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. 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. 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
N Engl J Med 2005;353:133-44.

21. 21
N Engl J Med 2005;353:133-44.

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. Copy number
alternations
(CNA) in
Chromosome 7p
High-density comparative
genomic hybridization
(CGH) array
23
J Clin Oncol 2011 Sep 1;29(25):3435-42.

24. 24
J Clin Oncol 2011 Sep 1;29(25):3435-42.

25. 25
J Clin Oncol 2011 Sep 1;29(25):3435-42.

26. Iressa Survival Evaluation in Lung
Iressa
Cancer(ISEL) Lancet 2005;366:1527-1537
Placebo Iressa Placebo
26

27. 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
27
Lancet 2005;366:1527-1537

28. Time to treatment
failure in all
populations
3.0 vs. 2.6 months
HR:0.82,P=0.006
28
Lancet 2005;366:1527-1537

29. Subgroup
analysis of
Iressa
29
Lancet 2005;366:1527-1537

30. Iressa Pan-
Asia Study
(IPASS)
1.Asia
2.Iressa vs
Carboplatin+Paclitaxel
3.First line
30
N Engl J Med 2009;361:947-957

31. 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
31
N Engl J Med 2009;361:947-957

32. 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
32
N Engl J Med 2009;361:947-957

33. Iressa vs.
Paclitaxel+carboplatin
(1st line) in
EGFR mutation
33
N Engl J Med 2010; 362:2380-2388

34. 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
34
N Engl J Med 2010; 362:2380-2388

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. 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. 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. 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. 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. Cost
• Erlotinib
– $4,000/month
– NTD 53490/month(1783/#)
• Gefitinib
– $1,800/month
– NTD 41280/month(1376/#)
40

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. 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. 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. Neutrophilic infiltration of the
dermis, involving most prominently the
infundibular portion of the hair follicles
44

45. Areas of uncertainty: other EGFR
mutations?
45
Clin Cancer Res 2006;12:7232-7241

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. TKI T790M resistance(Exon20)
47

48. Amplification of MET oncogene
48

49. Circulating tumor cells(CTC) chips
49
Nature 450, 1235-1239 (20 December 2007)

50. Detection of EGFR mutation in blood
Red (CTC)
Blue(CXR
tumor burden)
50
N Engl J Med 2008;359:366-77.

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. 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. Conclusion
53

54. NCCN guideline(Version 3.2011)
The National Comprehensive Cancer Network
54
home page. (http://www.NCCN.org.)

55. NCCN guideline(Version 3.2011)
The National Comprehensive Cancer Network
55
home page. (http://www.NCCN.org.)

56. NCCN guideline(Version 3.2011)
All including SCC
The National Comprehensive Cancer Network
56
home page. (http://www.NCCN.org.)

57. Erlotinib
1.
(1) 70
97/6/1
(2) platinum docetaxel paclitaxel
2.
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. Geftinib
1.
(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. Thanks for your attention!
59