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Treatment of non–small cell lung cancer

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Treatment of non–small cell lung cancer

  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 周益聖 Supervisor: Vs 顏厥全 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. 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 19 N Engl J Med 2008; 359:1367-1380
  20. 20. Iressa Survival Evaluation in Lung Iressa Cancer(ISEL) Lancet 2005;366:1527-1537 Placebo Iressa Placebo 20
  21. 21. 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 21 Lancet 2005;366:1527-1537
  22. 22. Time to treatmentfailure in allpopulations3.0 vs. 2.6 monthsHR:0.82,P=0.006 22 Lancet 2005;366:1527-1537
  23. 23. Subgroupanalysis of Iressa 23 Lancet 2005;366:1527-1537
  24. 24. Iressa Pan-Asia Study (IPASS)1.Asia2.Iressa vsCarboplatin+Paclitaxel3.First line 24N Engl J Med 2009;361:947-957
  25. 25. 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 25 N Engl J Med 2009;361:947-957
  26. 26. 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 26 N Engl J Med 2009;361:947-957
  27. 27. Iressa vs.Paclitaxel+carboplatin (1st line) in EGFR mutation 27 N Engl J Med 2010; 362:2380-2388
  28. 28. Progression freesurvival10.8 vs. 5.4 monthsHR:0.30,P<0.001Overall survival30.5 vs. 23.6 monthsP=0.31 28N Engl J Med 2010; 362:2380-2388
  29. 29. 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%) 29
  30. 30. 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% 30
  31. 31. 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) 31
  32. 32. 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 32
  33. 33. 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) 33
  34. 34. Cost• Erlotinib – $4,000/month – NTD 53490/month(1783/#)• Gefitinib – $1,800/month – NTD 41280/month(1376/#) 34
  35. 35. 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 35
  36. 36. 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 36
  37. 37. 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 37
  38. 38. Neutrophilic infiltration of thedermis, involving most prominently theinfundibular portion of the hair follicles 38
  39. 39. Areas of uncertainty: other EGFR mutations? 39 Clin Cancer Res 2006;12:7232-7241
  40. 40. 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 40 J Thorac Oncol 2008;3:S146-9
  41. 41. TKI T790M resistance(Exon20) 41
  42. 42. Amplification of MET oncogene 42
  43. 43. Conclusion 43
  44. 44. NCCN guideline(Version 3.2011) The National Comprehensive Cancer Network 44 home page. (http://www.NCCN.org.)
  45. 45. NCCN guideline(Version 3.2011) The National Comprehensive Cancer Network 45 home page. (http://www.NCCN.org.)
  46. 46. NCCN guideline(Version 3.2011)All including SCC The National Comprehensive Cancer Network 46 home page. (http://www.NCCN.org.)
  47. 47. Erlotinib 給付規定1. 限單獨使用於 (1) 先前已使用過第一線含鉑化學治療,或 70 歲 ( 含 ) 以上接受過第一線化 學治療,但仍局部惡化或轉移之腺性非小細胞肺癌之第二線用藥。 ( 97/6/1 ) ( 2) 先前已使用過 p la tinum 類及 d o c e ta xe l 或 p a c lita xe l 化學治療後,但 仍局部惡化或轉移之非小細胞肺癌之第三線用藥。2. 需經事前審查核准後使用,若經事前審查核准,因臨床治療需轉換同成份不同含量 品項,得經報備後依臨床狀況轉換使用,惟總使用期限不得超過該次申請事前審查 之療程期限。( 97/6/1 ) (1) 用於第二線用藥:檢具確實患有非小細胞肺癌之病理或細胞檢查報告,並附曾經 接受第一線含鉑化學治療,或 70 歲 ( 含 ) 以上接受過第一線化學治療之證明,及目 前又有疾病惡化之影像診斷證明(如胸部 X 光、電腦斷層或其他可作為評估的影 像),此影像證明以可測量( measurable )的病灶為優先,如沒有可以測量的病灶 ,則可評估( evaluable )的病灶亦可採用。( 97/6/1 ) (2) 用於第三線用藥:檢具確實患有非小細胞肺癌之病理或細胞檢查報告,並附曾經 接受第一線及第二線化學藥物如 platinum ( cisplatin 或 carboplatin )與 taxanes ( paclitaxel 或 docetaxel )治療之證明,及目前又有疾病惡化之影像診斷證 明(如胸部 X 光、電腦斷層或其他可作為評估的影像), 此影像證明以可測量 ( measurable )的病灶為優先,如沒有可以測量的病灶,則可評估( evaluable )的 病灶亦可採用。( 97/6/1 ) (3) 每次申請事前審查之療程以三個月為限,每三個月需再次申請,再次申請時並需 附上治療後相關臨床資料,如給藥四週後,需追蹤胸部 X 光、電腦斷層等影像檢查 47 一遍,評估療效,往後每四週做胸部 X 光檢查,每隔八週需追蹤其作為評估藥效的
  48. 48. Geftinib 給付規定1. 限單獨使用於 (1) 具有 E G F R- TK 基因突變之局部侵犯性或轉移性 ( 即第Ⅲ B 期或第Ⅳ 期 ) 之肺腺癌病患之第一線治療。 (100/6/1) (2) 先前已使用過第一線含鉑化學治療,或 70 歲 ( 含 ) 以上 接受過第一線化學治療,但仍局部惡化或轉移之肺腺癌。 (96/11/1 、 100/6/1)2. 需經事前審查核准後使用: (1) 用於第一線用藥:檢具確實患有肺腺癌之病理或細胞檢查報 告,及 EGFR-TK 基因突變檢測報告。 (100/6/1) (2) 用於第二線用藥:檢具確實患有肺腺癌之病理或細胞檢查報 告,並附曾經接受第一線含鉑化學治療,或 70 歲 ( 含 ) 以上 接受過第一線化學治療之證明,及目前又有疾病惡化之影像診 斷證明(如胸部 X 光、電腦斷層或其他可作為評估的影像), 此影像證明以可測量( measurable )的病灶為優先,如沒有 可以測量的病灶,則可評估( evaluable )的病灶亦可採用。 48
  49. 49. Thanks for your attention! 49

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