Treatment of Non–Small-Cell Lung Cancer with Erlotinib or Gefitinib

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Treatment of Non–Small-Cell Lung Cancer with Erlotinib or Gefitinib

  1. 1. Treatment of Non–Small-Cell Lung Cancer with Erlotinib or Gefitinib N Engl J Med. 2011 Mar 10;364(10):947-55. Presentor: CR Supervisor: Vs 1
  2. 2. Outline• Introduction of lung cancer• EGFR in NSCLC• Important clinical trials of TKI• To know about gefitinib and erlotnib• Conclusion with NCCN guideline and regulations of Bureau National health insurance, Taiwan, ROC 2
  3. 3. Lung cancer• Leading cause of cancer-related death worldwide• Estimated 157,300 deaths in the United States in 2010• 85% of lung cancer are non-small-cell-lung cancer(NSCLC)• Less than 30% respond to platinum based therapy 3
  4. 4. Chemotherapy in NSCLC 4 N Engl J Med 2002;346:92-98
  5. 5. General characteristicsN Engl J Med 2002;346:92-98 5
  6. 6. TTP:GC >PC, greater grade 3,4,5 renal toxicity(9% vs. 3%) 6 N Engl J Med 2002;346:92-98
  7. 7. Overall survival7.8-8.1 monthsTime to progression3.1-4.2 months 7 N Engl J Med 2002;346:92-98
  8. 8. EGFR in NSCLC 8
  9. 9. Drivermutations in NSCLC 9 Lancet Oncol 2011; 12: 175–80
  10. 10. HER3 hadnotyrosine EGFR signaling pathwayskinaseactivity 10
  11. 11. N Engl J Med 2008; 359:1367-1380EGFR amplifications1.Dysplasia (especially of ahigh grade)2. Increased lung-cancerrisk when detected in thesputum of smoker3. Poor prognosis4.Sensitivity to EGFRinhibitors 11
  12. 12. EGFR mutation 12
  13. 13. EGFR mutationLeu Arg Glu Ala (LREA) motif in exon 19 13 N Engl J Med 2005;353:133-44.
  14. 14. Gefitinib (Iressa) & Erlotinib(Tarceva) • EGFR tyrosine kinase inhibitors • Asian, non-smoker, and female • Gefitinib and erlotinib for EGFR mutation 14N Engl J Med 2008;359:1367-1380
  15. 15. Tarceva Tarcev Placebo a Erlotinib in NSCLC( 2 lines) 15 N Engl J Med 2005; 353:123-132
  16. 16. 16N Engl J Med 2005; 353:123-132
  17. 17. Overall survivalHR:0.706.7 vs. 4.7 monthsP<0.001Progression freesurvival2.2 vs 1.8 monthsP<0.001 17 N Engl J Med 2002;346:92-98
  18. 18. Univariate HR P value Multivariate HR P valueTreatment Erlotinib 0.7 <0.001 0.7 0.002 PlaceboPathologic subtypes Adenocarcinoma 0.7 0.008 0.8 0.004 Others 0.8 0.07EGFR Positive 0.7 0.02 Negative 0.9 0.7 Unknown 0.8 0.03Smoking Ever 0.9 0.14 Referrence Never 0.4 <0.001 0.8 0.048 Unknown 1.1 0.8 1 0.89Race Asian 0.6 0.06 0.7 0.01 Others 0.8 0.01 18 N Engl J Med 2002;346:92-98
  19. 19. High polysomy ( 4 gene copies in 40% of cells) Amplification (gene:chromosome 2 or 15 gene copies per cell in 10% of cells)Red (EGFR)Green (CEP7) 19 N Engl J Med 2005;353:133-44.
  20. 20. 20N Engl J Med 2005;353:133-44.
  21. 21. 21N Engl J Med 2005;353:133-44.
  22. 22. EGFR mutation• 10% of adenocarcinoma in USA• 30-50% of adenocarcinoma in Asia• Female & non-smokers• Exons 18, 19, and 20 and 21• Transform fibroblasts and lung epithelial cells• In transgenic mice->exon 19 deletion or L858R mutation->atypical adenomatous hyperplasia- >BAC->invasive adenocarcinoma in 8-10 weeks• >80% : exon 19 or the L858R within exon 21 22 N Engl J Med 2008; 359:1367-1380
  23. 23. Copy number alternations (CNA) in Chromosome 7p High-density comparative genomic hybridization (CGH) array 23J Clin Oncol 2011 Sep 1;29(25):3435-42.
  24. 24. 24J Clin Oncol 2011 Sep 1;29(25):3435-42.
  25. 25. 25J Clin Oncol 2011 Sep 1;29(25):3435-42.
  26. 26. Iressa Survival Evaluation in Lung Iressa Cancer(ISEL) Lancet 2005;366:1527-1537 Placebo Iressa Placebo 26
  27. 27. Overall survival in allpopulations5.6 vs. 5.1 monthsHR:0.89,P=0.087Overall survial inadenocarcinoma6.3 vs. 5.4 monthsHR:0.84,P=0.089 27 Lancet 2005;366:1527-1537
  28. 28. Time to treatmentfailure in allpopulations3.0 vs. 2.6 monthsHR:0.82,P=0.006 28 Lancet 2005;366:1527-1537
  29. 29. Subgroupanalysis of Iressa 29 Lancet 2005;366:1527-1537
  30. 30. Iressa Pan-Asia Study (IPASS)1.Asia2.Iressa vsCarboplatin+Paclitaxel3.First line 30N Engl J Med 2009;361:947-957
  31. 31. Progression freesurvival in allpopulations5.6 vs. 5.1 monthsHR:0.74,P<0.001Progression freesurvival in EGFRmutation6.3 vs. 5.4 monthsHR:0.48,P<0.001 31 N Engl J Med 2009;361:947-957
  32. 32. Progression freesurvival in EGFRmutation negative5.6 vs. 5.1 monthsHR:2.85,P<0.001Progression freesurvival in EGFRunknown6.3 vs. 5.4 monthsHR:0.68,P<0.001 32 N Engl J Med 2009;361:947-957
  33. 33. Iressa vs.Paclitaxel+carboplatin (1st line) in EGFR mutation 33 N Engl J Med 2010; 362:2380-2388
  34. 34. Progression freesurvival10.8 vs. 5.4 monthsHR:0.30,P<0.001Overall survival30.5 vs. 23.6 monthsP=0.31 34N Engl J Med 2010; 362:2380-2388
  35. 35. Erlotinib(Tarceva)• Approval from FDA in November,2004• Approval from European Medicines Agency in June,2005• Locally advanced or metastatic NSCLC• 2nd or 3rd line• 150mg/day PO QD• Bioavailability 100% when taken with food-> more side effect – One hour before or two hours after a meal ( Bioavailability:60%) 35
  36. 36. Gefitinib (Iressa)• Approval from FDA in 2003• ISEL-> use in who are currently benefiting or have previously benefited in USA• Approval from European Medicines Agency in July,2009 • Any line for NSCLC with EGFR mutations• In first line, inferior to chemotherapy but superior for those with EGFR mutations• 2 line, similar to standard chemotherapy• Not effected by food• 250 mg PO QD• Half life: 48 hours• Bioavailability:60% 36
  37. 37. Metabolism• By CYP3A4 – CYP3A5 and CYP1A1( lesser)• Careful with atazanavir, itraconazole, ritonavir,voriconazole, grape fruit juice• Not with CYP3A4 inducers – rifampicin, phenytoin, and St. John’s wort• Cigarrete induces CYP1A1 -> reduces erlotinib• Avoid H2 blocker or PPI (-> reduces gastric PH-> reduce plasma TKI) 37
  38. 38. Follow-up• Radiographic assessment no more frequent than every 6 to 8 weeks• Visit at least monthly• Medications continued as long as – ECOG adequate – No clinical or radiographic progression 38
  39. 39. Dosage• Reduced when rash or diarrhea• Monitor liver function• Discontinued when total bilirubin 3X or ALT/AST 5X• Erlotinib restated at a reduced dose with decrement of 50mg ( 100mg qd)• Gefitinib restated at initial dose(250mg) 39
  40. 40. Cost• Erlotinib – $4,000/month – NTD 53490/month(1783/#)• Gefitinib – $1,800/month – NTD 41280/month(1376/#) 40
  41. 41. Toxic effects• Discontinuation of drugs due to toxic effects – Erlotinib:5% – Geftinib:2%• Erlotinib – Diarrhea : 55% – Severe diarreha: 6%• Gefitinib – Diarrhea: 27 to 35%• Stopped for up to 14 days until the symptoms resolved• Loperamide 41
  42. 42. Rash• 75% of erlotinib• 33% of geftinib• 7-14 days after initiation of therapy• Association with improved OS and PFS – Surrogate indicator of effective EGFR inhibition? – Surrogate indicator of immue based local inflammatory reaction?• Follicular and papulopustular• Face, scalp, chest, and back• Antibiotics, glucocorticoids, and immunomodulators• Moisturizing of the skin• Avoid acne preparations(benzoyl peroxide)• Dose modifications 42
  43. 43. Interstitial lung disease• Less than 1% in white patients• About 5% in Japanese patients• 1st month of therapy• Risk factors – previous chemotherapy – previous radiation to the lungs – preexisting parenchymal lung disease – metastatic lung disease – Concomitant pulmonary infection• TKI permanently discontinued 43
  44. 44. Neutrophilic infiltration of thedermis, involving most prominently theinfundibular portion of the hair follicles 44
  45. 45. Areas of uncertainty: other EGFR mutations? 45 Clin Cancer Res 2006;12:7232-7241
  46. 46. Resistance of TKI• Almost for all• Median time to progression: 12 months• Secondary EGFR mutation – T790M in exon 20 in 50%-70% – amplification of the MET oncogene in 30 to 50%• Second generation TKI? – EKB-569 – HKI-272 – XL647 46 J Thorac Oncol 2008;3:S146-9
  47. 47. TKI T790M resistance(Exon20) 47
  48. 48. Amplification of MET oncogene 48
  49. 49. Circulating tumor cells(CTC) chips 49 Nature 450, 1235-1239 (20 December 2007)
  50. 50. Detection of EGFR mutation in blood Red (CTC) Blue(CXR tumor burden) 50 N Engl J Med 2008;359:366-77.
  51. 51. ATLAS trial• Chemotherapy + avastin-> Avastin + erlotinib vs. Avastin• Avastin + erlotinib vs. Avastin + placebo – PFS: 4.8 vs. 3.7 months – P=0.001 51 J Clin Oncol 2009;27.
  52. 52. BETA Lung Trial• Phase 3• Avastin + erlotinib vs erlotinib• 2nd line for advanced NSCLC• PFS – 3.4 vs. 1.7 months – P<0.001 Multidisciplinary Symposium in Thoracic 52 Oncology, Chicago, November 2008.
  53. 53. Conclusion 53
  54. 54. NCCN guideline(Version 3.2011) The National Comprehensive Cancer Network 54 home page. (http://www.NCCN.org.)
  55. 55. NCCN guideline(Version 3.2011) The National Comprehensive Cancer Network 55 home page. (http://www.NCCN.org.)
  56. 56. NCCN guideline(Version 3.2011)All including SCC The National Comprehensive Cancer Network 56 home page. (http://www.NCCN.org.)
  57. 57. Erlotinib1. (1) 70 97/6/1 (2) platinum docetaxel paclitaxel2. 97/6/1 (1) 70 ( ) X measurable evaluable 97/6/1 (2) platinum cisplatin carboplatin taxanes paclitaxel docetaxel X measurable evaluable 97/6/1 (3) X X 57
  58. 58. Geftinib1. (1) EGFR-TK (100/6/1) (2) 70 (96/11/1 100/6/1)2. (1) EGFR-TK (100/6/1) (2) 70 ( ) X measurable evaluable 58
  59. 59. Thanks for your attention! 59

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