New developments of targeted therapy in nsclc

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New developments of targeted therapy in nsclc

  1. 1. New Developments in Targeted Therapy in Lung Cancer Andrea Wang-Gillam MD, PhD Division of Oncology Washington University School of Medicine in St. Louis
  2. 2. Jemal, A. et al. CA Cancer J Clin 2010;60:277-300
  3. 3. Incidence of Mutations in Lung Cancer Mutation found in 54% (280/516) of tumors completely tested (95% CI 50-59%) Kris MG, J Clin Oncol 2011; 29: Abstr CRA 7506
  4. 4. Targeting EGFR Ciardiello F, N Engl J Med 2008; 358: 1160-1174
  5. 5. EGFR Mutations Sharma S, Nature Rev Cancer 2007;7:169-181.
  6. 6. Mok T, ESMO 2008. IPASS: Study Design Patients • Chemonaive • Age ≥8 years • Adenocarcinoma histology • Never or light ex-smokers* • Life expectancy ≥12 weeks • PS 0-2 • Measurable stage IIIB/ IV disease Gefitinib (250 mg / day) Endpoints Primary • Progression-free survival (non- inferiority) Secondary • Objective response rate • Overall survival • Quality of life • Disease-related symptoms • Safety and tolerability Exploratory • Biomarkers – EGFR mutation – EGFR-gene-copy number – EGFR protein expression • Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped ≥15 years ago and smoked ≤10 pack years Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m2) 3 weekly X 6 1:1 randomization
  7. 7. IPASS Mok TS, N Engl J Med 2009; 361: 947-957 RR CP – 23.5% Gef – 1.1% RR CP – 47.3% Gef – 71.2%
  8. 8. Randomized Studies on First Line EGFR TKI in Patients with EGFR Mutation Author Study N (EGFR mutation) RR (TKI vs chemotherapy) Median PFS (months) Mok IPASS 261 71.2% vs 47.3 9.8 vs 6.4 Mitsudomi WJTOG 3405 177 62.1% vs 32.2% 9.2 vs 6.3 Maemondo NEJGSG002 228 73.7% vs 30.7% 10.8 vs 5.4 Zhou OPTIMAL 154 82% vs 36% 13.1 vs 4.6 Rosell EURTAC 174 58% vs 15% 9.7 vs 5.2 Mok TS, New Engl J Med 2009 Mitsudomi T, Lancet Oncology 2010 Maemondo M N Engl J Med 2010 Zhou C, Lancet Oncol 2011 Rosell R, Lancet Oncol 2012 First-line EGFR TKI improves ORR and PFS compared to chemotherapy
  9. 9. Prevalence of Mechanisms of Resistance to EGFR TKIs Nguyen KSH, Clin Lung Cancer 2009; 10: 281-289
  10. 10. Mechanisms of Resistance to EGFR TKIs Repeated Biopsy Study Sequist LV, Sci Translat Med 2011, 3: 75ra26
  11. 11. Irreversible TKIs  Reversible TKIs such as erlotinib, gefitinib and icotinib are competitive inhibitors of ATP, blocking its binding to the TK domain of the EGFR.  The presence of T790M mutations increase the ATP affinity by approximately 5 fold compared to the initial EGFR mutation alone, decreasing the TKI efficacy.  Irreversible TKI inhibitors bind covalently with the Cys 797 at the ATP-binding cleft of mutant EGFR, providing a prolonged EGFR inhibition.  Preclinical studies have shown activity for irreversible TKIs in cell lines resistant to gefitinib.
  12. 12. LUX-Lung 1 Randomization 2:1 (Double Blind) Oral afatinib 50 mg once daily plus BSC Oral placebo once daily plus BSC Primary endpoint: Overall survival (OS) Secondary: PFS, RECIST response, QoL (LC13 & C30), safety • Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter • Exploratory biomarkers: Archival tissue testing for EGFR mutations (optional; central lab) Serum EGFR mutational analysis (all patients) Patients with: • Adenocarcinoma of the lung • Stage IIIB/IV • Progressed after one or two lines of chemotherapy (incl. one platinum-based regimen) and ≥12 weeks of treatment with erlotinib or gefitinib • ECOG 0–2 N=585
  13. 13. LUX-1: PFS by Independent Review Miller VA, Lancet Oncol 2012; 13: 428-538
  14. 14. LUX-Lung 2 Afatinib in EGFR Mutants  Phase II study  129 patients  1st line 61 patients 2nd line 68 patients  Afatinib 40 mg or 50 mg daily
  15. 15. LUX-Lung 2 – PFS and OS Yang JC, Lancet Oncol 2012; 13: 539-548
  16. 16. LUX-Lung 2 EGFR Exon 19 del Response Yang JC, Lancet Oncol 2012; 13: 539-548
  17. 17. Role of Afatinib – LUX-7 Clinicaltrials.gov, NCT01466660
  18. 18. ALK Pathway Shaw AT, Clin Cancer Res 2011; 17: 2081-2086
  19. 19. Crizotinib  Phase II trial  Approximately 1500 patients screened for ALK rearrangements  82 patients with advanced disease enrolled  Crizotinib 250 mg twice daily Kwak EL, N Engl J Med 2010; 363: 1693- 1703
  20. 20. Crizotinib Kwak EL, N Engl J Med 2010; 363: 1693- 1703
  21. 21. Crizotinib Kwak EL, N Engl J Med 2010; 363: 1693- 1703 Median PFS 9 months
  22. 22. New ALK Inhibitors
  23. 23. AP26113 Camidge DR, Proc Am Soc Clin Onc 2013 Abstr 8301
  24. 24. Targeting KRAS Mutation Selumetinib (MEK inhibitor) Jane PA, J Clin Oncol 2012; 30: Abstr 7503
  25. 25. Targeting KRAS Mutation Selumetinib (MEK inhibitor) Jane PA, J Clin Oncol 2012; 30: Abstr 7503 First prospective trial to demonstrate a clinical benefit from targeted therapy in patients with KRAS mutation
  26. 26. New Mutations Bergethon K, J Clin Oncol 2012; 30: 863-870 Kohno T, Nat Medicine 2012; 18: 375-377
  27. 27. ROS-1 Shaw AT, J Clin Oncol 2012; 30: Abstr 7508
  28. 28. BRAF Mutation  2% of lung cancer (V600E, and non-V600E)  Exon 11 & 15  Poor prognostic marker
  29. 29. BRAF Inhibition Dabrafenib Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009
  30. 30. Dabrafenib in Melanoma Phase 3 Study BREAK-3 Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009 FDA approved on 5/29/13
  31. 31. BRF113928 Design Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009
  32. 32. Dabrafenib in NSCLC Maximum Reduction in Stage 1 PR 40% SD 20% PD 30% NA 10% - SAE prior to assessment First 20 patients Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009
  33. 33. Dabrafenib Planchard D, Proc Am Soc Clin Onc 2013 Abstr 8009
  34. 34. GPS testing is done at Wash U
  35. 35. Questions?
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