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

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

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

Chemotherapy in NSCLC

N Engl J Med 2002;346:92-984

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

5

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

7

EGFR in NSCLC

8

Driver mutations in

NSCLC

Lancet Oncol 2011; 12: 175–809

EGFR signaling pathwaysHER3 had no tyrosine kinase activity

10

EGFR amplificationsEGFR amplifications1.Dysplasia (especially of a 1.Dysplasia (especially of a high grade)high grade)2. Increased lung-cancer 2. Increased lung-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

11

EGFR mutation

12

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

13

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

15

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

17

Univariate HR P value Multivariate HR P value

TreatmentErlotinib 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

18

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; 359:1367-138019

Iressa Survival Evaluation in Lung Cancer(ISEL)

Iressa Placebo Iressa Placebo

Lancet 2005;366:1527-1537

20

Overall survival in all populations5.6 vs. 5.1 months

Overall survial in adenocarcinoma6.3 vs. 5.4 months

Overall survial in adenocarcinoma6.3 vs. 5.4 months

HR:0.89,P=0.087

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

Lancet 2005;366:1527-153721

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

HR:0.82,P=0.006

Lancet 2005;366:1527-153722

Subgroupanalysis of

Iressa

Subgroupanalysis of

Iressa

Lancet 2005;366:1527-153723

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

24

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;361:947-95725

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;361:947-95726

Iressa vs. Paclitaxel+carboplatin

(1st line) in EGFR mutation

Iressa vs. Paclitaxel+carboplatin

(1st line) in EGFR mutation

N Engl J Med 2010; 362:2380-238827

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; 362:2380-238828

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

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

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

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

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

Cost

• Erlotinib – $4,000/month– NTD 53490/month(1783/#)

• Gefitinib – $1,800/month– NTD 41280/month(1376/#)

34

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

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

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

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

38

Areas of uncertainty: other EGFR mutations?

Clin Cancer Res 2006;12:7232-724139

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:S146-940

TKI T790M resistance(Exon20)

41

Amplification of MET oncogene

42

Conclusion

43

NCCN guideline(Version 3.2011)

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

44

NCCN guideline(Version 3.2011)

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

45

NCCN guideline(Version 3.2011)

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

All including SCC

46

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（如胸部電腦斷層）。 47

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。

48

Thanks for your attention!

49