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

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  • 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

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