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Outline

Drivers Oncogenetici Nel NSCLC: Impatto Nella Pratica Clinica Presente e Futura Raffaele Califano Department of Medical Oncology The Christie and University Hospital of South Manchester, Manchester, UK. Outline. Molecular events in NSCLC Beyond EGFR and ALK Conclusions.

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Outline

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  1. Drivers Oncogenetici Nel NSCLC: Impatto Nella Pratica Clinica Presente e FuturaRaffaele CalifanoDepartment of Medical OncologyThe Christie and University Hospital of South Manchester, Manchester, UK

  2. Outline Molecular events in NSCLC Beyond EGFR and ALK Conclusions

  3. Molecular events in NSCLC Adenocarcinoma Squamous-cell carcinoma EGFR resistance mutations 0.8% HER2 0.9% EGFR 9.5% KRAS 27% Unknown 53.8% BRAF 1.7% PI3K 2.6% ALK 3.7% Kris et al, JAMA 2014; Barlesi et al, JCO 2013

  4. KRAS Mutations

  5. KRAS Mutations Most common event (approx 25%) Mutually exclusive with EGFR and ALK mut Stimulus-independent downstream activation

  6. Selumetinib Potent and selective inhibitor of MEK 1/2 Greater sensitivity in BRAF/RAS-mutant cell lines Selumetinib Yeh et al. Clin Cancer Res 2007; Davies et al. Mol Cancer Ther 2007

  7. Placebo BID + docetaxel 75 mg/m2 Stage IIIB-IV NSCLC Failed first-line therapy KRAS mutant tumor WHO PS 0-1 NO symptomatic brain metastases Selumetinib 75 mg BID+ docetaxel 75 mg/m2 Selumetinib – Phase 2 Randomization1:1 Primary endpont: OS Janne et al., Lancet Oncology 2013

  8. Overall Survival 1.0 0.8 0.6 Proportion of patients alive 0.4 0.2 0.0 0 50 100 150 200 250 300 350 400 450 500 550 600 650 Days Janne et al., Lancet Oncology 2013

  9. Progression-Free Survival 1.0 0.8 0.6 Proportion of progression–free patients 0.4 0.2 0.0 0 50 100 150 200 250 300 350 400 450 Days Janne et al., Lancet Oncology 2013

  10. Response Rate Janne et al., Lancet Oncology 2013

  11. Adverse Events

  12. Placebo BID + docetaxel 75 mg/m2 Stage IIIB-IV NSCLC Failed first-line therapy KRAS mutant tumor WHO PS 0-1 Excluding symptomatic brain metastases Selumetinib 75 mg BID+ docetaxel 75 mg/m2 SELECT-1 Phase 3 Trial Randomization1:1 Primary endpont: PFS Prophylactic G-CSF NCT01933932

  13. Other agents in Kras Mutant

  14. Aberrant MET signaling

  15. MET Structure MET is a receptor tyrosine kinase Encodes protein called HGF-R Activated via binding with ligand HGF Facilitates embryonic development, wound healing, and tissue regeneration Gelsomino et al., CROH 2014

  16. MET deregulation Protein overexpression MET gene amplification MET gene activating mutations Tumor growth Progression invasion Gelsomino et al., CROH 2014

  17. High MET Copy Number: Poor Prognosis 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 ≥ 4 to < 5 copies/cell 0.6 0.6 MET < 5 copies/cell(n = 383) Cumulative Survival (proportion) < 2 copies/cell 0.5 0.5 ≥ 3 to < 4 copies/cell 0.4 0.4 ≥ 2 to < 3 copies/cell 0.3 0.3 ≥ 6 copies/cell 0.2 0.2 ≥ 5 to < 6 copies/cell MET ≥ 5 copies/cell(n = 48) 0.1 0.1 P = .0045 0 0 0 20 40 60 80 100 0 20 40 60 80 100 120 Time (months) Time (months) FISH positive: > 5 copies/cell Cappuzzo et al. JCO 2009

  18. MET Blocking Mechanisms Gelsomino et al., CROH 2014

  19. Erlotinib 150 mg QD + Tivantinib 28-day cycle NSCLC Stage IIIB/IV ≥1 prior chemo (no prior EGFR TKI) PS 0-1 N= 167 Erlotinib 150 mg QD + Placebo 28-day cycle Tivantinib Phase 2 Randomization1:1 Crossover allowed Primary endpoint: PFS Phase II Sequist et al, JCO 2011

  20. Progression-free survival Sequist et al, JCO 2011

  21. PFS: Subgroup analysis Sequist et al, JCO 2011

  22. Erlotinib 150 mg QD + Tivantinib 28-day cycle NSCLC Stage IIIB/IV Non-squamous ≥1 prior chemo (no prior EGFR TKI) PS 0-1 N=1048 Erlotinib 150 mg QD + Placebo 28-day cycle MARQUEE study Randomization1:1 Primary endpoint: OS Phase III – early discontinuation Scagliotti et al, JCO 2015

  23. Overall Survival - ITT Scagliotti et al, JCO 2015

  24. MET Diagnostic IHC Negative Weak Low Moderate Strong High Scagliotti et al, JCO 2015

  25. Biomarker analysis Scagliotti et al, JCO 2015

  26. PFS and OS in MET high Scagliotti et al, JCO 2015

  27. Subgroup Analysis

  28. Erlotinib 150 mg QD + Tivantinib 28-day cycle NSCLC Stage IIIB/IV - EGFR WT Non-squamous ≥1 prior chemo (no prior EGFR TKI) PS 0-1 N=307 Erlotinib 150 mg QD + Placebo 28-day cycle ATTENTION study Randomization1:1 Primary endpoint: OS Phase III – early discontinuation due to ILD (9%) Yoshioka et al, Ann Onc 2015

  29. PFS and OS in ITT Yoshioka et al, Ann Onc 2015

  30. Subgroup Analysis Yoshioka et al, Ann Onc 2015

  31. Erlotinib 150 mg QD + Metmab 21-day cycle NSCLC Stage IIIB/IV Pre-treated PS 0-1 N= 137 Erlotinib 150 mg QD + Placebo 21-day cycle Onartuzumab – Phase II Randomization1:1 Crossover allowed Primary endpoint: PFS in ITT and MET pos (IHC 2-3+) Spigel et al, JCO 2013

  32. PFS and OS in MET+ 1.0 1.0 0.8 0.8 0.6 0.6 Probability of progression free Probability of survival 0.4 0.4 0.2 0.2 0.0 0.0 0 3 6 9 12 15 18 0 3 6 9 12 15 18 21 Overall survival (months) Time to progression (months) Spigel et al, JCO 2013

  33. Erlotinib 150 mg QD + Metmab 21-day cycle NSCLC Stage IIIB/IV 2nd-3rd line MET IHC 2/3+ N= 490 Erlotinib 150 mg QD + Placebo 21-day cycle METLung Study Randomization1:1 NO Crossover Primary endpoint: OS Discontinued for futility Spigel et al, ASCO 2014

  34. Overall Survival 1.0 Median 9.1 months (95% CI 7.7–10.2) Placebo + erlotinib Onartuzumab + erlotinib 0.8 HR 1.27 (95% CI: 0.98–1.65) p=0.07 0.6 Probability of overall survival 0.4 0.2 Median 6.8 months (95% CI 6.1 – 7.5) 0 0 3 6 9 12 15 18 21 Months Spigel et al, ASCO 2014

  35. OS: Subgroups analysis Onartuzumab + erlotinib better Placebo + erlotinib better 1/100 1 100 Spigel et al, ASCO 2014

  36. Cohort 2 (n=4) 100 mg QD Cohort 1 (n=3) 50 mg QD Cohort 3 (n=8) 200 mg QD Cohort 4 (n=7) 200 mg BID PROFILE 1001 Expansion Cohorts Cohort 5 (n=6) 300 mg BID Part 1: Dose escalation Cohort 6 (n=9) 250 mg BIDMTD/RP2D Part 2: Dose expansion Molecularly enriched cohorts (c-MET, ALK, ROS1) Camidge et al., ASCO 2014

  37. MET expansion Cohort In archival tumor tissue, MET amplification was determined by FISH MET amplified (low MET level) MET/CEP7 ratio ≥1.8–≤2.2 MET not Amplified (not eligible) MET/CEP7 ratio <1.8 MET amplified (intermed MET level) MET/CEP7 ratio >2.2–<5.0 MET amplified (high MET level) MET/CEP7 ratio ≥5 CEP7, chromosome 7 centromere signal Camidge et al., ASCO 2014

  38. Demographics Camidge et al., ASCO 2014

  39. MET amplified pts Cappuzzo et al., JCO 2009

  40. Anti-tumor activity Camidge et al., ASCO 2014

  41. Other MET inhibitors Hellerstedt et al, ASCO 2012; Tarhini et al, ASCO 2015; Mok et al, ESMO 2012

  42. MET mutations causing exon 14 skipping MSKCC - Prospective series: 8 pt (4%)s with MET exon 14 splice site alterations Cabozantinib (n=1) or Crizotinib (n=3) Al pts had radiological response These mutations are activating and targetable Paik et al, Cancer Discovery 2015

  43. ROS1 gene Rearrangement

  44. ~1% of NSCLC cases FISH or IHC Younger pts, never or light smokers with adeno Very rarely overlap with other oncogenic drivers ROS1 rearrangement in NSCLC TPM3-ROS1 SDC4-ROS1 SLC34A2-ROS1 CD74-ROS1 EZR-ROS1 LRIG3-ROS1 ROS1 Shaw, et al., ASCO 2012

  45. Cohort 2 (n=4) 100 mg QD Cohort 1 (n=3) 50 mg QD Cohort 3 (n=8) 200 mg QD Cohort 4 (n=7) 200 mg BID PROFILE 1001 ROS1+ Expansion Cohort Cohort 5 (n=6) 300 mg BID Part 1: Dose escalation Cohort 6 (n=9) 250 mg BIDMTD/RP2D Part 2: Dose expansion Molecularly enriched cohorts (c-MET, ALK, ROS1) Shaw et al, NEJM 2014

  46. Antitumor Activity Shaw et al, NEJM 2014

  47. EUROS1 Cohort European retrospective series (N=31) 64% F, 67% never smokers, All adeno, FISH+ 13 pts received > 3 lines of Rx ORR: 80%, DCR 86%, PFS: 9,1 mos, PFS rate at 12 mos: 44% Mazieres et al, JCO March 2015

  48. BRAF Mutations

  49. BRAF mutation About 2-3% of mutations in NSCLC Most common is V600E Mut (50%) Usually Adeno histology Aggressive biology

  50. BRAF and MEK blockade RTKs SOS P P Grb2 SHC P P P P Dabrafenib RAS PI3K/AKT/mTOR pathway BRAF CRAF BRAF V600 MEK Trametinib p90RSK MSK1 ERK1/2 Proliferation, Growth, Survival Courtesy of D Planchard

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