Rolf Stahel
University Hospital
Zürich
Switzerland
New drugs in oncogenic-driven
malignacies
ESO Masterclass, Ermatingen, ...
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 S...
HE
4.jpg
30
HE20
CD5
ALK
Anaplastic T cell lymphoma
 ALK-positive anaplastic large cell lymphoma
represents about 6% of peripheral T-cell lymphoma...
ALK aberrations in malignancies
Mossé, CCR 2009
ALK in neuroblastoma
 Identification of ALK as familial predisposition gene
Mosse, Nature 2008
 Somatic and germline mua...
ALK in lung cancer
Pao & Girard, Lancet Oncol, 2011
Soda M et al. Nature 2007;448:561–567
Reprinted by permission from
Macmillan Publishers Ltd: Nature, © 2007
EML4–ALK is a ...
FISH
PCR/Sequencing IHC
Diagnosis of EML4-ALK positive NSCLC
2p23-21
ALK EML4~ 12 Mb
EML4-ALK fusion by inversion (~ 70%)
3‘ 5‘
Curtesy Lukas Bubendorf
Clinical features of patients with
EML4-ALK NSCLC
 Predominantly found adenocarcinoma. TTF1 pos.,
acinar histology, mutua...
60
40
20
0
–20
–40
–60
–80
–100
Progressive disease
Stable disease
Confirmed partial response
Confirmed complete response
...
Targeting ALK through HSP90
inhibitors?
 Mutated proteins – such as the ALK fusion gene
product – depend on HSP90 for mat...
MAPK pathway activation in melanoma:
BRAF and kit
Arkenau, Br J Cancer 2011
BRAF and kit mutations in
melanoma
 60% of melanoma cell lines and cultures show
oncogenic mutations of BRAF
Davis, Natur...
PLX4032 treatment of melanoma
with RBAF V600E mutations
ICH at baseline and day 15
on therapy:
Flaherty, NEJM 2010
PLX4032 treatment of melanoma
with RBAFV600E mutations
 32 patient treated with in recommended phase 2 dose
of 960 mg twi...
Kit mutations in melanoma
 Associated with a proportion of mucosal, acral and
chronically sun-damaged melanoma
 Clinical...
Hedgehog pathway
Low and de Sauvage, JCO 2010
Sonic hedgehog pathway driven tumors:
basal cell carcinoma and medulloblastoma
 Hedgehog pathway is inactive in adult tis...
Inhibition of hedgehog pathway in
advanced basal-cell carcinoma
 33 patients with advanced or metastatic basal
cell carci...
Treatment of medulloblastoma with
hedghog pathway inhibitor GDC-0449
 Case report of 26 y/o man with metastatic
medullobl...
Phase I trial of GDC-449 in patients with
refractory solid tumors
 Responses in 58% of 33 patients with basal cell
carcin...
RET (REarranged during Transfection)
receptor tyrosine kinase activation in cancer
 Ligands: glial cell line-
derived neu...
Medullary thyroid cancer
 Araise from parafollicular or calcitonin-producing
c-cells of the thyroid
 15% of thyroid mali...
Heredidary MTC-associated syndroms
 MEN-2A:
MTC with pheochromocytoma or parathyroid
hyperplasia or adenoma
 MEN-2A:
MTC...
Vandetanib for medullary thyroid
carcinoma
 Oral TKI targeting VEGFR, EGFR und RET
 30 patients, RR 20% (mean durstions ...
Vandetanib vs placebo in medullary
thyroid cancer
Wells, ASCO 2010
Motesanib in locally advanced or
metastatic hereditary MTC
 Oral TKI targeting VEGFR, PDGF, Kit and RET
 Phase II study
...
Targeted therapy for metastatic
differentiated thyroid cancer
 Most frequent - mutually exclusive - mutations: in
papilla...
Sorafenib in thyroid cancer
 Sorafenib: TKI against VEGFR2, PDGF, BRAF,
 Medullary thyroid cancer:
16 pts, 1 objective r...
Pazopanib in radioiodine-refractory
metastatic differentiated thyroid cancer
 Oral TKI targeting VEGFRs, PDGFR and kit
 ...
MET in lung cancer
Pao & Girard, Lancet Oncol, 2011
Why targeting MET and HGF in NSCLC:
Met amplification and EGFR resistance
 NSCLC cell lines with met
amplification depend...
How to target MET
Anti-HGF Ab
• AMG102
• SCH900105
Non-selective
c-MET inhibitors
• PF02341066
• Cabozantinib
(XL184)
• Fo...
MetMab
MetMAb
Met
 
HGF HGF
Met
Growth, Migration, Survival No Activity
In Vivo
Erlotinib+
MetMAb
Control
EGFR WT NSCLC
...
38
1+ 2+ 3+
 Intensity of Met staining on tumor cells scored on 0–3+ scale
 Tissue was obtained from 100% of patients.
...
39
Anti-Met Monovalent Antibody:
PFS Subgroup Analyses in ITT
Spigel, ESMO 2010
Selective oral MET inhibitor ARQ 197
(tavantinib)
 Tivantinib (ARQ 197) targets inactive kinase
conformations
 Phase II ...
Phase II trial of erlotinib plus ARQ 197 vs erlotinib
plus placebo in second line:
Histologic and molecular subgroups
Schi...
Cabozantinib (XL184) multikinase
inhibitor
ATP competitive, reversible
RTK Cellular IC50 (nM) autophosphorylation
MET 8
VE...
Cabozantinib (XL184): Promising activity
in previously treated NSCLC patients
Best Radiologic Time Point Response of Patie...
Upcoming SlideShare
Loading in...5
×

MCO 2011 - Slide 20 - R.A. Stahel - Spotlight session - New drugs in oncogenic-driven malignancies (thyroid, melanoma)

883

Published on

0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
883
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
0
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide

MCO 2011 - Slide 20 - R.A. Stahel - Spotlight session - New drugs in oncogenic-driven malignancies (thyroid, melanoma)

  1. 1. Rolf Stahel University Hospital Zürich Switzerland New drugs in oncogenic-driven malignacies ESO Masterclass, Ermatingen, April 4, 2011
  2. 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. 3. HE
  4. 4. 4.jpg 30 HE20 CD5 ALK
  5. 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. 6. ALK aberrations in malignancies Mossé, CCR 2009
  7. 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. 8. ALK in lung cancer Pao & Girard, Lancet Oncol, 2011
  9. 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. 10. FISH PCR/Sequencing IHC Diagnosis of EML4-ALK positive NSCLC
  11. 11. 2p23-21 ALK EML4~ 12 Mb EML4-ALK fusion by inversion (~ 70%) 3‘ 5‘ Curtesy Lukas Bubendorf
  12. 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. 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. 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. 15. MAPK pathway activation in melanoma: BRAF and kit Arkenau, Br J Cancer 2011
  16. 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. 17. PLX4032 treatment of melanoma with RBAF V600E mutations ICH at baseline and day 15 on therapy: Flaherty, NEJM 2010
  18. 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. 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. 20. Hedgehog pathway Low and de Sauvage, JCO 2010
  21. 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. 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. 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. 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. 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. 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. 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. 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. 29. Vandetanib vs placebo in medullary thyroid cancer Wells, ASCO 2010
  30. 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. 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. 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. 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. 34. MET in lung cancer Pao & Girard, Lancet Oncol, 2011
  35. 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. 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. 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. 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. 39 Anti-Met Monovalent Antibody: PFS Subgroup Analyses in ITT Spigel, ESMO 2010
  40. 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. 41. Phase II trial of erlotinib plus ARQ 197 vs erlotinib plus placebo in second line: Histologic and molecular subgroups Schiller, ASCO 2010
  42. 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. 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

×