Treatment Paradigm in NSCLC Treatment

Which factors taken to beaccount in NSCLC treatment ?• 1. Staging• 2. ECOGperformance status• 3. Histology

Early stagePotentially resectablediseaseLocally advanced :unresectable diseaseMetastatic disease

Early stage (resectable disease)Adjuvant Chemotherapy begin at stage IIA(IB +/- ; Category 2B)

Adjuvant Chemo in NSCLC; with what?Patient Regimen 1st Agent 2nd AgentFit,young - bestNPq 3 x 4Vinorelbine25-30 D1,8Cis75-80 D1Fit,young -alternativeEPq 3-4 x 4Etoposide100 D1-3Cis100 D1AcceptableregimenGCq 3 x 4Gem1250 D1,8Cis75 D1Pt withcomorbid, nottolerate cisTCarq 3 x 4Taxol200 D1CarboAUC 6 D1

Stage I,II,III(except IA)

Early stagePotentially resectablediseaseLocally advanced :unresectable diseaseMetastatic disease

Confirm pathologic N2 (if possible)

Early stagePotentially resectablediseaseLocally advanced :unresectable diseaseMetastatic disease

Which factors taken to beaccount in NSCLC treatment ?• 1. Staging• 2. ECOGperformance status• 3. Histology

American Society of ClinicalOncology Clinical PracticeGuideline on CT for stage IV NSCLCAzzoli C, Baker S, Temin S, et al. JCO 2009

First line treatment in NSCLCASCODetailR A1 CT indicate in ECOG 0,1 possibly 2R A2PS 0,1 = 2 drugs Platinum preferredR A3 Single CT in PS 2R A4R A5R A6R A7R A8Not use age alone in decideEither Cis or Carbo are acceptable1 line should be stop at PD, or after 4 in NR1 line Gefitinib may be for pt EGFR mutationBev + tax/carboplatin recommend except SCCR A9 Cet + V/C may consider in EGFR +

V 2012

Which factors taken to beaccount in NSCLC treatment ?• 1. Staging• 2. ECOGperformance status• 3. Histology

Histological type of NSCLC////

Which factors taken to beaccount in NSCLC treatment ?• 1. Staging• 2. ECOGperformance status• 3. Histology• Squamous cell carcinoma• Non-squamous cell carcinoma- Adenocarcinoma- Large cell carcinoma

Squamous histologyClinical Male,smokerClinicalCentral,cavitationSmall cellSquamous cell CAMolecularRas and EGFR mutationrareHigh TS and EGFR overexpression common

Smoker adeno histologyNon smoker - adeno histologyClinicalClinicalMolecularMale,smokerPeripheral,pleural diseaseHigh ras mutation, EGFRover expression,low EGFR mutation, lowTSClinicalClinicalMolecularFemale, non smoker, asianPeripheral, multifocal,groundglass appearanceFrequent EGFR mutation, EGFRover expressionRas mutation rare, low TS

From pathologyto molecularbiology1. EGFR mutation + : EGFR-TKIs2. EGFR over expression : EGFR-Mob(cetuximab)3. EML4-ALK translocation : Crizotinib

Systemic Treatment Options inNSCLC•1. Standard doublet chemotherapy•2. Targeted therapy with EGFR-TKIs- Gefitinib, Erlotinib•3. Targeted therapy plus standard chemotherapy- Bevacizumab plus GC or TCar- Cetuximab plus VC

Limitation of 1 st line doublet CT in NSCLCSurvival: ECOG 15941 st line 3 rd generation chemotherapy in NSCLCRR = 19 %TTP = 3.6 monthsMST = 7.9 months1 yr survival = 33%2 yr survival = 11%Schiller et al. NEJM 2002.

Does histology matter ...For the selection of CT in NSCLC

Squamous histologyClinical Male,smokerClinicalCentral,cavitationSmall cellSquamous cell CAMolecularRas and EGFR mutationrareHigh TS and EGFR overexpression common

Smoker adeno histologyNon smoker - adeno histologyClinicalClinicalMolecularMale,smokerPeripheral,pleural diseaseHigh ras mutation, EGFRover expression,low EGFR mutation, lowTSClinicalClinicalMolecularFemale, non smoker, asianPeripheral, multifocal,groundglass appearanceFrequent EGFR mutation, EGFRover expressionRas mutation rare, low TSPemetrexed

CONSORT: Phase III Gemcitabine orPemetrexed + Cisplatin as First-line TherapyAdvanced-stage,previously untreatedNSCLC patients(N = 1725)Stratified by: ECOG PS (0 vs 1) Disease stage (IIIB vs IV) Brain metastases (yes vs no) Sex (male vs female) Pathologic diagnosis (histologic vs cytologic) Treatment centerCisplatin 75 mg/m 2 on Day 1Gemcitabine 1250 mg/m 2 on Days 1 and 8Six 3-wk cyclesCisplatin 75 mg/m 2 on Day 1Pemetrexed 500 mg/m 2 on Day 1Six 3-wk cyclesScagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

CONSORT: EfficacySurvivalMedian OS, mosPemetrexed+ Cisplatin(n = 862)10.3 10.3Gemcitabine +Cisplatin(n = 863)HR(95% CI)0.94(0.84-1.05)P ValueNoninferiorAdenocarcinoma(N = 847)Large-cellcarcinoma(N = 153)Squamous cellcarcinoma(N = 473)12.6 10.910.4 6.79.4 10.80.84(0.71-0.99) .030.67(0.48-0.96) .031.23(1.00-1.51) .05Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

Targeted Therapy in NSCLC1. Target at tumor cells- over expression of EGFR : cetuximab- EGFR mutation : TKIs2. Target at vascular endothelial cells- Inc VEGF : anti-VEGF (bevacizumab )

EGFR expression in NSCLCxxxx

Proposed MoA of Bevacizumab: A dynamic effect throughout treatmentEARLY EFFECTSCONTINUED EFFECTS1 Regression 2 Normalization3 InhibitionDecreasestumour sizeImprovesdelivery ofCTxSuppresses new vesselgrowthSuppresses regrowthvia vessel ‘scaffolds’

Bevacizumab plus TCarb in non-squamous NSCLCE4599: OS1.00.90.80.70.60.50.40.30.20.10OS estimateOverall populationCP10.3 12.3Bevacizumab 15mg/kg + CP0 6 12 182430 36 42MonthsMedian OS (months)CP: 10.3Bevacizumab 15mg/kg + CP: 12.3HR=0.79; p=0.003OS estimateAdenocarcinoma*1.00.9CP0.8Bevacizumab 15mg/kg + CP0.70.60.50.40.30.20.1 10.3 14.200 6 12 182430 36 42 48MonthsMedian OS (months)CP: 10.3Bevacizumab 15mg/kg + CP: 14.2HR=0.691. Sandler, et al. NEJM 20062. Sandler, et al. JTO 2010 (in press)

Only PFS benefit in AVAiL(Bevacizumab+GC in non-squamous NSCLC)1.00.90.80.70.60.50.40.30.20.10PFS estimateE4599 1Bev 15mg/kg + CPCP0 6 1218 2430Time (months)1.00.90.80.70.60.50.40.30.20.10AVAiL 2Bev 7.5mg/kg + CGBev 15mg/kg + CGPlacebo + CG0 6 12 1824 30Time (months)Bevacizumab 15mg/kgBevacizumab 7.5mg/kgBevacizumab 15mg/kgMedian PFS6.2 vs 4.5 monthsHR=0.66; p

EGFR expression in NSCLCEGFR TKIsxxxx

Role of EGFR-TKIs in NSCLCClinical selection- Female- Non smoker- Asian ethnicity- Adenocarcinoma histo

Role of EGFR-TKIs in NSCLCClinical selectionMolecular selection- Female- Non smoker- EGFR mutation- EGFR amplification- Asian ethnicity- Adenocarcinoma histo

NSCLC patients with somatic mutation of EGFR havebeen shown to be hyperresponsive to the EGFR TKIsThe most common NSCLC-associated EGFR mutationsare– In-frame deletion in exon 19 (E746-A750del)– Point mutation in exon 21 (L858R)46%39%

Mutations in EGFR TK inUnselected Patients With NSCLCSubgroupTumorsScreened, nMutations Mean %(Range)United States 262 25 9 (2-14)Europe 860 39 5 (NR)Australia 83 6 7 (NR)Eastern Asia 1273 413 32 (26-40)Adenocarcinoma 907 245 27 (9-55)Other histology 837 9 1 (0-3)Men 865 108 12 (6-32)Women 369 143 38 (20-59)Smokers 662 66 10 (5-22)Nonsmokers 517 180 35 (12-69)Haber DA, et al. AACR 2005.

IPASS biomarkers study

At least 2 positive clinical factors(1 = Asean ethnicity)

V 2012

Overall survival (ITT population)Gefitinib CBDCA/TXL(n=98) Logrank (n=100) testMedian survival 28.0 23.6 mHR (95%CI) 0.793 (0.485-1.296)p value* 0.354Overall survival (%)*Log-rank test2-year survival rateGefitinib 61%CBDCA/TXL 45%Inoue et al. ECCO-ESMO 2009; Abstract 9LBA

Summary• Overall population• HRQoL endpoints were consistent with efficacy outcomes inIPASS• EGFR M+ population• Improvement rates in HRQoL and symptoms significantlyfavored gefitinib over C/P• Times to worsening of HRQoL and symptoms were substantiallylonger for gefitinib than C/P• Median time to improvement in HRQoL and symptoms were asrapid as 8 days with gefitinib in patients who improved• EGFR M- population• Improvement rates in HRQoL and symptoms significantlyfavored C/P over gefitinib• Times to worsening for HRQoL and symptoms were longer forC/P than gefitinibThongprasert et al. ELCC 2010; Abstract 205O

EURTAC: First-line Erlotinib vs Chemo in European PatientsWith EGFR Mutations174 patientsTrial run in Europe (lead by Spanish group)Outcome CT Erlotinib HR P ValueResponse rate, % 15 58 - NRMedian PFS,mos5.2 9.7 0.37 < .0001Median OS, mos NR NR 0.80 .42Most commontoxicities, %ALT elevation: 72Anemia: 46Neutropenia: 36ALT elevation:80Rash: 80Diarrhea: 57Rosell R, et al. ASCO 2011. Abstract 7503.

Evidence based management decision for 1st lineNSCLC good ECOGEGFR mutation +EGFR unknownSquamous CANon-squamousEGFR TKIsTraditional 3rd gendoublet CT(non-pemetrexed)Bev + doublet CTOrPem doublet CTOrTraditional CT

ASCO : RecommendationsECOG 0-1 :1 st -line platinum doublet(4–6 cycles)ECOG 2 : single agent CT“Wait andWatch policy”2nd-linetreatmentDiagnosisCR,PR orSDPDPDWhen should 1 st line be stopped1. PD while on treatment2. After 4 cycles in patient whose disease is not responding to Px (SD)3. 2 drug combinations should be administered for no more than 6cyclesAmerican Society of Clinical Oncology CPG update onchemotherapy for stage IV NSCLC. JCO 2009.

Second line treatment in Advanced NSCLCBSC Docetaxel Pemetrexed Erlotinib2000 2004 2005

2004: pemetrexed versus docetaxel –efficacy and tolerability1.00D(n=276)P(n=265)Median OS (mos) 7.9 8.3Variable Pemetrexed Docetaxel p-valueOverall response (%) 9.1 8.8 NSProgression-free survival, median(mos)2.9 2.9 NSTime to progression, median (mos) 3.4 3.5 NS0.751-yr survival (%) 29.7 29.7Duration of response,median (mos)4.6 5.3 NSOS probability0.500.250PemetrexedDocetaxelHR=0.99 (0.8–1.2)Survival time, median (mos) 8.3 7.9 NS1-year survival rate (%) 29.7 29.7 NSNeutropenia grade 3–4 (%) 5.3 40.2

2005: erlotinib showed OS advantage in pre-treatedNSCLC (BR.21)1.00Erlotinib(n=488)Placebo(n=243)0.75Median OS (months) 6.7 4.7OS probability0.500.25HR=0.73 (0.60–0.87), p=0.001*00 5 10 1520 2530Time (months)Shepherd, et al. NEJM 2005

Second line treatment in Advanced NSCLCGefitinib ?BSC Docetaxel Pemetrexed Erlotinib2000 2004 2005

Maintenance TherapyEmerging Approach in NSCLCHistoricalapproachFirst-line treatmentPlatinum doubletchemotherapy(4–6 cycles)‘Watch andwait’Second andfurther linesof treatmentDiagnosisCR/PR/SDPDPDIncreasedtime to PDNewapproachMaintenance therapyDiagnosis CR/PR/SD PD PD

Summary of available clinical evidences of“Maintenance therapy”• 1. Maintenance therapy with same drug : Continuation1.1 Gem after GC x 41.2 Gem or Erlotinib after GC x 4• 2. Maintenance therapy with different drug : Switching2.2 Doc after GC x 42.1 Pem after GC x 4 (JMEN)2.2 Erlotinib after GC x 4 (SATURN)• 3. Maintenance therapy with “Both”3.1 Bev + Erlotinib after Bev + CT (ATLAS)

JMEN (maintenance pemetrexed):PFS and OS in ITT populationPatients with stage IIIB/IVNSCLC and PS 0–1 who hadreceived 4 previous cycles ofgemcitabine, docetaxel, orpaclitaxel + platinum with CR, PR,or SD (n=663)RANDOMISE2:1Pemetrexed 500mg/m 2 on d1q21d + BSC(n=441)Placebo on d1 q21d + BSC(n=222)PFS probability1.00.80.60.40.2PemetrexedPlaceboHR=0.60 (95% CI 0.49–0.73);p

Maintenance Pemetrexed : DFSBenefit of non-squamous histologyCiuleanu et al. Lancet 2009.

Evidence base systemic treatmentin NSCLC stage IV

1st Line

1st Line2nd Line Doublet ChemotherapyTCarbPemCisGC(Adenocarcinoma)3rd LinePemetrexedDocetaxel4th LineAYCAYC

1st Line2nd Line Docetaxel Docetaxel

1st Line2nd LineDocetaxelDocetaxel3rd LineEGFR-TKIsEGFR-TKIs