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
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
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
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
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
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
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
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
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