1. Recent progress of targeted kinase inhibitors in thyroid cancer
A/Prof Rory Clifton-Bligh
Kolling Institute of Medical Research, University of Sydney
Department of Endocrinology
Royal North Shore Hospital, St Leonards, NSW
Royal North
Shore Hospital
10th Asia and Oceania Thyroid Association Congress, Bali 23rd October 2012

2. Overview Scope of problem for thyroid cancer
Molecular targets for thyroid cancer
Data
Success of kinase inhibitors in other cancers
Pharmacogenomics
Conclusions

3. Thyroid cancer subtypes DTC
85%
cured with treatment 7%
15%
25%
35%
100%
“Unmet need”
~1/3 controlled by
I-131, T4 and/or local Rx
Thyroid carcinoma has 3 main histologic types: differentiated (including papillary, follicular, and Hürthle cell), medullary, and anaplastic (aggressive undifferentiated tumor). Of 53,856 patients treated for thyroid carcinoma between 1985 and 1995, 80% had papillary carcinoma, 11% had follicular carcinoma, 3% had Hürthle cell carcinoma, 4% had medullary carcinoma, and 2% had anaplastic thyroid carcinoma.12 The 10-year relative survival rates for patients with papillary, follicular, and Hürthle cell carcinomas were 93%, 85%, and 76%, respectively.12
Almost 10% of patients with papillary carcinoma and up to 25% of those with follicular carcinoma develop distant metastases. Approximately 50% of these metastases are present at diagnosis.48
Distant metastases occur even more often in patients with Hürthle cell cancer (35%) and those diagnosed after age 40 years.82,84 The sites of reported distant metastases among 1231 patients in 13 studies were lung (49%), bone (25%), both lung and bone (15%), and the central nervous system (CNS) or other soft tissues (10%) Although some patients, especially younger ones, with distant metastases survive for decades, approximately 50% die within 5 years regardless of tumor histology.48
…10-year mortality
15% recurrent/metastatic disease
Tuttle et al J Natl Compr Canc Netw 2010;8:

4. Metastatic Disease: existing therapies
Regional LNs
-surgery
Brain
-Surgery
-XRT
-RAI
Lung
Bone
-Bisphosphonates
Of all mets: Brain 10%, lung 65%, bone 40%

5. Challenge in designing clinical trials in DTC: (sometimes) indolent natural history
Waterfall plot of best percentage change in target lesion size from baseline, placebo group from Vandetanib trial in DTC, phase II !
Leboulleux et al Lancet Oncol 2012;13:897–905

6. Growth signalling: targets for new drugs
Somatic mutations in papillary thyroid cancer:
BRAF %
RAS 0-20%
RET/PTC %
PI3-kinase pathway also involved (PIK3CA copy number gain and mutation; PTEN):
FTC 55%
PTC 24%
ATC 58%
BRAF
RAS
RET
RET/PTC
PI3K
PIK3CA copy number gain and mutation, Ras mutation, and PTEN mutation
25 of 81 (31%) benign thyroid adenoma (BTA), 47 of 86 (55%) follicular thyroid cancer (FTC), 21 of 86 (24%) papillary thyroid cancer (PTC), and 29 of 50 (58%) anaplastic thyroid cancer (ATC)
Cell proliferation
Differentiation
Gild et al Nat Rev Endocrinol 2011; Hou et al Clin Cancer Res 2007;13:

7. Growth signalling: targets for new drugs
Tumor endothelial cell
DTC tumor cell
PDGF-β
VEGF
VEGFR-2
PDGFR-β
PI3K
BRAF
RAS
RET
RET/PTC
Adapted from Brose et al BMC Cancer 2011;11:349

8. 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:

9. Rationale for targeting growth factor signalling cascades in thyroid cancer - Clinical data
Cote et al., 2003 N Engl J Med 2003;349:
Medullary thyroid cancer in MEN2:
RET genotype/activity determines biological aggressiveness
Papillary thyroid cancer:
BRAFV600E connotes risk of death

10. BRAFV600E and immunohistochemistry mouse monoclonal antibody, clone VE1 (Capper and von Deimling)
BRAFV600E positive by IHC positive by sequencing
BRAFV600E positive by IHC
negative by sequencing
10%
(32% negative for both IHC and sequencing)
58%
Bullock et al Endocr Rel Cancer 2012

11. Kinase inhibitors mimicking ATP within catalytic sites pseudosubstrate
Wan et al Cell 2004;116:
mimicking ATP within catalytic sites
pseudosubstrate
alteration of kinase stability
sorafenib
BRAF kinase

12. Phase Drug n CR(%) PR(%) SD(%)
Medullary thyroid cancer
Cohen et al 2 Axitinib
Schlumberger et al 2 Motesanib
Wells et al 2 Vandetanib
Robinson et al 2 Vandetanib
Kuzrock et al 1 Cabozantinib
Ahmed et al 2 Sorafenib na
Lam et al 2 Sorafenib
Hong et al 1 Sor’+tipifarnib
Carr et al 2 Sunitinib na
Differentiated thyroid cancer
Cohen et al 2 Axitinib
Sherman et al 2 Motesanib
Gupta-Abramson et al 2 Sorafenib
Kloos et al 2 Sorafenib
Ahmed et al 2 Sorafenib
Carr et al 2 Sunitinib
Hong et al 1 Sor’+tipifarnib
Bible et al 2 Pazopanib nr

13. Data from randomized, placebo-controlled studies

14. 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)

15. Medullary Thyroid Cancer
Vandetanib
Cabozantinib

16. Vandetanib RET, VEGF receptor, and EGFR tyrosine kinases
MTC: approved for patients with unresectable locally advanced or metastatic disease (US, Canada, Europe)

17. Vandetanib in MTC: phase III
Placebo
n = 100
HR/OR
p value
1°endpoint
Progression free survival
30.5 mo
19.3 mo
0.46
( )
0.0001
2°endpoints
Objective response rate
45%
13%
5.48
( )
<0.001
Disease control rate
87%
71%
2.64
( )
0.001
Calcitonin response rate
69% 3%
72.9
( )
CEA response rate
52% 2%
52.0
( )
Wells et al J Clin Oncol 2012;30:

18. Vandetanib in MTC: phase III- PFS
Wells et al J Clin Oncol 2012;30:

19. Vandetanib in MTC: phase III- OS
Overall survival data immature (HR 0.89; )
A final survival analysis planned when 50% pts dead
Wells et al J Clin Oncol 2012;30:

20. 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:

21. 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, , p < )
ORR: 28% 0% (p, ns)
Documented RECIST progression at baseline
Schoffski et al J Clin Oncol 2012;30: suppl abstr 5508

22. Side-effects: cabozantinib
Diarrhoea (16%)
Palmar-plantar erythrodysethesia (13%)
Hypertension (8%)

23. Differentiated thyroid cancer
Vandetanib
(Lenvatinib)
(Sorafenib)

24. Vandetanib in DTC: phase II
16 medical centres in Belgium, Denmark, France, Norway, Spain, Sweden, and Switzerland
Vandetanib
n = 72
Placebo
n = 73
HR/OR
p value
1°endpoint
Progression free survival
11.1 mo
5.9 mo
0.63
( )
0.008
2°endpoints
Objective response rate 8% 5%
1.57
( )
0.501
Disease control rate
57%
42%
1.79
( )
0.082
one-sided p
Leboulleux et al Lancet Oncol 2012;13:897–905

25. Vandetanib in DTC: phase II - PFS
Progression-free survival
numerical improvement in PFS benefit for patients with papillary thyroid cancer who were treated with vandetanib compared with other histological subtypes, although this difference was not significant (papillary thyroid cancer HR 0・52, 95% CI 0・26–1・02, two-sided p=0・056; follicular thyroid cancer or poorly differentiated carcinoma 0・83, 0・51–1・36, p=0・461; figure 3).
Leboulleux et al Lancet Oncol 2012;13:897–905

26. Vandetanib in DTC: phase II - OS
(crossover from placebo to vandetanib allowed,
confouding assessment of the effects of treatment on overall survival)
Almost half of patients treated with vandetanib (30 [41%] of 73 patients) had a dose reduction=(16 [22%]) and/or dose interruption (28 [38%]), mainly because of adverse events- diarrhoea, QT prolongation etc
Leboulleux et al Lancet Oncol 2012;13:897–905

27. Vandetanib in DTC: phase II - OS
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)
Leboulleux et al Lancet Oncol 2012;13:897–905

28. 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
35% of pts required dose reduction for management of toxicity, and 23% were withdrawn from therapy due to toxicity. The most common adverse events were hypertension 64% (Gr 3: 4%), fatigue 55% (Gr3: 7%), diarrhea 45% (Gr3: 5%), decreased appetite 44% (Gr3: 2%), weight loss 43% (Gr3: 4%), and proteinuria 39% (Gr3: 7%). 5 pts (8.6%) experienced Gr 4 events.
Sherman et al, J Clin Oncol 29: 2011 (suppl; abstr 5503)

29. 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 weeks
Partial responses in up to 25%
Disease control rates (SD+PR) %
Dose reductions due to AEs (mostly grade I-II) in 62%
Brose et al BMC Cancer 2011;11:349

30. 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 toxic
effect of targeted therapy. Nat Rev Clin Oncol 2009;6:219–28.

31. Other kinase inhibitors
Dabrafenib
selective for mutant BRAF
Motesanib
Axitinib
Pazopanib
Sunitinib
Targeted inhibition of Src kinase with dasantinib blocks thyroid cancer growth and metastasis

32. Combinations Receptor tyrosine kinase + MEK inhibitor
dabrafenib + MEKi
RAI + MEK inhibitor
Selumetinib (AZD6244)*
TKI + mTOR inhibitor
Temsirolimus + sorafenib*
BRAF
MEK
mTOR
AZD6244 particularly enhances I-131 uptake in RAS mutated tumors
*Ho et al J Clin Oncol 2012;30:suppl abstr 5509
Sherman E et al J Clin Oncol 2012;30:suppl abstract 5514

33. Kinase inhibitors in other malignancies

34. 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

35. Kinase inhibitors: melanoma
Chapman et al N Engl J Med 2011;364:
Flaherty et al N Engl J Med 2012;367:
BRAF inhibitor
MEK inhibitor

36. Kinase inhibitor combinations to overcome resistance: melanoma
dabrafenib+trametinib
dabrafenib
Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P = 0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%).
Flaherty et al N Engl J Med 2012;doi:

37. Pharmacogenomics

38. BRAFV600E mutation: pharmacogenomics
Clear evidence from hairy cell leukemia and melanoma that response to BRAF-targeted therapy is strongly associated with tumor genotype
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)
DCR
BRAF+ 60% (6/10)
BRAF- 33% (5/15)
MEK inhibitors preferentially inhibit cells lines containing mutant BRAF; Leboeuf et al JCEM 2008;93:2194
Sorafenib preferentially inhibits PTCs with RET/PTC1; Henderson et al Clin Cancer Res 2008;14:4908 ns
Leboeuf et al JCEM 2008;93:2194 Sherman et al N Engl J Med 2008;359:31

39. 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:

40. 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

41. Thyroid Group at RNSH, Sydney
Endocrine Surgeons
Endocrinologists
Pathologist
Scientists
Bruce Robinson
Stan Sihdu
Mark Sywak
Diana Learoyd
Dindy Benn
Anne-Louise Richardson
Anthony Gill
Leigh Delbridge
Martyn
Bullock
Rory
Clifton-Bligh
Julian Ip
Jimmy
Lee
Justin
Gundara
PhD students
and Matti Gild