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Treatment of Non–Small-Cell Lung Cancer with Erlotinib or Gefitinib
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
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
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.
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
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
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
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
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
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
