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Session Outline• Background on NSCLC• Chemotherapy paradigms in first-line NSCLC• Role of histology in NSCLC• Role of molecular targeted agents in NSCLC• New concept of maintenance therapy (beforeprogression)


Lung Cancer in the United States2009• Estimated 219,440 new cases• Approximately 159,390 deaths• Approximately 28% of all cancer deaths• Leading cause of cancer mortality in menand women• Cigarette smoking responsible for 87%of all lung cancer deaths• 5-year relative survival 15%American Cancer Society. Cancer Facts & Figures 2009. Atlanta; 2009.


Lung Cancer FactsLung cancer will kill:• More people thanbreast, prostate,colon, liver, kidneyand melanomacancers…combined• Over three times asmany men as prostatecancer• Nearly twice as manywomen as breastcancer• An average of 437people a dayEstimated Cancer Deaths 2009*Estimate of never-smoker cancer deaths (15%).


Percent of New Lung Cancer Cases• Over 60% of new cases are never smokers or formersmokers, many of whom quit decades ago• One in five women and one in twelve men diagnosedwith lung cancer have never smokedCurrent Smokers35% 50% 15%Former SmokersNever Smoked0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%


Stage of DiagnosisOnly 16% of lung cancer is being diagnosed at its earliestand most curable stage100%80%60%40%20%061.2%80.4%39.6%16.2%31.5%11.4%36.0%22.0%4.8%4.2%18.5%52.8%2.6%BreastProstateColonLung4.0%5.9%9.0%Localized Regional Distant UnstagedLocalized: confined to primary siteRegional: spread beyond primary site to lymph nodesDistant: cancer has metastasized


Individualized Therapy• Prognostic marker: a parameter that impacts onoutcome independent of the treatment– Good prognostic markers• Lower stage• Female gender• Good performance status• Never smoker• Predictive marker: a parameter that isassociated with efficacy of a specific therapy– Currently no molecular markers in routine use forselection of chemotherapy for advanced NSCLC


METASTATIC NON-SMALLCELL LUNG CANCER


NSCLC SurvivalState-of-the-Art 2003Survival BSC Old NewMST (mo) 4 6 81-year (%) 10 20 302-year (%) 0 < 5 10


Chemotherapy Issues in NSCLC• Two agents versus one• Three agents versus two• Duration of therapy• Cisplatin versus carboplatin• Role of histology• Role for maintenance therapy• Role of molecularly targeted therapy


Platinum-Based Doublet vs Single AgentSurvival• N = 2374 (8 trials)• RR favors doublets(OR = 2.32, P not stated)• Survival favoredplatinum doublets(HR = 0.87, P < 0.001)• No significantdifference intreatment-relatedmortalityHotta K, et al. Ann Oncol. 2004;15:1782-1789.


Chemotherapy Issues in NSCLC• Two agents versus one• Three agents versus two• Duration of therapy• Cisplatin versus carboplatin• Role of histology• Role for maintenance therapy• Role of molecularly targeted therapy


Three vs Two Drugs: Meta-Analysis• N ~ 2200 forresponse• N = 4550 forsurvival• Three-drug regimenfavored for– RR(OR = 0.66, P = 0.001)• No difference for– 1-year survival(OR = 1.01, P = 0.88 )– Median survival(OR = 1.00, P = 0.97)Delbaldo C, et al. JAMA. 2004;292:470-484.


Chemotherapy Issues in NSCLC• Two agents versus one• Three agents versus two• Duration of therapy• Cisplatin versus carboplatin• Role of histology• Role for maintenance therapy• Role of molecularly targeted therapy


Duration of Therapy in Advanced NSCLCAuthor N Regimen Design SurvivalSmith 280 MitomycinVinblastineCisplatin3 cyclesvs6 cyclesNodifferenceWesteel,179 MitomycinAfter 4 cycles,NoDePierreIfosfamideCisplatinVinorelbinevsObservationdifferenceSocinski 230 CarboplatinPaclitaxel4 cyclesvsContinuousNodifferenceSmith IE, et al. J Clin Oncol. 2001;19:1336-1343.Westeel V, et al. J Natl Cancer Inst. 2005;97:499-506.Socinski MA, et al. J Clin Oncol. 2002;20:1335-1343.


Chemotherapy Issues in NSCLC• Two agents versus one• Three agents versus two• Duration of therapy• Cisplatin versus carboplatin• Role of histology• Role for maintenance therapy• Role of molecularly targeted therapy


Cisplatin vs Carboplatin• Cisplatin plus a newer agent yields an 11% longersurvival than carboplatin plus the same neweragent– HR = 1.106; 95% CI 1.005-1.218; P = 0.039• Cisplatin: more frequent grade 3 or higher nauseaand vomiting• Carboplatin: more frequent grade 3 or higherthrombocytopenia• No significant difference in treatment-related deaths– 3.9% with cisplatin vs 2.9% with carboplatinHotta K, et al. J Clin Oncol. 2004;22:3852-3859.


Role of Histology


Cisplatin + Pemetrexed vs Cisplatin+ Gemcitabine in First-Line NSCLCBackground• Pemetrexed inhibits thymidylate synthase (TS) and otherfolate-dependent enzymes• Baseline expression of the TS gene and protein aresignificantly higher in squamous cell carcinoma whencompared with adenocarcinoma 1• Preclinical data indicated that high expression of TScorrelates with reduced sensitivity to pemetrexed 2-3• Cells with MTAP deletions may be particularly sensitive toagents that reduce de-novo purine synthesis 41. Ceppi P, et al. Cancer. 2006;107:1589-1596; 2. Sigmond J, et al. Biochem Pharmacol. 2003;66:431-438;3. Giovannetti E, et al. Mol Pharmacol. 2005;68:110-118; 4. Schmid S, et al. Oncogene. 1998;17:2669-2675.


TS Expression According toHistologic SubtypeP = 0.001• FFPE tissueTS Relative mRNA Levels(Unit-Less Ratio)P = 0.001P = 0.001P = 0.001 P = 0.33P = 0.002– Adeno (n = 41)– Squamous (n = 30)– Non-NE LCC (n = 34)– LCNEC (n = 8)– Small Cell LC (n = 33)• Other pre-clinicaldata correlates highTS expression withreduced pemetrexedsensitivityScagliotti G, et al. J Clin Oncol. 2009;27(15S). Abstract 7521.


First-Line Pemetrexed + Cisplatin vsGemcitabine + Cisplatin in Stage IIIB or IVJMDB TrialNSCLC (no centralized pathology review)> 1 Measurable lesion per RECISTPrior radiation allowed to < 25% marrowNo symptomatic brain metastasesNo peripheral neuropathy ≥ grade 1ECOG PS 0-1Pemetrexed 500 mg/m 2 day 1RACisplatin 75 mg/m 2 day 1Nn = 862DOEvery 3 weeks up to 6 cyclesMIZZEGemcitabine 1250 mg/m 2 day 1 & 8Cisplatin 75 mg/m 2 day 1n = 863Non-inferiority designPrimary endpoint: overall survival (OS)Secondary endpoints: response rate, duration of response (DOR),progression-free survival (PFS), time to progression, time to treatmentfailure, toxicityScagliotti GV, et al. J Clin Oncol. 2008;26:5343-5351.


First-Line Pemetrexed + Cisplatin vsGemcitabine + Cisplatin in Stage IIIB or IVOverall SurvivalScagliotti GV, et al. J Clin Oncol. 2008;26:5343-5351.


First-Line Pemetrexed + Cisplatin vsGemcitabine + Cisplatin in Stage IIIB or IVPre-Planned Histology AnalysisAdenocarcinoma(n = 847)Squamous(n = 473)Large cell(n = 153)Indeterminate(n = 252)Non-squamous(n = 1000)Pem+CisMedian OS(mos)>Gem+CisMedian OS(mos)HR (CI)12.6 10.9 0.84 (0.71-0.99)P = 0.0310.4 6.7 0.67 (0.48-0.96)P = 0.038.6 9.2 1.08 (0.8-1.45)P = 0.586>11.8 10.4 0.81 (0.70-0.94)P = 0.005Scagliotti GV, et al. J Clin Oncol. 2008;26:5343-5351.


Randomized Trials With CT+/- TargetedTherapies in Treatment-Naïve NSCLCTrial Target CT Group CommentZD1839 EGFR GC AstraZeneca Closed, no benefitZD1839 EGFR PC AstraZeneca Closed, no benefitOSI774 EGFR PC Genentech/OSI Closed, no benefitOSI774 EGFR GC Genentech/OSI Closed, no benefitABXEGFR EGFR PC Amgen Closed, no benefitAG3340 MMP PC Agouron Closed, no benefitAG3340 MMP GC Agouron Closed, no benefitBMS275291 MMP PC BMS Closed, no benefitLonafarnib FT (ras) PC Schering Closed, no benefitISIS 3521 PKCα PC ISIS Closed, no benefitTargretin RXR PC Ligand Closed, no benefitEGFR = epidermal growth factor receptor; MMP = matrix metallo-protease;FT = farnesyl transferase; PKC = protein kinase C; RXR = retinoic acid receptor;GC = gemcitabine + platinum analog; PC = paclitaxel + platinum analog


Targeted Therapy in First-LineNSCLCInhibition of Angiogenesis


Agents Targeting the Vascular EndothelialGrowth Factor (VEGF) PathwayAnti-VEGFantibodies(bevacizumab)VEGFSolubleVEGFRs(VEGF-Trap)Small-molecule VEGFR inhibitors– Vatalanib (PTK 787)– Sunitinib (SU11248)– Sorafenib (Bay 43-9006)– ZD6474PPPPVEGFR-1PPPPVEGFR-2Endothelial cellAnti-VEGFRantibodies(IMC-1121b)Podar K, et al. Blood. 2005;105:1383-1395.


Randomized Trial of Paclitaxel / CarboplatinWith or Without Bevacizumab in NSCLCPaclitaxel 200 mg/m 2Stage IIIb/IV*Carboplatin AUC = 6patients(N = 99) + Bevacizumab (7.5 mg/kg)+ Bevacizumab (15 mg/kg)*Control patients permitted to cross-over to bevacizumab15 mg/kg at progression.Johnson DH, et al. J Clin Onc. 2004;22:2184-2191.


Randomized Trial of Paclitaxel / CarboplatinWith or Without Bevacizumab in NSCLCPaclitaxel/Carboplatin(PC)PC + Low-DoseBevacizumabPC + High-DoseBevacizumabRR-investigator 18.8% 28.1% 31.4% NSRR-independent 25% 21.9% 34.3% NSTTP-investigator 18.4 wk 18.7 wk 32.1 wk < 0.044TTP-investigator 25.8 wk 17.7 wk 29.6 wk NSMST 56.8 wk 49.9 wk 61.5 wk NSPRR = response rate, TTP = time to progression, MST = median survival timeJohnson DH, et al. J Clin Onc. 2004;22:2184-2191.


Phase II Trial of Bevacizumab inNSCLC: Adverse Events• 6 life-threatening pulmonary hemorrhages (4 of themfatal) in 66 bevacizumab-treated patients (9%)• Analysis of risk factors supports a possible associationwith squamous cell histology– 4 of 6 (67%) of pulmonary hemorrhages had squamous cellhistology, although this histology comprised only 19% ofenrolled patients• Similar bleeds not seen in all trialsNovotny WF, et al. Proc Am Soc Clin Oncol. 2001;20. Abstract 1318.


Phase III Trial of Bevacizumabin Non-Squamous NSCLC: ECOG 4599N = 855 (Eligible)Eligibility:• Non-squamous NSCLC• No Hx of hemoptysis• No CNS metastasesStratification Variables:• RT vs no RT• Stage IIIB or IV vs recurrent• Wt loss < 5% vs > 5%• Measurable vs non-measurable(PC)Paclitaxel 200 mg/m 2Carboplatin AUC = 6(q 3 weeks) x 6 cycles(PCB)PC x 6 cycles+Bevacizumab(15 mg/kg q 3 wks) to PDNo crossover tobevacizumabpermittedSandler A, et al. N Engl J Med. 2006;355:2542-2550.


E4599 Patient Characteristics(Eligible Patients)PC(n = 431)Stage IIIB 14% 13%PCB(n = 424)Measurable disease 91% 91%Prior weight loss > 5% 28% 28%Age > 65 years 44% 43%ECOG performance status = 0 38% 40%Male 58% 50%Caucasian 91% 90%Sandler A, et al. N Engl J Med. 2006;355:2542-2550.


E4599 Patient Characteristics(Continued)PC(n = 444)Adenocarcinoma (%) 68 69Bronchoalveolar carcinoma (%) 3 3Large cell carcinoma (%) 7 18NSCLC not otherwise specified (%) 20 18Other 3 5PCB(n = 434)Sandler A, et al. N Engl J Med. 2006;355:2542-2550.


E4599: Key Clinical OutcomesResponse rate: 15% for PC vs 35% for chemo + bevacizumabPatients Progression- -Free (%)100806040200Progression-Free SurvivalCarboplatin/paclitaxelCarboplatin/paclitaxel +bevacizumabP < 0.001; HR = 0.66Median PFS: 6.2 months vs4.5 months6-Month PFS: 55% vs 33%1-Year PFS: 15% vs 6%0 6 12 18 24 30 36MonthsPatients Surviving (%)100806040200Overall SurvivalCarboplatin/paclitaxelCarboplatin/paclitaxel +bevacizumabP = 0.003; HR = 0.79Median OS: 12.3 months vs10.3 months1-Year OS: 51% vs 44%2-Year OS: 23% vs 15%0 6 12 18 24 30 36MonthsHR = hazard ratio; OS = overall survival; PFS = progression-free survivalSandler A, et al. N Engl J Med. 2006;355:2542-2550.


E4599: Grade 3-5Non-Hematologic ToxicityPC(n = 441)PCB(n = 427)Hemorrhage 1.1% 4.7% 0.001Hemoptysis 0.5% 2.1%CNS 0.2% 0.7%GI 0.5% 1.2%Other 0.2% 1.2%Hypertension 0.7% 7.7% < 0.001Proteinuria --- 3.1% < 0.001Venous thrombosis 3.2% 5.6%Arterial thrombosis 1.6% 2.8%PSandler A, et al. N Engl J Med. 2006;355:2542-2550.


Targeted Therapy in First-LineNSCLCEGFR Pathway


EGFR-Related Signaling Impacts aWide Variety of Intracellular Processes


Cisplatin / Vinorelbine (CV) + CetuximabStage IIIB / IVFLEX StudyAll histologic typesNo prior chemotherapy orEGFR therapyEGFR IHC positive in >1% tumor cellsPS 0-2RANDOMIZZECisplatin 80 mg/m 2 day 1Vinorelbine 25 mg/m 2 day 1, 8q 3 wks x 6 cyclesCetuximab 400 mg/m 2 day 1 then250 mg/m 2 day 1 weeklyCisplatin 80 mg/m 2 day 1Vinorelbine 25 mg/m 2 day 1, 8q 3 wks x 6 cyclesIf no PD,cetuximabmaintenancePrimary endpoint: OSSecondary endpoints: response rate, PFS, DCR, quality of life, safetyTotal randomized = 1125Pirker R, et al. Lancet. 2009;373:1525-1531.


Cisplatin / Vinorelbine (CV) + CetuximabStage IIIB / IVOverall Survival (%)100908070CT + Cetuximab (n = 557)CT (n = 568)Median OS11.3 months10.1 months1-yearsurvival47%42%60HR = 0.871 (95% CI 0.762-0.996) P = 0.04450403020100Patients at riskCT + CetuximabCT0 6 12 18 24 30557 383 251 155 53 3568 383 225 134 48 0MonthsP value = stratified log-rank test (2-sided)Pirker R, et al. Lancet. 2009;373:1525-1531.


Two Studies of Cetuximab (CET) WithChemotherapy in First-LineBMS 099• Carboplatin / taxane (CT)• With or without CETFLEX• Cisplatin / vinorelbine (CV)• With or without CETCT CT + CET CV CV + CETn 338 338 568 557RR (%) 17 26 29 ‡ 36 ‡PFS (mo) 4.2* 4.4* 4.8 † 4.8 †OS (mo) 8.4 † 9.7 † 10.1 § 11.3 §*Primary endpoint (by independent review), P = NS.†P = NS.‡P = 0.012.§Primary endpoint, P = 0.044.Lynch T, et al. J Thorac Oncol. 2007;2(8 suppl):S340-S341.Lynch TJ, et al. J Thorac Oncol. 2008;3(4 suppl):S305.Pirker R, et al. Lancet. 2009;373:1525-1531.


KRAS Mutation Analysis: Overall SurvivalOverall Survival (%)10090807060504030201000FLEX StudyKRAS wild typeCT + cetuximab (n = 161)CT (n = 159)KRAS mutantCT + cetuximab (n = 38)CT (n = 37)Months6 12 18 24 30O’Byrne KJ, et al. J Clin Oncol. 2009;27(18S). Abstract 8007.


Targeted Therapy in First-LineNSCLCEGFR Pathway – EGFR Mutation Positive


Gefitinib vs Carboplatin / Paclitaxel(CP) in Never- or Light Ex-SmokersIPASS (Iressa Pan-Asia Study)Measurable stage IIIB or IVAdenocarcinoma histologyNo prior chemotherapyPS 0-2< 100 cigarettes / lifetime or < 10 pack /years and stopped > 15 years priorRANDOMIZZEGefitinib 250 mg dailyCarboplatin AUC 5 or 6Paclitaxel 200 mg/m 2q 3 wks (max 6 cycles)CP offeredfor PDPrimary endpoint: PFS (non-inferiority)Secondary endpoints: response rate, OS, quality of lifeTotal randomized = 1217Mok T, et al. N Engl J Med. 2009;361:947-957.


Gefitinib vs Carboplatin / Paclitaxel(CP) in Never- or Light Ex-SmokersProbability of Progression-Free SurvivalAt risk:GefitinibCP1.00.80.60.40.20.0nMedian PFS (months)4 months progression-free6 months progression-free12 months progression-freeHR = 0.741 (0.651-0.845)Gef6095.761%48%25%609 363 212 76 24 5 0608 412 118 22 3 1 0CP6085.874%48%7%0 4 8 12 16 20 24 MonthsMok T, et al. N Engl J Med. 2009;361:947-957.


Gefitinib vs Carboplatin / Paclitaxel(CP) in Never- or Light Ex-SmokersProbability of Progression-Free Survival1.00.80.60.40.20.0Gefitinib EGFR M+ (n = 132)Gefitinib EGFR M- (n = 91)Carboplatin / paclitaxel EGFR M+ (n = 129)Carboplatin / paclitaxel EGFR M- (n = 85)Gefitinib HR = 0.19,95% CI 0.13, 0.26, P < 0.0001No. events M+ = 97 (73.5%)No. events M- = 88 (96.7%)Carboplatin / paclitaxel, HR = 0.78,95% CI 0.57, 1.06, P = 0.1103No. events M+ = 111 (86.0%)No. events M- = 70 (82.4%)0 4 8 12 16 20 24Time From Randomization (months)Mok T, et al. N Engl J Med. 2009;361:947-957.


Gefitinib vs Carboplatin / Paclitaxelin NSCLC With EGFR MutationNorth East Japan (NEJ) Gefitinib Study GroupRStage IIIB or IVA GefitinibN (n = 160 planned)Sensitive EGFR mutationDNo prior chemotherapyOMPS 0-1IZCarboplatinAge 20-75 years Z PaclitaxelE(n = 160 planned)EGFR mutation by PNA-LNA PCR clamp methodPrimary endpoint: PFSSecondary endpoints: response rate, OS, quality of life, side effectsKobayashi K, et al. J Clin Oncol. 2009;27(18s). Abstract 8016.


Gefitinib vs Carboplatin / Paclitaxelin NSCLC With EGFR Mutation• Interim analysis• Progression-free survival– Gefitinib (n = 98): median 10.4 months– Chemotherapy (n = 96): median 5.5 months– Log rank P < 0.001, HR 0.357 (95% CI 0.25-0.51)• Adverse events (gefitinib vs chemotherapy)– Grade 4 neutropenia 1% vs 33%– Grade 3-4 liver dysfunction 25% vs 1%– Grade 3 neuropathy 0% vs 5% P < 0.01– One toxic death due to ILD in gefitinib arm• Independent safety committee recommended nofurther enrollmentKobayashi K, et al. J Clin Oncol. 2009;27(18s). Abstract 8016.


Summary: ANTI-VEGF and EGFR Inhibition inFirst-Line Therapy for Stage IV NSCLC• Bevacizumab improves ORR and PFS– And OS when added to paclitaxel / carboplatin in patients with nonsquamouspredominant histology (ECOG 4599)– But not OS when added to gemcitabine / cisplatin (AVAiL)• Cetuximab– Improves OS and ORR, but not PFS, when added to vinorelbine /cisplatin (FLEX)– Does not improve PFS or OS when combined with paclitaxel /carboplatin (BMS 099)– Benefit does not show a correlation with KRAS mutation, unlikecolon cancer• EGFR-TKI– Improves PFS in EGFR mutation (+) patients as compared tochemotherapy


MAINTENANCE THERAPY


Maintenance Therapy After 3-4Cycles of ChemotherapyAuthor Treatment Median PFS (mo) Median OS (mo)Fidias Delayed docetaxel 2.7 9.7Ciuleanu,BelaniImmediate docetaxel 5.7 (HR NR) 12.3 (HR NR)Placebo 2.0 10.6Pemetrexed 4.0 (HR 0.60) 13.4 (HR 0.79)HidaNo treatment 4.3 12.9(WJTSG)Gefitinib 4.6 (HR 0.68) 13.7 (HR 0.86)Cappuzzo(SATURN)Miller(ATLAS)Placebo NR* NRErlotinib NR* (HR 0.71) NR (HR 0.81)Erlotinib + placebo 3.8 NRErlotinib + bevacizumab 4.8 (HR 0.722) NRStatisticallySignificantNotStatisticallySignificantNR = not reported; HR = hazard ratio *PFS at 12 weeks: 40% placebo vs 53% erlotinib.Fidias PM, et al. J Clin Oncol. 2009;27:591-598; Ciuleanu TE, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 8011;Belani CP, et al. J Clin Oncol. 2009;27(18s). Abstract CRA8000; Hida T, et al. J Clin Oncol. 2008;26(May 20 suppl).Abstract LBA 8012; Cappuzzo F, et al. J Clin Oncol. 2009;27(18s). Abstract 8001; Cappuzzo F, et al. 13th WorldLung Cancer Conference, San Francisco; Miller VA, et al. J Clin Oncol. 2009;27(18s). Abstract LBA8002.


Overall Survival by HistologyPemetrexed MaintenanceNon-squamous (n = 481)Squamous (n = 182)Survival Probability1.00.90.80.70.60.50.40.30.20.10.0HR = 0.70 (95% CI:0.56-0.88)P = 0.002Placebo10.3 mosPemetrexed 15.5 mo0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 481.00.90.80.70.60.50.40.30.20.10.00Placebo10.8 mosHR = 1.07 (95% CI:0.49-0.73)P = 0.678Pemetrexed 9.9 mo3 6 9 12 15 18 21 24 27 3033 36 39 42 45 48Time (months)Time (months)Only 67% of patients in control arm received any second-line therapyand 19% received pemetrexedBelani CP, et al. J Clin Oncol. 2009;27(18s). Abstract CRA8000.


Summary of Maintenance Therapy• All studies utilized 4 cycles of first-linechemotherapy followed by “different” drugs withproven second-line activity• Improves PFS, but at the cost of immediateadditional side effects• Some trials show improved OS• Impact on OS may be related to increasedlikelihood of exposure to second-line therapy• Is there a difference between “maintenance”,early second-line, and delayed second-line?• Which patients are candidates?


Summary

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