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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. 財團法人台灣癌症臨床研究發展基金會. Outline. Introduction of lung cancer EGFR in NSCLC Important clinical trials of TKI
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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 財團法人台灣癌症臨床研究發展基金會
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
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
Chemotherapy in NSCLC N Engl J Med 2002;346:92-98
General characteristics N Engl J Med 2002;346:92-98
TTP:GC >PC, greater grade 3,4,5 renal toxicity(9% vs. 3%) N Engl J Med 2002;346:92-98
Overall survival 7.8-8.1 months Time to progression 3.1-4.2 months N Engl J Med 2002;346:92-98
Driver mutations in NSCLC Lancet Oncol 2011; 12: 175–80
HER3 had no tyrosine kinase activity EGFR signaling pathways
N Engl J Med 2008; 359:1367-1380 EGFR amplifications 1.Dysplasia (especially of a high grade) 2. Increased lung-cancer risk when detected in the sputum of smoker 3. Poor prognosis 4.Sensitivity to EGFR inhibitors
EGFR mutation Leu Arg Glu Ala (LREA) motif in exon 19 N Engl J Med 2005;353:133-44.
Gefitinib (Iressa) & Erlotinib(Tarceva) • EGFR tyrosine kinase inhibitors • Asian, non-smoker, and female • Gefitinib and erlotinib for EGFR mutation N Engl J Med 2008;359:1367-1380
Tarceva Tarceva Placebo Erlotinib in NSCLC(≧2 lines) N Engl J Med 2005; 353:123-132
Overall survival HR:0.70 6.7 vs. 4.7 months P<0.001 Progression free survival 2.2 vs 1.8 months P<0.001 N Engl J Med 2002;346:92-98
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 N Engl J Med 2008; 359:1367-1380
Iressa Survival Evaluation in Lung Cancer(ISEL) Lancet 2005;366:1527-1537 Iressa Placebo Iressa Placebo
Overall survival in all populations 5.6 vs. 5.1 months HR:0.89,P=0.087 Overall survial in adenocarcinoma 6.3 vs. 5.4 months HR:0.84,P=0.089 Lancet 2005;366:1527-1537
Time to treatment failure in all populations 3.0 vs. 2.6 months HR:0.82,P=0.006 Lancet 2005;366:1527-1537
Subgroupanalysis of Iressa Lancet 2005;366:1527-1537
Iressa Pan-Asia Study(IPASS) 1.Asia 2.Iressa vsCarboplatin+Paclitaxel 3.First line N Engl J Med 2009;361:947-957
Progression free survival in all populations 5.6 vs. 5.1 months HR:0.74,P<0.001 Progression free survival in EGFR mutation 6.3 vs. 5.4 months HR:0.48,P<0.001 N Engl J Med 2009;361:947-957
Progression free survival in EGFR mutation negative 5.6 vs. 5.1 months HR:2.85,P<0.001 Progression free survival in EGFR unknown 6.3 vs. 5.4 months HR:0.68,P<0.001 N Engl J Med 2009;361:947-957
Iressa vs. Paclitaxel+carboplatin (1st line) in EGFR mutation N Engl J Med 2010; 362:2380-2388
Progression free survival 10.8 vs. 5.4 months HR:0.30,P<0.001 Overall survival 30.5 vs. 23.6 months P=0.31 N Engl J Med 2010; 362:2380-2388
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%)
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%
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)
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
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)
Cost • Erlotinib • $4,000/month • NTD 53490/month(1783/#) • Gefitinib • $1,800/month • NTD 41280/month(1376/#)
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
Rash • 75% of erlotinib • 33% of geftinib • 7-14 days after initiationof 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
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
Neutrophilic infiltration of the dermis, involving most prominently the infundibular portion of the hair follicles
Areas of uncertainty: other EGFR mutations? Clin Cancer Res 2006;12:7232-7241
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 J Thorac Oncol 2008;3:S146-9
NCCN guideline(Version 3.2011) The National Comprehensive Cancer Network home page. (http://www.NCCN.org.)
NCCN guideline(Version 3.2011) The National Comprehensive Cancer Network home page. (http://www.NCCN.org.)
NCCN guideline(Version 3.2011) All including SCC The National Comprehensive Cancer Network home page. (http://www.NCCN.org.)
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platinum類及docetaxel或paclitaxel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影像(如胸部電腦斷層)。
Geftinib給付規定 • 限單獨使用於 (1)具有EGFR-TK基因突變之局部侵犯性或轉移性(即第ⅢB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。