Rolf Stahel presented a document on various oncogenic pathways and targeted therapies. The document discussed: 1) The ALK pathway and its role in cancers like NSCLC and neuroblastoma. Drugs like Crizotinib have shown responses in ALK-positive NSCLC. 2) The RET pathway's role in medullary thyroid cancer. Drugs like Vandetanib have shown responses in RET-mutated MTC. 3) The Hedgehog pathway's role in basal cell carcinoma and medulloblastoma. Inhibitors like GDC-0449 have induced responses in Hedgehog pathway-driven tumors.

1. Rolf Stahel
University Hospital
Zürich
Switzerland
New drugs in oncogenic-driven
malignacies
ESO Masterclass, Ermatingen, April 4, 2011

2. ALK (Anaplastic Lymphoma Kinase)
pathway
1. Inamura K et al. J Thorac Oncol 2008;3:13–17
2. Soda M et al. Proc Natl Acad Sci U S A 2008;105:19893–19897
Figure based on: Chiarle R et al. Nat Rev Cancer 2008;8(1):11–23;
Mossé YP et al. Clin Cancer Res 2009;15(18):5609–5614; and Data on file. Pfizer Inc.
*Subcellular localization of the ALK
fusion gene, while likely to occur in
the cytoplasm, is not confirmed.1,2
Translocation
Or
ALK ALK fusion protein*
Tumor cell
proliferation
Inversion
Cell survival
PI3K
BAD
AKT
STAT3/5
mTOR
S6K
RAS
MEK
ErK
PLC-Y
PIP2
IP3

3. HE

4. 4.jpg
30
HE20
CD5
ALK

5. Anaplastic T cell lymphoma
 ALK-positive anaplastic large cell lymphoma
represents about 6% of peripheral T-cell lymphomas
 Molecularly chararcterized
by t(2;5) resulting in a fusion
protein of ALK (anaplastic
lymphoma kinase) and
NPM (nucleophosmin)
 Good prognosis treated
by CHOP chemotherapy
Dunleavy, Clin Cancer Res 2010

6. ALK aberrations in malignancies
Mossé, CCR 2009

7. ALK in neuroblastoma
 Identification of ALK as familial predisposition gene
Mosse, Nature 2008
 Somatic and germline muations of the ALK kinase
receptor in neuroblastoma
Janoueix-Lerosey, Nature 2008
 Activating mutations
in ALK provide a
therapeutic target
for neuroblastomas
George, Nature 2008
 Alk mutations in 6.9% of 709 tumors, similar rate in
favorable and unfavorable neuroblastoma: Two
hotspots R1174 and F1174
De Brouwer, CCR 2010

8. ALK in lung cancer
Pao & Girard, Lancet Oncol, 2011

9. Soda M et al. Nature 2007;448:561–567
Reprinted by permission from
Macmillan Publishers Ltd: Nature, © 2007
EML4–ALK is a potent
“oncogenic” driver
3T3
Nude
mice
Tumor/
injection 0/8 0/8 0/8 8/8 0/8 8/8 2/2
Vector EML4 ALK EML4–ALK NPM–ALK v-Ras
Inhibition of ALK leads to dramatic in vivo tumor regression
EML4 = echinoderm microtubule-associated protein-like 4;
NPM = nucleophosmin
EML4–ALK
(K589M)

10. FISH
PCR/Sequencing IHC
Diagnosis of EML4-ALK positive NSCLC

11. 2p23-21
ALK EML4~ 12 Mb
EML4-ALK fusion by inversion (~ 70%)
3‘ 5‘
Curtesy Lukas Bubendorf

12. Clinical features of patients with
EML4-ALK NSCLC
 Predominantly found adenocarcinoma. TTF1 pos.,
acinar histology, mutually exclusive with EGFR and
KRAS mutations
Takeuchi, CCR 2008; Inamura,
Modern Path, 2009; Takahashi,
ASCO 2010; Zhang, Mol Cancer 2010
 More frequent in never or
former light smokers
Sasaki, EJC 2010
 Predominant in younger patients
– 36% (4/11) under 50 y/o (compared to 5% ALK-negative
adenocarcinomas)
Inamura, Modern Path, 2009
– Median age 52 yrs vs 66 and 64 for mEGFR or WT tumors
Shaw, JCO 2009

13. 60
40
20
0
–20
–40
–60
–80
–100
Progressive disease
Stable disease
Confirmed partial response
Confirmed complete response
Maximumchangeintumorsize(%)
–30%
Responses to Crizotinib for patients
with ALK-positive NSCLC
*
Bang, ASCO 2010: Kwak, NEJM 2010
Response rate:
• 57% (95% CI: 46, 68%)
• 63% including 5 as yet unconfirmed
PFS:
• Median not yet reached
(median f/u for PFS of 6.4 months)
F1174L mutation associated with resistance
Sasaki, CR 2010

14. Targeting ALK through HSP90
inhibitors?
 Mutated proteins – such as the ALK fusion gene
product – depend on HSP90 for maturation and
conformational stability
 Inhibition of murine
ALK-driven adeno-
carcinoma by HSP90
inhibitor
Chen, CR 2010
 HSP90 inhibitor lowers
EML-ALK levels and
induces tumor regression
in NSCLC model
Normant, Oncogene, 2011
ALK
Inhibitor
HSP90
inhibitor

15. MAPK pathway activation in melanoma:
BRAF and kit
Arkenau, Br J Cancer 2011

16. BRAF and kit mutations in
melanoma
 60% of melanoma cell lines and cultures show
oncogenic mutations of BRAF
Davis, Nature 2002
 Distinct set of genetic alteration in different types of
melanoma
Curtin, NEJM 2003
CSD: chronic
sun-induced damage

17. PLX4032 treatment of melanoma
with RBAF V600E mutations
ICH at baseline and day 15
on therapy:
Flaherty, NEJM 2010

18. PLX4032 treatment of melanoma
with RBAFV600E mutations
 32 patient treated with in recommended phase 2 dose
of 960 mg twice daily: CR 2 pts, PR 24 pts
 Estimated median progression-free survival 7 months
 Resistance mechanisms: Preclinical evidence for
concomitant PTEN loss, AKT activation, cyclineD/DK5
activation, MEK mutation, …
Flaherty, NEJM 2010; Puzanov Mol Oncol 2011,

19. Kit mutations in melanoma
 Associated with a proportion of mucosal, acral and
chronically sun-damaged melanoma
 Clinical studies with imatinib and nilotinib ongoing
 Patient with metastatic melanoma of the vulva treated
with imatinib
June 09 September 09
Dummer, USZ 2009

20. Hedgehog pathway
Low and de Sauvage, JCO 2010

21. Sonic hedgehog pathway driven tumors:
basal cell carcinoma and medulloblastoma
 Hedgehog pathway is inactive in adult tissue
 Gorlin syndrome: germ line mutation in PTCH1:
numerous basal cell carcinomas and other tumors,
especially medulloblastoma
 Basal cell carcinoma associated with mutations in the
hedgehop signaling pathway (PCHT1 > SMO) which
causes constitutive pathway signaling
 About 30% of medulloblastomas have activating
mutations in PTCH1
 GDC-0449 is a selective hedgehog signalling pathway
inhibitor

22. Inhibition of hedgehog pathway in
advanced basal-cell carcinoma
 33 patients with advanced or metastatic basal
cell carcinoma treated with GDC-0449, a small
molecule inhibitor of SMO
 RR 54%, SD 33%,
median response
duration 8.8+ mths
 No DLT
Von Hoff, NEJM 2009

23. Treatment of medulloblastoma with
hedghog pathway inhibitor GDC-0449
 Case report of 26 y/o man with metastatic
medulloblastoma with a PTCH1 mutation treated with
GDC-449. Rapid response with response duration of 3
months
 Resistance due to SMO mutation
Yauch, Science 2009
Baseline 2 months 3 months
Rudin, NEJM 2009

24. Phase I trial of GDC-449 in patients with
refractory solid tumors
 Responses in 58% of 33 patients with basal cell
carcinoma, duration 12.8+ months, 1/1 patient with
medulloblastoma and none of 34 patients with oder
solid tumors (including 3 SCLC and 3 mesothelioma)
 Downregulation of GLI1 as compared to baseline
LoRusso, CCR 2011
GLI1 expression

25. RET (REarranged during Transfection)
receptor tyrosine kinase activation in cancer
 Ligands: glial cell line-
derived neurotrophic
factor (GDNF) family
 Activation requires the
formation of a multimere
complex including the
ligand, a GDNF-family
receptor-α protein
binding binding the
ligand and ret
 Ret know-out mice: lack
of enteric neurons and
agenesis of the kidney
Phay, CCR 2010

26. Medullary thyroid cancer
 Araise from parafollicular or calcitonin-producing
c-cells of the thyroid
 15% of thyroid malignancies
 70-80% sporadic, 20-30% familial
 Associated with paraneoplastic syndroms related to
hormone production of c-cells (diarrhea)
 Activation of TET critical in MTC tumorigenesis
 RET mutation:
– 100% of hereditary MTC (autosomal dominat)
– >40% of sporadic thyroid cancer

27. Heredidary MTC-associated syndroms
 MEN-2A:
MTC with pheochromocytoma or parathyroid
hyperplasia or adenoma
 MEN-2A:
MTC with pheochromocytoma and associated clinical
abnormalities (mucosal neuromas, intestinal
ganglioneuromtosis, delayed puberty, marfanoid
habitus, skeletal abnormalities, corneal nerve
thickening
 FMCT:
Familial disease with no evidence for
pheochromocytom or parathyroid adenoma

28. Vandetanib for medullary thyroid
carcinoma
 Oral TKI targeting VEGFR, EGFR und RET
 30 patients, RR 20% (mean durstions 311+ days),
additional SDR at 24 weeks 53%
Wells, JCO 2009

29. Vandetanib vs placebo in medullary
thyroid cancer
Wells, ASCO 2010

30. Motesanib in locally advanced or
metastatic hereditary MTC
 Oral TKI targeting VEGFR, PDGF, Kit and RET
 Phase II study
 Response in 2%
of 91 patients,
stable disease
(>24 weeks) in 81%
 Decrease in calcitonin 83%
Schlumberger, JCO 2009

31. Targeted therapy for metastatic
differentiated thyroid cancer
 Most frequent - mutually exclusive - mutations: in
papillary thyroid cancer
– BRAF 45%, almost all V600E
– RAS 15%
– RET-translocations 20%
 Most frequent mutations in follicular thyroid cancer:
– RAS 45%
– PAX8-PPARϒ rearrangement 35%
– Mutation in PI3K/Akt pathway 10%
O’Neill, Oncologist, 2010

32. Sorafenib in thyroid cancer
 Sorafenib: TKI against VEGFR2, PDGF, BRAF,
 Medullary thyroid cancer:
16 pts, 1 objective response,
14 stable disease
 Differentiated thyroid cancer:
Ongoing randomized phase III study versus placebo
with cross over
Lam, JCO 2010

33. Pazopanib in radioiodine-refractory
metastatic differentiated thyroid cancer
 Oral TKI targeting VEGFRs, PDGFR and kit
 Responses in 49%
of 39 patients
 1-year PFS 47%
Bible, Lancet Oncol 2010

34. MET in lung cancer
Pao & Girard, Lancet Oncol, 2011

35. Why targeting MET and HGF in NSCLC:
Met amplification and EGFR resistance
 NSCLC cell lines with met
amplification depend on
MET for growth and survival
Lutterbach, CR 2007
 Increased MET copy number
(4%) associated with worse
prognosis in resected NSCLC.
Cappuzzo, JCO 2009
 MET amplification and resistance
to EGFR TKIs:
– Combination of gefitinib and
MET inhibitor
Engleman, Science 2007;
Spigel, ESMO 2010
Erloti
nib+
MetM
Ab
Cont
rol

36. How to target MET
Anti-HGF Ab
• AMG102
• SCH900105
Non-selective
c-MET inhibitors
• PF02341066
• Cabozantinib
(XL184)
• Foretinib
(GSK1363089)
• MK-2461
• MP470
• MGCD265
Anti-c-METAb
• METMAb
Selective
c-MET inhibitors
• Tivantinib
(ARQ 197)
• JNJ-38877605
• PF04217903
Curtesy Alex Adjei

37. MetMab
MetMAb
Met
 
HGF HGF
Met
Growth, Migration, Survival No Activity
In Vivo
Erlotinib+
MetMAb
Control
EGFR WT NSCLC
XenograftNSCLC
Spigel, ESMO 2010

38. 38
1+ 2+ 3+
 Intensity of Met staining on tumor cells scored on 0–3+ scale
 Tissue was obtained from 100% of patients.
 95% of patients had adequate tissue for evaluation of Met by IHC.
 54% patients had ‘Met High’ NSCLC.
Development of Met IHC as a Diagnostic
 Estimated that ~50% of patients would have ‘Met High’ tumors
 Met by IHC was assessed after randomization
‘Met High’ was defined prior to unblinding as:
≥50% tumor cells with a staining intensity of 2+ or 3+
Spigel, ESMO 2010

39. 39
Anti-Met Monovalent Antibody:
PFS Subgroup Analyses in ITT
Spigel, ESMO 2010

40. Selective oral MET inhibitor ARQ 197
(tavantinib)
 Tivantinib (ARQ 197) targets inactive kinase
conformations
 Phase II trial comparing erlotinib plus ARQ 197 to
erlotinib plus placebo in second line
Schiller, ASCO 2010
Tivantinib
c-MET
Key motifs

41. Phase II trial of erlotinib plus ARQ 197 vs erlotinib
plus placebo in second line:
Histologic and molecular subgroups
Schiller, ASCO 2010

42. Cabozantinib (XL184) multikinase
inhibitor
ATP competitive, reversible
RTK Cellular IC50 (nM) autophosphorylation
MET 8
VEGFR2 4
Kinase IC50 (nM)
MET 1.8
VEGFR2 0.035
RET 5.2
KIT 4.6
AXL 7.0
TIE2 14
FLT3 14
S/T Ks (47) >200

43. Cabozantinib (XL184): Promising activity
in previously treated NSCLC patients
Best Radiologic Time Point Response of Patients with >1 Post-baseline Tumor Assessment
Interim RDT data presented at 2010 EORTC-NCI-AACR Symposium