboulleux et al Lancet Oncol 2012;13:897–905
Pro
gre
ssio
n-fr
ee
su
rviv
al
Vandetanib in DTC: phase II - OS
Leboulleux et al Lancet Oncol 2012;13:897–905
(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
Leboulleux et al Lancet Oncol 2012;13:897–905
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
Wells et al J Clin Oncol 2012;30:134-141
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