The document summarizes a clinical trial comparing the treatments erlotinib and gefitinib for non-small cell lung cancer. It found that erlotinib improved overall survival compared to standard chemotherapy, with a median survival of 6.7 months for erlotinib versus 4.7 months for chemotherapy. Erlotinib also prolonged progression-free survival compared to chemotherapy. The study provides support for using erlotinib or gefitinib as treatments for non-small cell lung cancer.

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. 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. 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. Chemotherapy in NSCLC
4
N Engl J Med 2002;346:92-98

5. General characteristics
N Engl J Med 2002;346:92-98
5

6. TTP:GC >PC, greater grade 3,4,5 renal toxicity(9% vs. 3%)
6
N Engl J Med 2002;346:92-98

7. Overall survival
7.8-8.1 months
Time to progression
3.1-4.2 months
7
N Engl J Med 2002;346:92-98

8. EGFR in NSCLC
8

9. Driver
mutations in
NSCLC
9
Lancet Oncol 2011; 12: 175–80

10. HER3 had
no
tyrosine
EGFR signaling pathways
kinase
activity
10

11. 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
11

12. EGFR mutation
12

13. EGFR mutation
Leu Arg Glu Ala (LREA) motif in exon 19
13
N Engl J Med 2005;353:133-44.

14. Gefitinib (Iressa) & Erlotinib(Tarceva)
• EGFR tyrosine kinase inhibitors
• Asian, non-smoker, and female
• Gefitinib and erlotinib for EGFR mutation
14
N Engl J Med 2008;359:1367-1380

15. Tarceva
Tarcev Placebo
a
Erlotinib in
NSCLC(≧2 lines)
15
N Engl J Med 2005; 353:123-132

16. 16
N Engl J Med 2005; 353:123-132

17. 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
17
N Engl J Med 2002;346:92-98

18. Univariate HR P value Multivariate HR P value
Treatment
Erlotinib 0.7 <0.001 0.7 0.002
Placebo
Pathologic subtypes
Adenocarcinoma 0.7 0.008 0.8 0.004
Others 0.8 0.07
EGFR
Positive 0.7 0.02
Negative 0.9 0.7
Unknown 0.8 0.03
Smoking
Ever 0.9 0.14 Referrence
Never 0.4 <0.001 0.8 0.048
Unknown 1.1 0.8 1 0.89
Race
Asian 0.6 0.06 0.7 0.01
Others 0.8 0.01 18
N Engl J Med 2002;346:92-98

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. Iressa Survival Evaluation in Lung
Iressa
Cancer(ISEL) Lancet 2005;366:1527-1537
Placebo Iressa Placebo
20

21. 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
21
Lancet 2005;366:1527-1537

22. Time to treatment
failure in all
populations
3.0 vs. 2.6 months
HR:0.82,P=0.006
22
Lancet 2005;366:1527-1537

23. Subgroup
analysis of
Iressa
23
Lancet 2005;366:1527-1537

24. Iressa Pan-
Asia Study
(IPASS)
1.Asia
2.Iressa vs
Carboplatin+Paclitaxel
3.First line
24
N Engl J Med 2009;361:947-957

25. 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
25
N Engl J Med 2009;361:947-957

26. 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
26
N Engl J Med 2009;361:947-957

27. Iressa vs.
Paclitaxel+carboplatin
(1st line) in
EGFR mutation
27
N Engl J Med 2010; 362:2380-2388

28. 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
28
N Engl J Med 2010; 362:2380-2388

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. 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. 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. 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. 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. Cost
• Erlotinib
– $4,000/month
– NTD 53490/month(1783/#)
• Gefitinib
– $1,800/month
– NTD 41280/month(1376/#)
34

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. 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. 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. Neutrophilic infiltration of the
dermis, involving most prominently the
infundibular portion of the hair follicles
38

39. Areas of uncertainty: other EGFR
mutations?
39
Clin Cancer Res 2006;12:7232-7241

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. TKI T790M resistance(Exon20)
41

42. Amplification of MET oncogene
42

43. Conclusion
43

44. NCCN guideline(Version 3.2011)
The National Comprehensive Cancer Network
44
home page. (http://www.NCCN.org.)

45. NCCN guideline(Version 3.2011)
The National Comprehensive Cancer Network
45
home page. (http://www.NCCN.org.)

46. NCCN guideline(Version 3.2011)
All including SCC
The National Comprehensive Cancer Network
46
home page. (http://www.NCCN.org.)

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
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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. 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。
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49. Thanks for your attention!
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