treatment of non–small-cell lung cancer with erlotinib or gefitinib

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

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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

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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

N Engl J Med 2002;346:92-984

General characteristicsN Engl J Med 2002;346:92-98

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N Engl J Med 2002;346:92-98

TTP:GC >PC, greater grade 3,4,5 renal toxicity(9% vs. 3%) 6

N Engl J Med 2002;346:92-98

Overall survival7.8-8.1 months

Time to progression3.1-4.2 months

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EGFR in NSCLC

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Driver mutations in

NSCLC

Lancet Oncol 2011; 12: 175–809

EGFR signaling pathwaysHER3 had no tyrosinekinaseactivity

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EGFR amplificationsEGFR amplifications11.Dysplasia.Dysplasia (especially of a (especially of a high grade)high grade)2. Increased lung2. Increased lung--cancer cancer risk when detected in the risk when detected in the sputum of smokersputum of smoker3. Poor prognosis 3. Poor prognosis 4.Sensitivity to EGFR 4.Sensitivity to EGFR inhibitorsinhibitors

N Engl J Med 2008; 359:1367-1380

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EGFR mutation

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EGFR mutation

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

Leu Arg Glu Ala (LREA) motif in exon 19Leu Arg Glu Ala (LREA) motif in exon 19

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Gefitinib (Iressa) & Erlotinib(Tarceva)

• EGFR tyrosine kinase inhibitors• Asian, non-smoker, and female• Gefitinib and erlotinib for EGFR mutation

N Engl J Med 2008;359:1367-138014

Erlotinib in NSCLC( 2 lines)

N Engl J Med 2005; 353:123-132

Tarceva

Tarceva Placebo

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N Engl J Med 2005; 353:123-13216

N Engl J Med 2002;346:92-98

Overall survivalHR:0.706.7 vs. 4.7 monthsP<0.001

Progression free survival2.2 vs 1.8 monthsP<0.001

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Univariate HR P value Multivariate HR P valueTreatment

Erlotinib 0.7 <0.001 0.7 0.002Placebo

Pathologic subtypesAdenocarcinoma 0.7 0.008 0.8 0.004

Others 0.8 0.07EGFR

Positive 0.7 0.02Negative 0.9 0.7Unknown 0.8 0.03

SmokingEver 0.9 0.14 Referrence

Never 0.4 <0.001 0.8 0.048Unknown 1.1 0.8 1 0.89

RaceAsian 0.6 0.06 0.7 0.01

Others 0.8 0.01N Engl J Med 2002;346:92-98

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

Red (EGFR) Green (CEP7)

High polysomy ( 4 gene copies in 40% of cells)Amplification (gene:chromosome 2 or 15 gene copies per cell in 10% of cells)

High polysomy ( 4 gene copies in 40% of cells)Amplification (gene:chromosome 2 or 15 gene copies per cell in 10% of cells)

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N Engl J Med 2005;353:133-44.20

N Engl J Med 2005;353:133-44.21

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; 359:1367-138022

Copy number alternations

(CNA) in Chromosome 7p

J Clin Oncol 2011 Sep 1;29(25):3435-42. 23

High-density comparative genomic hybridization (CGH) array

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

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

Iressa Survival Evaluation in Lung Cancer(ISEL)

Iressa Placebo Iressa Placebo

Lancet 2005;366:1527-1537

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Overall survival in all populations5.6 vs. 5.1 months

Overall survial inadenocarcinoma6.3 vs. 5.4 months

Overall survial inadenocarcinoma6.3 vs. 5.4 months

HR:0.89,P=0.087

HR:0.84,P=0.089HR:0.84,P=0.089

Lancet 2005;366:1527-153727

Time to treatment failure in all populations3.0 vs. 2.6 months

HR:0.82,P=0.006

Lancet 2005;366:1527-153728

Subgroupanalysis of

Iressa

Subgroupanalysis of

Iressa

Lancet 2005;366:1527-153729

Iressa Pan-Asia Study

(IPASS)

Iressa Pan-Asia Study

(IPASS)

N Engl J Med 2009;361:947-957

1.Asia2.Iressa vs Carboplatin+Paclitaxel3.First line

1.Asia2.Iressa vs Carboplatin+Paclitaxel3.First line

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Progression free survival in all populations5.6 vs. 5.1 months

Progression free survival in EGFR mutation6.3 vs. 5.4 months

Progression free survival in EGFR mutation6.3 vs. 5.4 months

HR:0.74,P<0.001

HR:0.48,P<0.001HR:0.48,P<0.001

N Engl J Med 2009;361:947-95731

Progression free survival in EGFR mutation negative5.6 vs. 5.1 months

Progression free survival in EGFR unknown6.3 vs. 5.4 months

Progression free survival in EGFR unknown6.3 vs. 5.4 months

HR:2.85,P<0.001

HR:0.68,P<0.001HR:0.68,P<0.001

N Engl J Med 2009;361:947-95732

Iressa vs.Paclitaxel+carboplatin

(1st line) in EGFR mutation

Iressa vs.Paclitaxel+carboplatin

(1st line) in EGFR mutation

N Engl J Med 2010; 362:2380-238833

Progression free survival10.8 vs. 5.4 months

Overall survival30.5 vs. 23.6 monthsOverall survival30.5 vs. 23.6 months

HR:0.30,P<0.001

P=0.31P=0.31

N Engl J Med 2010; 362:2380-238834

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

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)37

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• 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

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 discontinued43

Neutrophilic infiltration of the dermis, involving most prominently theinfundibular portion of the hair follicles

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Areas of uncertainty: other EGFR mutations?

Clin Cancer Res 2006;12:7232-724145

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:S146-946

TKI T790M resistance(Exon20)

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Amplification of MET oncogene

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Circulating tumor cells(CTC) chips

Nature 450, 1235-1239 (20 December 2007)49

Detection of EGFR mutation in blood

N Engl J Med 2008;359:366-77.

Red (CTC) Blue(CXR tumor burden)

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ATLAS trial

• Chemotherapy + avastin-> Avastin + erlotinibvs. Avastin

• Avastin + erlotinib vs. Avastin + placebo– PFS: 4.8 vs. 3.7 months– P=0.001

J Clin Oncol 2009;27.51

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 Oncology, Chicago, November 2008.

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Conclusion

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NCCN guideline(Version 3.2011)

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

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NCCN guideline(Version 3.2011)

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

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NCCN guideline(Version 3.2011)

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

All including SCC

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Erlotinib1.

(1) 7097/6/1

(2) platinum docetaxel paclitaxel

2.

97/6/1(1)

70 ( )X

measurableevaluable 97/6/1

(2)platinum cisplatin carboplatin taxanes

paclitaxel docetaxelX measurable

evaluable97/6/1

(3)X

X57

Geftinib1.

(1) EGFR-TK(100/6/1)

(2) 70(96/11/1

100/6/1)2.

(1)EGFR-TK (100/6/1)

(2)70 ( )

Xmeasurable

evaluable

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Thanks for your attention!

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