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
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Outline
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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
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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
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Chemotherapy in NSCLC
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N Engl J Med 2002;346:92-98
General characteristics
N Engl J Med 2002;346:92-98
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TTP:GC >PC, greater grade 3,4,5 renal toxicity(9% vs. 3%)
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N Engl J Med 2002;346:92-98
Overall survival
7.8-8.1 months
Time to progression
3.1-4.2 months
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N Engl J Med 2002;346:92-98
EGFR in NSCLC
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Driver
mutations in
NSCLC
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Lancet Oncol 2011; 12: 175–80
HER3 had
no
tyrosine
kinase
activity
EGFR signaling pathways
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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
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EGFR mutation
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EGFR mutation
Leu Arg Glu Ala (LREA) motif in exon 19
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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
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Tarceva
Tarcev
a
Placebo
Erlotinib in
NSCLC(≧2 lines)
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N Engl J Med 2005; 353:123-132
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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
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N Engl J Med 2002;346:92-98
Univariate HR
P value
Multivariate HR
P value
0.7
<0.001
0.7
0.002
0.7
0.8
0.008
0.07
0.8
0.004
0.7
0.9
0.8
0.02
0.7
0.03
0.9
0.4
1.1
0.14
<0.001
0.8
Referrence
0.8
1
0.048
0.89
0.6
0.8
0.06
0.01
0.7
0.01
Treatment
Erlotinib
Placebo
Pathologic subtypes
Adenocarcinoma
Others
EGFR
Positive
Negative
Unknown
Smoking
Ever
Never
Unknown
Race
Asian
Others
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N Engl J Med 2002;346:92-98
EGFR mutation
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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
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N Engl J Med 2008; 359:1367-1380
Iressa Survival Evaluation in Lung
Cancer(ISEL) Lancet 2005;366:1527-1537
Iressa
Placebo
Iressa
Placebo
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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
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Lancet 2005;366:1527-1537
Time to treatment
failure in all
populations
3.0 vs. 2.6 months
HR:0.82,P=0.006
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Lancet 2005;366:1527-1537
Subgroup
analysis of
Iressa
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Lancet 2005;366:1527-1537
Iressa PanAsia Study
(IPASS)
1.Asia
2.Iressa vs
Carboplatin+Paclitaxel
3.First line
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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
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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
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N Engl J Med 2009;361:947-957
Iressa vs.
Paclitaxel+carboplatin
(1st line) in
EGFR mutation
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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
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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%)
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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%
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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)
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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
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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)
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Cost
• Erlotinib
– $4,000/month
– NTD 53490/month(1783/#)
• Gefitinib
– $1,800/month
– NTD 41280/month(1376/#)
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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
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Rash
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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?
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Follicular and papulopustular
Face, scalp, chest, and back
Antibiotics, glucocorticoids, and immunomodulators
Moisturizing of the skin
Avoid acne preparations(benzoyl peroxide)
Dose modifications
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Interstitial lung disease
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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
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Neutrophilic infiltration of the
dermis, involving most prominently the
infundibular portion of the hair follicles
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Areas of uncertainty: other EGFR
mutations?
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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
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J Thorac Oncol 2008;3:S146-9
TKI T790M resistance(Exon20)
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Amplification of MET oncogene
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Conclusion
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NCCN guideline(Version 3.2011)
The National Comprehensive Cancer Network
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home page. (http://www.NCCN.org.)
NCCN guideline(Version 3.2011)
The National Comprehensive Cancer Network
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home page. (http://www.NCCN.org.)
NCCN guideline(Version 3.2011)
All including SCC
The National Comprehensive Cancer Network
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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
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（如胸部電腦斷層）。
Geftinib給付規定
1. 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。
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Thanks for your attention!
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