Mantenimiento ca pulmón 2013-05

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  • NSCLC, non-small-cell lung cancer; PS, performance score. So, we now have a second molecular criterion, but you can see the remainder is still histology and clinical, such that the patient would be considered either on a nonsquamous histology base or squamous histology for various chemotherapy combinations, with or without bevacizumab for nonsquamous. Also, there is the new consideration of cetuximab, which although it is not FDA approved in the United States, it is going through that process and is part of the guidelines for therapy.
  • PD, progressive disease. The next slide shows the scenarios for the maintenance therapy trials that have been done. These considered giving platinum-based doublet chemotherapy plus an additional agent, so it is either cisplatin or carboplatin plus an additional agent. After 4 cycles, they either continued the drug that was given, which we will call continuation maintenance, or in other trials, switched to a different agent, which is switch maintenance.
  • Analyzing the data by histology, both histologies seem to benefit from erlotinib maintenance in terms of progression-free survival. The hazard ratio for adenocarcinomas was 0.60, and, interestingly, even for squamous cell carcinomas there was a statistically significant benefit with a hazard ratio of 0.76.
  • POINTBREAK was a superiority study with as primary objective Overall survivalFor OS the assumed HR was 0.80, 676 events were require in 900 patients to yield at least an 80% power to demonstrate superiority of Pem+Cb+Bev followed by Pem+Bev over Pac+Cb+Bev followed by Bev; using a log-rank test with 1-sided type 1 error of .025Secondary objectives included PFS, TTPD, ORR, Safety and patient reported outcomes (FACT-L/Ntx)Prespecified exploratory analyses- OS and PFS for maintenance population- PFS without Grade 4 toxicity (G4 PFS)
  • The primary endpoint of OS was not metOS in the two study arms was similar: HR 1.00 (0.86, 1.16); P=0.949The median OS for ALIMTA/Carbo/Avastin (ACA) arm was 12.55 months and for the control arm Paclitaxel/Carbo/Avastin (TCA) arm was 13.40 months
  • The authors’ conclusions on the POINTBREAK data are summarized in the 4 key points on this slideNB - What does this all mean for us @Lilly?Because superiority was not demonstrated – this study will not be submitted to regulatory authoritiesAs a consequence of that, the EU Alimta label will not include Avastin and Carboplatin. So there will be no opportunities for promotional discussions on AlimtaCarbo/AlimtaAvastin combinationsThe impact of all this in EU is considered low from an Avastin perspective (Avastin has 1) limited SOM in EU 2) has a ‘broad’ label, so if drs want to use Alimta+Avastin this is possible. We know from numbers in France that most Avastin is given in combination with Alimta. The main ‘treath’ foreseen is the impact this data might have on AlimtaCarbo use. The impact of this on the Alimta market will have to be seen. The outcome of the PRONOUNCE study – see later slides - will also be important in this perspective.We will have to monitor Roche/Genetech’s strategy with respect to the interpretation and messaging of the POINTBREAK data – at the Roche Symposium @ ESMO BejaminBesse mentioned that ‘Avastin is efficacious with all platinum-based backbone’ and recommended to use the cheapest one
  • NSCLC, non-small-cell lung cancer. This hypothesis that treatment of non-small-cell lung cancer should be histology based is related to the observation primarily that there is differential activity of pemetrexed in squamous vs nonsquamous subtypes of non-small-cell lung cancer, and that is from 3 studies as shown here.
  • Adeno, Adenocarcinoma; Adv, Advanced; CDDP/vin, cisplatin/vinorelbine; HR, hazard ratio; NOS, not otherwise specified; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival; SCCA, squamous cell carcinoma; SWOG, Southwest Oncology Group. Now, that being said, what does this mean for other agents? If you look at the next slide, you will see the SWOG database analysis on almost 750 patients treated with taxanes or vincas combined with platinums. You can see there was no difference in any outcome based on histology for those drug classes.
  • Adeno, adenocarcinoma; OS, overall survival. Similarly, as shown on the next slide, an analysis of studies done in Europe by Dr. Scagliotti showed that in his analysis, histology was also not a predictor of survival for either antimicrotubule- or gemcitabine-based therapy. So, the histology appears to be related primarily to pemetrexed activity.
  • AC, adenocarcinoma; NSCLC, non-small-cell lung cancer; SCCA, squamous cell carcinoma; TS, thymidylate synthetase.  Shown in the next slide is our own analysis of over 1500 patients for TS levels by gene expression and mRNA expression in squamous cell vs adenocarcinoma. What is shown here, and this confirms the earlier observations, is that squamous cell carcinomas tend to have higher levels of TS compared with adenocarcinoma. However, what is also shown on this slide is that the range of TS expression in individual patient tumors varies tremendously and in fact, some of the very lowest levels of TS are in individual patients with squamous cell carcinoma. My own opinion is that in the future, whether it is TS or another biomarker, that this important drug, pemetrexed, will be given based on a molecular predictive biomarker rather than histology.
  • OS, overall survival; PFS, progression-free survival; PS, performance score; WHO, World Health Organization. We will now look at one of these studies in particular, because it is very instructive. This is the IPASS trial by Dr. Mok, published in the New England Journal of Medicine. This was the clinical characteristic selection. This was done entirely in East Asia. It compared gefitinib with chemotherapy using paclitaxel and carboplatin. All of the patients were East Asian. All of the patients had adenocarcinoma. Ninety-four percent of the patients were never-smokers, and 80% were females. So, it was an ideal population to benefit from an EGFR TKI. They were randomized, and the primary endpoint was progression-free survival.
  • For patients who are EGFR-mutation positive, there was a significant advantage to treating with erlotinib first-line compared with chemotherapy first-line in terms of progression-free survival. The median progression-free survivals were 9.7 months vs 5.2 months.
  • Looking at the overall survival—and this is an interim analysis just reported last year—there was no difference between the chemotherapy and erlotinib arms, with a hazard ratio of 0.80. However, this again allowed crossover in all patients.
  • FDA, US Food and Drug Administration; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; NSCLC, non-small-cell lung cancer. The reason it is worth looking for is demonstrated on this slide. This abnormality is identified by the break-up FISH assay, which is the FDA-approved test, or other tests, which would be still not be considered standard of care at this point, but likely to be effective. You can see on the waterfall plot on the right that crizotinib is extraordinarily effective in these patients, with an approximately 65%–70% resist response rate, and almost all patients having tumor shrinkage. So, there is a cytotoxic effect in these patients.
  • NSCLC, non-small-cell lung cancer. So, we have talked already about emerging drivers, mutations, and ALK fusion, which could dictate therapy for patients with adenocarcinoma of the lung. Shown on the right are recent data presented at our World Conference, showing emerging druggable targets in squamous cell carcinoma. There are now both drugs and studies directed against several of these abnormalities, where we are likely to find new therapies that are squamous cell specific in the future.
  • These mutations are mutually exclusive. Ninety-seven percent of the time there was only 1 mutation per patient. This highlights the fact that these mutations are driver events, and it is quite likely that only 1 driver event is needed to promote and maintain carcinogenesis.
  • NSCLC, non-small-cell lung cancer; PS, performance score. So, we now have a second molecular criterion, but you can see the remainder is still histology and clinical, such that the patient would be considered either on a nonsquamous histology base or squamous histology for various chemotherapy combinations, with or without bevacizumab for nonsquamous. Also, there is the new consideration of cetuximab, which although it is not FDA approved in the United States, it is going through that process and is part of the guidelines for therapy.
  • Mantenimiento ca pulmón 2013-05

    1. 1. Martín LázaroOncología Médica CHU VigoBraga, 16 de mayo de 2013-
    2. 2. EquivalenciaSchiller; NEJM 2002; 346:92-98
    3. 3. MolecularAdvanced-Stage NSCLC & PS 0-1EFGR mutation and ALKnegative and nonsquamoushistologyEFGR mutation and ALKnegative and squamoushistologyBevacizumabappropriateBevacizumabinappropriateEGFR mutationpositiveErlotinib orgefitinibfirst lineConsider crizotinibfirst or second lineELM4-ALKpositiveProposed Treatment Algorithm for AdvancedNSCLC: First-line TherapyConsidercisplatin/pemetrexedOrcarboplatin/paclitaxel+ bevacizumabConsidercisplatin orcarboplatincombined withdocetaxel orgemcitabine orpaclitaxelorcisplatin/vinorelbine± cetuximabConsidercisplatin orcarboplatincombined withpemetrexed, docetaxel or gemcitabineor paclitaxelorcisplatin/vinorelbine± cetuximabHistology: Clinical
    4. 4. Histology Maintenance TherapyPredictive BiomarkersFactors are interlinking and not independentInterrelationships Among Histology, MaintenanceTherapy, and Predictive Biomarkers
    5. 5. Histology Maintenance TherapyPredictive BiomarkersFactors are interlinking and not independentInterrelationships Among Histology, MaintenanceTherapy, and Predictive Biomarkers
    6. 6. Platinum-based doubletchemotherapy:4 cycles of “induction”eg, cisplatin +agent “A”Same agent “A” until PDor toxicityDifferent agent “C” until PDor toxicityContinuation maintenanceSwitch maintenanceMaintenance Therapy Terminology:―A Rose by Any Other Name‖?
    7. 7. 100 pctes.tratados condoblete de QT en 1ªlínea~75 pctes.obtienen beneficioclínico(RC/RP/EE)~38 pctes.reciben tratamiento de2ª líneaEsperar yobservar(2–3 m)Deterioro sintomáticoydel PSStinchcombe, et al. J Thoracic Oncol 2009;4:243–50
    8. 8. ¿Es real este porcentaje?Pacientes que recibensegunda línea en el brazocontrol (%)PARAMOUNT 64Fidias 63JMEN 67IFCT 90Sun 84
    9. 9. Doblete basado en platinoPeriodo libre de progresiónSólo BSCMonoterapia desegunda lineaParadigma AnteriorProgresiónTratamiento hastala progresiónIntervalo libre detratamientoCPNM: cáncer de pulmón no microcítico; BSC: mejores cuidados de soporte (Best supportive care).Evolución del paradigma en el tratamiento de CPNM11. Hensing et al. Lung Cancer 2005;47(2):253.
    10. 10. Doblete o triplete basado enplatinoMás tiempo hasta la progresiónSiguientes líneas detratamientoNuevo ParadigmaDoblete basado en platinoPeriodo libre de progresiónSólo BSCMonoterapia desegunda lineaParadigma AnteriorProgresiónTratamiento hastala progresiónProgresiónIntervalo libre detratamientoTratamiento de mantenimiento(monoterapia o combinación)CPNM: cáncer de pulmón no microcítico; BSC: mejores cuidados de soporte (Best supportive care).Evolución del paradigma en el tratamiento de CPNM11. Hensing et al. Lung Cancer 2005;47(2):253.
    11. 11. • Extension of treatment duration by administration of ≥1 agents aftera defined no. of treatment cycles• Patients must demonstrate a defined tumor response to be eligibleMantenimiento: continuaciónDefined timeoruntil PDDefined no. of cyclesGrossi et al. Oncologist 2007;12:451–464Mantenimiento/SecuenciaDefined tumorresponse• Therapy for a defined no. of cycles, followed by a different therapy for a defined no. of cycles• Switch between therapies does not require documented disease progression vs.regular switch from 1st- to 2nd-line treatmentSecuencial (consolidación; cambio; segunda línea temprana)Defined no. of cycles Defined no. of cycles
    12. 12. Objetivos del tratamiento demantenimientoRetrasar la progresión tumoralRetrasar deterioro sintomáticoMínimo impacto en calidad de vida y toxicidadMejorar supervivencia
    13. 13. Induction Therapy MaintenanceTherapyMedian PFS,MosMedianOS, MosBrodowiczLung Ca 2006Gem + cisplatin x 4 GemcitabineBSC6.65.0(P < .001)13.011.0(p = .195)BelaniASCO 2010Gem + carbo x 465%: PS>2GemcitabineBSC7.47.7(P = .575)8.09.3(P = .838)PérolJCO 2012Gem + cisplatin x 4 GemcitabineBSC3.81.9(P < .001)12.110.8(p = .386)PARAMOUNTASCO 2012Pem + cisplatin x 4 PemetrexedBSC4.12.8(P = .00006)13.911(p = .019)1.56 m 1.58 m
    14. 14. Agent/ControlArmN PFS SalvageTreatm,%OSFidiasJCO 2010DocetaxelDelayed docetaxel309 5.7 m (HR: 0.63)2.7 m (P = .001)63 12.3 HR: 0.809.7 P = .085JMENLancet 09PemetrexedPlacebo663 4.0 m (HR: 0.50)2.6 m (P <.0001)67 13.4 HR: 0.7910.6 P = .012SATURNL Onc 09ErlotinibPlacebo889 12.3 s (HR: 0.71)11.1 s (P <.0001)72 12.0 HR: 0.8111.0 P = .0088MillerASCO ‘09Erlotinib +bevacizumabPlacebo +bevacizumab768 4.8 m (HR: 0.72)3.7 m (P = .001)55.5 15.9 HR: 0.9013.9 P = .2686PérolJCO ‘12ErlotinibObservation310 2.9 m (HR: 0.82)1.9 m (P = .002)81.9 11.4 HR: .8710.8 p = .304ZhangASCO ‘11GefitinibPlacebo296 4.8 m (HR:0.42)2.6 m (P <.0001)58.8 18.7 HR: .8416.9 p.2608
    15. 15. Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region1:1ChemonaïveadvancedNSCLCn=1,949Non-PDn=8894 cycles of1st-lineplatinum-baseddoublet*Placebo PDErlotinib150mg/dayPDMandatory tumoursampling*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine;carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxelEGFR = epidermal growth factor receptor; IHC = immunohistochemistryCo-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumoursSecondary endpoints: Overall survival (OS) in all patients and those withEGFR IHC+ tumours; OS and PFS in EGFR IHC–tumours; biomarker analyses; safety; time tosymptom progression; quality of life (QoL)ESTUDIO SATURNCapuzzo et al; Lancet Oncol 2010;11:521-9
    16. 16. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529.Cappuzzo F, et al. ASCO 2009. Abstract 8001.Wks100806040200PatientsWithoutProgression(%)P < .001SATURN Phase III Study: Erlotinib ImprovesPFS as Maintenance in Advanced NSCLC PFSsignificantlyimproved by41% vsplacebo Significantimprovementsin responseand disease-control ratesErlotinibPlacebo960 8 16 24 32 40 48 56 64 72 80 88Response Erlotinib(n = 437)Placebo(n = 447)Median PFS, wks 12.3 11.1PFS at 12 wks, % 53 40PFS at 24 wks, % 31 17PFS at 48 wks, % 13 5
    17. 17. Log-rank P < .0001HR: 0.60 (95% CI: 0.48-0.75)PFSprobabilityTime (Wks)Erlotinib (n = 204)Placebo (n = 197)AdenocarcinomaLog-rank P = .0148HR: 0.76 (95% CI: 0.60-0.95)SCCErlotinib (n = 166)Placebo (n = 193)Cappuzzo F, et al. ASCO 2009. Abstract 8001.SATURN Phase III Study: PFS by Histology0 8 16 24 32 40 48 56 64 72 80 881.00.80.60.40.20PFSprobabilityTime (Wks)0 8 16 24 32 40 48 56 64 72 80 881.00.80.60.40.20S S
    18. 18. Brugger W, et al. J Clin Oncol. 2011;29:4113-4120.WksPatientsWithoutProgression(%)WksPatientsWithoutProgression(%)PFS: Wild-Type EGFR PFS: Mutated EGFRHR: 0.78P = .0185HR: 0.10P < .00010204060801000 8 16 24 32 40 48 56 640204060801000 8 16 24 32 40 48 56 64Erlotinib (n = 22)Placebo (n = 27)Erlotinib (n = 199)Placebo (n = 189)SATURN Ph III: Strong PFS Benefit for ErlotinibMaintenance With Mut EGFRS S
    19. 19. OSprobability1.00.80.60.40.200 3 6 9 12 15 18 21 24 27 30 33 36Time (months)9.6 11.91.00.80.60.40.200 3 6 9 12 15 18 21 24 27 30 33 36Time (months)12.0 12.5Log-rank p=0.0019HR=0.72 (0.59–0.89)Erlotinib (n=252)Placebo (n=235)Log-rank p=0.6181HR=0.94 (0.74–1.20)Erlotinib (n=184)Placebo (n=210)SD CR/PRMeasured from time of randomisation into the maintenance phaseEstudio SATURNSupervivencia según respuesta a la 1ª LíneaMultivariate HR for OS in SD population0.71, p=0.0019
    20. 20. Pérol et al; JCO 2012; 30:3516-24IFCT-GFPC 0502Chemonaïveadvanced NSCLC(brain metsallowed)Non-PDN=464Cis/GemX4N=834PlaceboErlotinibPmtxed(at PD)Tumor issueEGFR (IHC,mutat)PDOffGemcitabineEstratificación:-Género.-Histología (adenocarcinoma vs otras histologías).-Historial tabaquismo.-Centro de tratamiento.-Respuesta vs EE en el momento de la randomización.OP: PFS
    21. 21.  Stage IIIB/IV NSCLC ECOG PS 0-1 4 prior cycles of gem, doc, ortax + cis or carb, with CR, PR,or SD Randomization factors:• gender• PS• stage• best tumor response• non-platinum drug• brain mets2:1RandomizationPemetrexed 500 mg/m2 (d1,q21d)+ BSC (N=441)*Placebo (d1, q21d) + BSC(N=222)*Objetivo primario: Supervivencia libre de progresión, incremento de un 23% (HR: 0,76)Poder estadístico del 80%Número de eventos 462Estudio JMENPrimary Endpoint = PFSCiuleanu et al; Lancet 2009;374:1432-40
    22. 22. Estudio JMENSupervivencia según respuesta a la 1ª LíneaOS nonsquamousfor CR/PRPemetrexed+ BSCPlacebo+ BSCMedian survival(95% CI)14.4(12.3-18.2)11.7(8.5-15.3)HR(95% CI)0.81(0.58-1.12)p=0.19854OS nonsquamousfor SDPemetrexed+ BSCPlacebo+ BSCMedian survival(95% CI)16.6(13.0-20.9)8.6(7.2-11.3)HR(95% CI)0.61(0.45-0.83)p=0.00171Patients at riskPem 148 125 84 50 18 9 3 0Plac 78 59 35 21 7 2 1 0Patients at riskPem 174 139 94 67 33 16 6 0Plac 78 53 28 21 13 5 2 0
    23. 23. Prolongar elcontrol de laenfermedadMantener latolerabilidadObjetivos1Mejorar laSupervivenciaGlobalObjetivos de la terapia de mantenimiento1. Paz-Ares et al. Lancet Oncol 2012;13:247.
    24. 24. Ventajas1-3Maximizar elpotencial delfármacoutilizado en la1a líneaLa tolerancia alfármaco esconocida desdela inducciónReservar unfármaco paralíneasposterioresVentajas del mantenimiento de continuación vs cambio:1-31. Stinchcombe et al. J Thorac Oncol 2009;4:24350; 2. Novello et al. J ExpClin Cancer Res 2011;30:50. 3. Fidias et al. J Clin Oncol 2010; 28:5116.
    25. 25. ESTUDIO PARAMOUNTTratamiento de inducción4 ciclos, cada 21 díasTratamiento de mantenimiento de continuacióncada 21 días hasta progresiónPemetrexed +BSCPlacebo +BSCPemetrexed+ CisplatinoCR/PR/SDsegúnRECISTR2:1OP: SLPEstratificados según:• PS (0 vs 1)• Estadio de la enfermedad (IIIB vs IV)• Respuesta a la inducción (CR/PR vs SD)• No tratadospreviamente• PS 0/1• CPNM-NSestadio IIIB-IV1. Paz-Ares et al. Lancet Oncol 2012;13:247.2. Paz-Ares et al. J Clin Oncol 2012;30 (# LBA7507).N=539N=939
    26. 26. Tiempo (meses)0.00.20.40.60.81.0ProbabilidaddeSupervivenciaSLP: revaluada en el momento del análisis de la SGPatients at riskPem + BSCPlac + BSC35918013933679224100000 3 15 21 27 336 9 12 18 24 3021575971647732616250Pemetrexed en mantenimiento de continuacióndemostró un beneficio significativo en la SLPPemetrexed + BSC (n=359)Placebo + BSC (n=180)HR no ajustada: 0.60 (0.50–0.73); p<0.0001HR=0.60Paz-Ares et al. J Clin Oncol 2012;30 (suppl; abstr LBA7507).4.1 vs 2.8 m
    27. 27. Pemetrexed/cisplatino seguido de Pemetrexed demostró unbeneficio significativo en la SG0 3 6 9 12 15 18 21 24 27 30 33 36Tiempo desde la aleatorización (meses)0.00.10.20.30.40.50.60.70.80.91.0Pemetrexed+ BSC (n=359)Placebo + BSC (n=180)Log-rank P=0.0195HR no ajustada: 0.78 (95% CI: 0.64–0.96)SG desde la aleatorización11.0 mPatients at riskPem + BSC 359 333 272 235 200 166 138 105 7943 15 2 0Placebo + BSC 180 169 131 103 78 65 49 35 2312 8 3 0ProbabilidaddeSupervivenciaPaz-Ares et al. J Clin Oncol 2012;30 (suppl; abstr LBA7507).
    28. 28. 0 3 6 9 12 15 18 21 24 27 30 33 360.00.10.20.30.40.50.60.70.80.91.0Pemetrexed+ BSC (n=359)Placebo + BSC (n=180)21 %Tiempo desde la aleatorización (meses)SG desde la aleatorizaciónProbabilidaddeSupervivenciaPaz-Ares et al. J Clin Oncol 2012;30 (suppl; abstr LBA7507).Pemetrexed/cisplatino seguido de Pemetrexed demostró unbeneficio significativo en la SG
    29. 29. Tasa de Supervivencia a 2 añosPemetrexed + BSC 32%Placebo + BSC 21% Tras 2 años desde el fin de la inducción, 1 de cada 3 pacientes permanecíavivo en el brazo de pemetrexed mientras que sólo 1 de cada 5 sobrevivía enel brazo de placeboPaz-Ares et al. J Clin Oncol 2012;30 (suppl; abstr LBA7507).
    30. 30. Paramount: SG desde el inicio de la inducción0 3 6 9 12 15 18 21 24 27 30 33 360.00.10.20.30.40.50.60.70.80.91.0SG desde inicio de la inducción:PemetrexedMediana SG=16.9 meses (95% CI: 15.8–19.0)PlaceboMediana SG=14.0 meses (95% CI: 12.9–15.5)Log-rank P=0.0191HR=0.78 (95% CI: 0.64–0.96)Patients at riskPem + BSC 359 333 272 234 200 166 138 105 7943 15 2 0Placebo + BSC 180 169 131 103 78 65 49 35 2312 8 3 0ProbabilidaddeSupervivenciaTiempo desde la inducción (meses)14.0Diferencia de 3 mesesen supervivencia globalPaz-Ares et al. J Clin Oncol 2012;30 (suppl; abstr LBA7507).
    31. 31. El beneficio en la SG se observó en todos los subgruposFavors Pemetrexed Favors PlaceboHazard Ratio0.780.790.820.810.760.820.700.750.830.820.730.750.890.820.710.810.440.80Treatment Hazard Ratio (95% CI)0.0 0.5 1.0 1.5 2.0 2.5Adenocarcinoma (n=471)Large Cell Carcinoma (n=36)Other Histologic Diagnosis (n=32)Age 65 (n=189)Age < 65 (n=350)Age 70 (n=92)Age < 70 (n=447)Female (n=226)Male (n=313)Smoker (n=418)Non-smoker (n=117)Pre-randomization ECOG PS 0 (n=173)Pre-randomization ECOG PS 1 (n=363)Induction Response SD (n=285)Induction Response CR/PR (n=234)Stage IIIB (n=49)Stage IV (n=490)All Randomized Patients (N=539)1. Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507).2. Reck et al. Ann Oncol 23, 2012 (suppl; abstr 1235PD).PARAMOUNT: Hazard Ratios de SG por subgrupos
    32. 32. Ambos subgrupos, CR/PR y SD, se beneficiaron deltratamiento de mantenimiento con PemetrexedLa respuesta tumoral a la inducción NO es un factor determinante de la SGReck et al. Ann Oncol 23, 2012 (suppl; abstr 1235PD).CR, respuesta completaPR, respuesta parcialSD, enfermedad estable
    33. 33. El PS es un factor pronóstico en CPNM avanzado Mientras que los pacientes con PS 0 sobreviven más tiempo que aquéllos con PS 1,ambos subgrupos muestran una mayor supervivencia con tratamiento demantenimiento con Pemetrexed que con PlaceboReck et al. Ann Oncol 23, 2012 (suppl; abstr 1235PD).
    34. 34. Pemetrexed(N=359) %*Placebo(N=180)%*Pacientes que recibierontratamiento post-discontinuación (PDT)64 72Erlotinib 40 43Docetaxel† 32 43Gemcitabina 10 8Vinorelbina 8 6Fármaco en investigación 6 4Carboplatino 5 4Paclitaxel 3 3Pemetrexed 2 4Cisplatino 1 2PARAMOUNT: tratamiento post-discontinuación El porcentaje de pacientes que recibieron PDT fue similar en ambos brazos Esto indica que Pemetrexed en mantenimiento de continuación no reduce laelegibilidad de los pacientes para líneas posteriores de tratamientoPaz-Ares et al. J Clin Oncol 2012;30 (suppl; abstr LBA7507).
    35. 35. Resumen de ciclos de mantenimiento administradosPemetrexed (n=359) Placebo (n=180)Mediana (rango de ciclos) 4 (1,44) 4 (1,38)Media (SD) de ciclos 8 (8) 5 (5)% de pacientes que recibieron mantenimiento≤10 ciclos>10 ciclos7624909% de discontinuaciones debidas a acontecimientosadversos posiblemente relacionados con eltratamiento12 4Pujol et al. Ann Oncol 23, 2012 (suppl; abstr 1275P).01020304050607080901001 2 3 4 5 6 7 8 9 10 15 20 25 30 35 40 44%depacientesaleatorizadosencadaciclodemantenimientoCiclosPemetrexed (N=359) Placebo (N=180)
    36. 36. 5.30.66.70.60.66.12.20.30.82.20.60.31.10.00.60.00.60.00.00.00.00.60.80.00.0 5.0 10.0 15.0 20.0 25.0 30.0FatigaŦNáuseasŦAnemiaMucositis/estomatitisNeuropatía sensitivaNeutropeniaŦLeucopeniaALT (SGPT)Toxicidades renalesRash cutáneoConjuntivitisVómitosPemetrexed (n=359)Placebo (n=180)Paramount: acontecimientos adversos de grado 3/4 (CTCAEs)Valores expresados como % de pacientes aleatorizadosŦtoxicidades de grado 3/4 con diferencia estadísticamente significativa respecto a placebo(p-valor <0.05). La frecuencia de toxicidades de grado3/4 fue baja, no sobrepasando el 7% enninguno de los casosPujol et al. Ann Oncol 23, 2012 (suppl; abstr 1275P).
    37. 37. CTCAEPemetrexed (n=359) Placebo (n=180)Grado 1%Grado 2%Grado 3/4%Grado 1%Grado 2%Grado 3/4%Fatiga 8.9 9.7 5.3* 5.6 5.0 1.1Náuseas 8.9* 5.8* 0.6 1.1 1.1 0.0Anemia 4.2 10.0* 6.7* 1.1 3.3 0.6Edema 4.2 3.6* 0.0 3.3 0.0 0.0Mucositis/estomatitis3.9 2.2 0.6 1.1 1.1 0.6Neuropatíasensitiva4.5 0.6 0.6 5.0 1.1 0.0Neutropenia 1.9 3.6* 6.1* 0.0 0.6 0.0Leucopenia 1.4 1.7 2.2 0.0 0.0 0.0ALT (SGPT) 0.8 1.7 0.3 0.0 0.6 0.0Toxicidades renales 3.1 3.9 0.8 1.7 0.6 0.0Rash cutáneo 2.2 0.6 0.0 2.2 0.0 0.0Conjuntivitis 0.6 0.8 0.0 0.0 0.0 0.0PARAMOUNT: CTCAEs posiblemente relacionados con el tratamiento*Con diferencia significativa respecto a placebo (p-valor <0.05).Pujol et al. Ann Oncol 23, 2012 (suppl; abstr 1275P).
    38. 38. AnaemiaNeutropeniaLeucopeniaThrombo-cytopeniaFatigueInfectionPainNeuropathyPemetrexed(n=359)placebo(n=180)0 10 20 30 0 10 20 30QoL and safety in PARAMOUNTRate of AEs possibly related to maintenance pemetrexed vs placebo†* Difference between treatment groups was significant (Fisher’s exact test p≤0.05).† Adverse events were reported using Common Terminology Criteria for Adverse Events version 3.0 (NCI 2006). Alanine aminotransferase, Nausea, Vomiting, Mucositis orstomatitis, Oedema, Anorexia, Diarrhoea, Watery eye, Constipation Grade 3/4 adverse events were reported for less than 1% of patients.Adopted from: 1,24%* n=15<1%* n=11% n=41% n=21% n=30% n=11% n=11% n=14%* n=16<1%* n=14%* n=130%* n=12% n=60%* n=11% n=40% n=1Low rate of discontinuations due toadverse events39.2% for maintenance pemetrexed3.9% for placebo
    39. 39. 1009080706050403020100%ChangefromBaselineinECOGPerformanceStatusPemetrexed PlaceboWorseNo ChangeBetterQoL and safety in PARAMOUNTChange in ECOG PS from randomisation to last maintenance treatment14.7% 12.6%77.8% 77.3%7.5% 10.2%* Difference between treatment groups was significant (Fisher’s exact test p≤0.05).† Adverse events were reported using Common Terminology Criteria for Adverse Events version 3.0 (NCI 2006). Alanine aminotransferase, Nausea, Vomiting, Mucositis orstomatitis, Oedema, Anorexia, Diarrhoea, Watery eye, Constipation Grade 3/4 adverse events were reported for less than 1% of patients.Adopted from: 1,2
    40. 40. QoL and safety in PARAMOUNTEQ-5D index scores: Quality of life was maintained throughout treatment30.80.70.6ImprovementMeanscoreInduction cycles Maintenance cyclesPemetrexedPlacebo1 2 3 4 1 2 3 4 5 6* p≤0.05, within-group change from baseline. † p≤0.05, comparing the difference in mean changes from baseline between treatment arms.Adopted from: 3
    41. 41. QoL and safety in PARAMOUNT• Survival significantly improved with pemetrexed continuationmaintenance therapy vs placebo5• HR=0.78 (95% CI: 0.64-0.96)5• No statistical differences observed in patient-reported QoLbetween maintenance treatment arms3
    42. 42. How robust are the findings of PARAMOUNT tosupport a change in the treatment paradigm?
    43. 43. Datos del estudio PARAMOUNT: cambio de paradigmaThe PARAMOUNT results arebased on a number of validpoints
    44. 44. Direction of magnitude of PFSand OS results are consistentand favour pemetrexedcontinuation maintenancePFS: 4.1 vs 2.8 monthsHR 0.62 (95% CI 0.49-0.79; p<0.0001)OS: 16.9 vs 14.0 monthsfrom inductionHR 0.78 (95% CI 0.64-0.96; p=0.0195)Datos del estudio PARAMOUNT: cambio de paradigma
    45. 45. Investigator-determined PFSresults confirmed byindependent reviewDirection of magnitude of PFSand OS results are consistentand favour pemetrexedcontinuation maintenancePFS: Primary endpoint1.00.90.80.70.60.50.40.30.20.10Survivalprobability(%)0 3 6 9 12 15pemetrexed + BSC (n=358)placebo + BSC (n=180)HR 0.62 (0.49–0.79)Time (months)Datos del estudio PARAMOUNT: cambio de paradigma
    46. 46. Investigator-determined PFSresults confirmed byindependent reviewDirection of magnitude of PFSand OS results are consistentand favour pemetrexedcontinuation maintenanceRelative treatment effect ofpemetrexed consistent acrosssubgroupsFavours pemetrexed 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0 Favours placeboSubgroup OS Hazard Ratio N HR (95% CI)All 539 0.78Stage IV 490 0.79IIIB 49 0.82Induction responseCR/PR 234 0.81SD 285 0.76Pre-randomisationECOG PS1 363 0.820 173 0.70Smoking status Never-smoker 117 0.75Smoker 418 0.83Sex Male 313 0.82Female 226 0.73Age (years) <70 447 0.75≥70 92 0.89<65 350 0.82≥65 189 0.71Histology Adenocarcinoma 471 0.80Large cell carcinoma 36 0.44Other 32 0.81CR/PR patients: OS HR=0.81SD patients: OS HR=0.76Datos del estudio PARAMOUNT: cambio de paradigma
    47. 47. Investigator-determined PFSresults confirmed byindependent reviewDirection of magnitude of PFSand OS results are consistentand favour pemetrexedcontinuation maintenancePost-discontinuation treatmentoptions were well balancedbetween the two armsRelative treatment effect ofpemetrexed consistent acrosssubgroupsplacebo(n=180) %*7243438644342pemetrexed(n=359) %*64403210865321Patients with PDTDrug nameErlotinibDocetaxel†GemcitabineVinorelbineInvestigational drugCarboplatinPaclitaxelPemetrexedCisplatin* Data expressed as % of randomized patients. Systemic therapies used in ≥2% of patients in either arm are shown.† Only docetaxel usage differed significantly between arms (p=0.013).64 72Datos del estudio PARAMOUNT: cambio de paradigma
    48. 48. Bevacizumab:Supervivencia Global en No escamoso12.3 monthsOS bevacizumab15mg/kg1Sandler, et al. NEJM 2006; 2Reck, et al. JCO 2009; 3Reck, et al. Ann Oncol 2010HR=0.79p=0.00313.6 monthsOS bevacizumab7.5mg/kgOS bevacizumab15mg/kgHR=0.93p=NSHR=1.03p=NS
    49. 49. AVAPERL: Trial designPrimary endpoints: PFSStratification factors– gender– smoking status (never smokervs. past/current smoker)– response (CR/PR vs. SD)Previouslyuntreatedstage IIIB/IVnon-squamousNSCLCARM A:Bevacizumab 7.5mg/kg every 3weeksARM B:Bevacizumab 7.5mg/kg + pemetrexedevery 3 weeksBevacizumab 7.5 mg/kg+ pemetrexed* +cisplatin*every 3 weeksInduction therapy (4 cycles)Maintenance therapyPDPD1:1CR/PR/SD(per RECIST)Barlesi F, et al. ASCO 2011. #7562; EMCC 2011N=253N=376123 patients not randomized• 50 discontinued due to AEs• 49 discontinued due to PD• 9 patients died• 7 withdrew consent• 5 discontinued for other reasons• 3 did not start treatment
    50. 50. AVAPERL: PFS from inductionBev+pem 10.2 months (81 events)Bev 6.6 months (104 events)HR, 0.50 (0.37–0.69); P <.001Progression-freesurvival(%)Time (months)128 126 103 66 25 4 0125 122 73 38 12 2 010075502500 3 6 9 12 15 18Pts at risk Bev+pemBeva Randomized pts, Intent-to-treat populationCont. maintenance bev+pem (n=128)Cont. maintenance bev (n=125)
    51. 51. AVAPERL: PFS from randomizationBev+pem 7.4 months (81 events)Bev 3.7 months (104 events)HR, 0.48 (0.35–0.66); P <.001Progression-freesurvivalfromdateofrandomization(%)Time (months)128 104 67 25 4 0125 73 36 13 2 010075502500 3 6 9 12 15Pts at risk Bev+pemBevCont. maintenance bev+pem (n=128)Cont. maintenance bev (n=125)
    52. 52. AVAPERL: OS from inductionOverallsurvival(%ofpatients)10075502500 3 6 9 12 15 18 21128 127 120 103 56 20 3 0125 123 110 96 45 17 2 0Time (months)Bev+pem NR (34 events)Bev 15.7 m (42events)HR,0.75 (0.47–1.20); P=0.23Pts at risk Bev+pemBevMedian follow-up time: 11 months (8 months, excluding induction).30% of events at the time of analysis for overall survivalCont. maintenance bev+pem (n=128)Cont. maintenance bev (n=125)
    53. 53. 63PointBreak: Study Design• Randomized, open-label, Phase III superiority study conducted in US• Pemetrexed 500 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg• Paclitaxel 200 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kgStratified for: PS (0 vs. 1); sex (M vs. F); disease stage (IIIB vs. IV); measurable vs. nonmeasurable diseaseInclusion:- No prior systemic therapyfor lung cancer- PS 0/1- Stage IIIB-IV NS-NSCLC- Stable, treated brainmetastasisExclusion:- Peripheral neuropathy≥ Grade 1- Uncontrolled pleuraleffusionsInduction Phaseq21d, 4 cyclesMaintenance Phaseq21d until PDPemetrexed+ Carboplatin+ BevacizumabPaclitaxel+ Carboplatin+ BevacizumabR1:1Pemetrexed(folic acid & vitamin B12 )+ BevacizumabBevacizumab450 patients eachPatel et al. J Thorac Oncol 2012;7(15, Suppl 4):S336OP: OS
    54. 54. 64PointBreak:OS from Randomization (ITT)Censoring rate for Pem+Cb+Bev was 27.8; for Pac+Cb+Bev was 27.2Pem+Cb+Bev Pac+Cb+BevOS median (months) 12.6 13.4HR (95% CI); p-value 1.0 (0.86, 1.16); p = .949Survival rate (%)1-year 52.7 54.12-year 24.4 21.20 3 6 9 12 15 18 21 24 27 30 33 36 390.00.10.20.30.40.50.60.70.80.91.0Time from Induction (Months)SurvivalProbabilityPatel et al. J Thorac Oncol 2012;7(15, Suppl 4):S336
    55. 55. 65PointBreak: Conclusions• The primary endpoint of superior OS was not met in this trial:- OS HR 1.00, p = .949- Median OS 12.6 mo. for Pem+Cb+Bev → Pem+Bevvs. 13.4 mo. for Pac+Cb+Bev → Bev- Efficacy reported here was similar to previously published data1for Pac+Cb+Bev →Bev• Pem+Cb+Bev → Pem+Bev had superior median PFS compared withPac+Cb+Bev → Bev: HR 0.83, p = .012, 6.0 vs. 5.6 mo. respectively• Prespecified exploratory noncomparative analyses for the maintenancepopulation who received Pem+Cb+Bev → Pem+Bev vs. Pac+Cb+Bev →Bev showed OS of 17.7 and 15.7 mo, and PFS of 8.6 and 6.9 mo resp.• The toxicity profiles differed and both regimens demonstrated tolerabilityPatel et al. J Thorac Oncol 2012;7(15, Suppl 4):S336Index
    56. 56. Histology Maintenance TherapyPredictive BiomarkersFactors are interlinking and not independentInterrelationships Among Histology, MaintenanceTherapy, and Predictive Biomarkers
    57. 57. Observation: Differential efficacy of pemetrexed insquamous vs nonsquamous subtypes of NSCLC JMDB: Pemetrexed/cisplatin vs gemcitabine/cisplatinin first-line therapy of advanced NSCLC[1] JMEI: Pemetrexed vs docetaxel in second-linetherapy of advanced NSCLC[2] JMEN: Pemetrexed vs placebo as maintenancetherapy of NSCLC[3]1. Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.2. Otani S, et al. Gan To Kagaku Ryoho. 2012;39:59-62.3. Greenhalgh J, et al. Health Technol Assess. 2010;14(suppl 2):33-39.Hypothesis: Treatment of NSCLCShould Be Histology Based
    58. 58. No difference in overall PFS orsurvival between study armsCis/Pem improves survival over CGin non-SCCA (HR: 0.81; P = .005)Cis/Gem improves survival over CPin SCCA (HR: 1.23; P = .05)Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.JMDB Trial: Cisplatin/Pemetrexed vsCisplatin/Gemcitabine in Advanced NSCLC0 6 12 18 24 300.10.20.30.40.50.60.70.80.91.0Survival Time (Mos) in All PatientsSurvivalProbabilityCPCGCP vs CGMedian (95% CI)10.3 (9.8-11.2)10.3 (9.6-10.9)Adjusted HR (95% CI)0.94 (0.84-1.05)0 6 12 18 24 300.10.20.30.40.50.60.70.80.91.0Survival Time (Mos) in All PatientsWith Nonsquamous HistologySurvivalProbabilityCPCGCP vs CGMedian (95% CI)11.8 (10.4-13.2)10.4 (9.6-11.2)Adjusted HR (95% CI)0.81 (0.70-0.94)0 6 12 18 24 300.10.20.30.40.50.60.70.80.91.0Survival Time (Mos) in All PatientsSurvivalProbabilityCPCGCP vs CGMedian (95% CI)9.4 (8.4-10.2)10.8 (9.5-12.1)Adjusted HR (95% CI)1.23 (1.00-1.51)
    59. 59.  Un THI significativo implica que la histología es predictiva de respuesta y beneficio La histología no escamosa es predictivo de respuesta a Pemetrexed en CPNMTest de Interacción del tratamiento porHistología (THI) para Pemetrexed1. Scagliotti et al. Oncologist 2009;14:253-63.2. Ciuleanu et al. Lancet 2009 doi:10.1016/S0140-6736(09)61497-5Segunda LíneaJMEIPem vs DocN=571Primera LíneaJMDBCis-Pem vs Cis-GemN=1725MantenimientoJMENPem vs PlaceboN=663No escamoson=399Escamoson=172No escamoson=1252Escamoson=473No escamoson=481Escamoson=182SG HR (95% CI) 0.78(0.61-1.00)1.56(1.08-2.26)0.84(0.74-0.96)1.23(1.00-1.51)0.66(0.49-0.88)1.28(0.85-1.93)THI HR (95% CI)p-value0.48(0.32-0.74)0.0010.69(0.54-0.87)0.0020.52(0.31-0.86)0.033
    60. 60. SWOG Database Analysis of Taxane/Vinca-Based Therapy in Adv NSCLC by Histology N = 741 S9806, S0003, and CDDP/vin arm of S9308 No difference in any efficacy outcome by histologyHistology N (%)OS PFSMedian, Mos Adjusted HR* Median, Mos Adjusted HR*Adeno 424 (57) 8.5 1.00 (referent) 4.3 1.00 (referent)SCCA 128 (17) 8.4 0.987 (P = .89)† 4.5 0.986 (P = .89)‡Large cell 82 (11) 7.9 0.974 (P = .83) 4.2 1.03 (P = .81)NSCLC,NOS 107 (14) 9.6 0.971 (P = .79) 5.0 0.87 (P = .20)*HR from Cox proportional hazards model with adenocarcinoma as referent, adjusted for sex.†HR for SCCA vs all others combined, OS: 0.995 (95% CI: 0.82-1.21; P = .96).‡HR for SCCA vs all others combined, PFS: 1.01 (95% CI: 0.83-1.22; P = .94)Chansky K, et al. IASLC WCLC 2009. Abstract B2.7
    61. 61. Scagliotti G, et al. J Thorac Oncol. 2009;4:1568-1571.Histology Not a Predictor of Survival FromAntimicrotubule or Gem.-Based Therapy0 6 12 18 24 3600.20.40.60.81.0OS (Mos)ProportionSurviving30All Patients (N = 607)AdenoOtherLarge cellSquamous0 6 12 18 24 3600.20.40.60.81.0ProportionSurviving30PC Patients (n = 201)AdenoOtherLarge cellSquamousOS (Mos)0 6 12 18 24 3600.20.40.60.81.0OS (Mos)ProportionSurviving30VC Patients (n = 201)AdenoOtherLarge cellSquamous0 6 12 18 24 3600.20.40.60.81.0ProportionSurviving30GC Patients (n = 205)AdenoOtherLarge cellSquamousOS (Mos)
    62. 62. TS SCLC: highest TS Squamous: high TS Adeno: low TSBhattacharjee A, et al. Proc Natl Acad Sci U S A.2001;98:13790-13795.Thymidylate Synthase Expressionin Lung Cancer
    63. 63. TS mRNA Results by Histology (N = 1671):Squamous vs AdenocarcinomaBiomarker NSCLC: Total (N= 1671)NSCLC: SCCA(n = 316)NSCLC: AC (n =649)SCCA vs AC PValueTS Median 2.71 4.1 2.5 < .001*Range 0.14-68.0 0.14-59.3 0.39-68.0 *Mann-Whitney testTS (Reference< 2.33 for Pemetrexed)% BelowReference LevelNSCLC: total 41.3NSCLC: adenoca 45.7NSCLC: SCCA 25.9Gandara DR, et al. ASCO 2010. Abstract. 7513.141210TS86420AC SCCA
    64. 64. Histology Maintenance TherapyPredictive BiomarkersFactors are interlinking and not independentInterrelationships Among Histology, MaintenanceTherapy, and Predictive Biomarkers
    65. 65. Evolución de la histología a mutacionesdriver en CPNMPao W et al. Lancet Oncology 2011;12:175-180.Mutaciones en genes crucialespara la proliferación ysupervivencia celularesEstas mutaciones ―dirigen‖ laformación y el mantenimiento deltumorAdicción Oncogénica
    66. 66. Lee et al 2009, Maemondo et al 2010; Mitsudomi et al 2009, Mok et al 200920 4030100800204060100Time from randomisation (months)Cisplatin/docetaxelGefitinibWJTOG3405 (n=172)HR (95% CI) = 0.49 (0.34, 0.71), p<0.0001ORR 62% vs 32%, p<0.000120 3025100800204060100Time from randomisation (months)First-SIGNAL (n=42)HR (95% CI) = 0.61 (0.31, 1.22), P=0.084ORR 85% vs 38%, p=0.002240800204060100Time from randomisation (months)IPASS (n=261)HR (95% CI) = 0.48 (0.36, 0.64), p<0.0001ORR 71% vs 47%, p=0.0001Time from randomisation (months)NEJ0002 (n=224)HR (95% CI) = 0.30 (0.22, 0.41), p<0.001ORR 74% vs 31%, p<0.001ProbabilityofPFS4 8 12 16 20GefitinibCarboplatin /paclitaxelGefitinibCarboplatin /paclitaxel5 15Gemcitabine /cisplatinGefitinib00.20.40.60.81.00 3 6 9 12 15 18 21 24 27PFS and ORR for gefitinib vs. doublet chemotherapy in EGFR M+ patients4 Phase III first-line trials
    67. 67. Carboplatin+ PaclitaxelGefitinibPrimary Endpoint PFS (noninferiority)Secondary Endpoints Objective response rate OS Quality of life Disease-related symptoms Safety and tolerabilityExploratory Biomarkers– EGFR mutation– EGFR gene copy number– EGFR protein expressionPatients Chemo naive 18 yrs of age orolder Adenocarcinomahistology Never or ex-lightsmokers* Life expectancy≥ 12 wks WHO PS 0-2 Measurable stageIIIB/IV diseaseConducted in China, Japan, Thailand, Taiwan, Indonesia, Malaysia,Philippines, Hong Kong, and Singapore94% never-smokers; ~ 80% femaleMok TS, et al. N Engl J Med. 2009;361:947-957.IPASS: Importance of EGFR Mutation onPatient Outcome—Gefitinib vs ChemoN=1217
    68. 68. EGFR Mutation Positive EGFR Mutation NegativeTreatment by subgroup interaction test, P < .0001HR: 0.48 (95% CI: 0.36-0.64;P < .0001)Gefitinib events , n (%) 97 (73.5)C/P events, n (%) 111 (86.0)Gefitinib (n = 132)Carboplatin/paclitaxel (n = 129)HR: 2.85 (95% CI: 2.05-3.98;P < .0001)Gefitinib events, n (%) 88 (96.7)C/P events, n (%) 70 (82.4)0 4 8 12 16 20 2400.20.40.60.81.0ProbabilityofPFS0 4 8 12 16 20 2400.20.40.60.81.0ProbabilityofPFSGefitinib (n = 91)Carboplatin/paclitaxel (n = 85)Mos Mos Clinical characteristics are insufficient for selection of first-line EGFR TKI therapy Front-line EGFR TKI should be restricted to EGFR mutation–positive patientsMok TS, et al. N Engl J Med. 2009;361:947-957.IPASS: PFS in EGFR Mutation–Positive and–Negative Patients
    69. 69. EURTAC: Diseño del estudioPrimary endpoint• Progression-free survival (PFS)– interim analysis planned at 88 eventsSecondary endpoints• Objective response rate• Overall survival (OS)• Location of progression• Safety• EGFR mutation analysis in serum• Quality of life Chemonaїve Stage IIIB/IV NSCLC EGFR exon 19 deletion or exon 21L858R mutation ECOG PS 0–2(n=174)RPlatinum-based doubletchemotherapy q3wksx 4 cycles*PDErlotinib 150mg/day PDStratification• Mutation type• ECOG PS (0 vs 1 vs 2)Rosell et al. J Clin Oncol 29: 2011; (suppl; abstr 7503)*Cisplatin 75mg/m2 d1 / docetaxel 75mg/m2 d1;cisplatin 75mg/m2 d1 / gemcitabine 1250mg/m2 d1,8;carboplatin AUC6 d1 / docetaxel 75mg/m2 d1;carboplatin AUC5 d1 / gemcitabine 1000mg/m2 d1,81227 pts screened  224 mut +ive (17.6%)(50 pts not eligible)
    70. 70. Rosell R, et al. ASCO 2011. Abstract 7503.EURTAC: PFS Results (ITT) Significant PFS benefit with erlotinib vs chemotherapyErlotinib (n = 86)Chemotherapy (n = 87)HR: 0.37 (95% CI: 0.25-0.54;log-rank P < .0001)PFSProbability1.00.80.60.40.200 3 6 9 12 15 18 21 24 27 30 33Mos5.2 9.7Patients at Risk, nErlotinibChemo868763495420328215174937140202000
    71. 71. EURTAC: OS Results (ITT) Interim analysis (8/2/2010)Rosell R, et al. ASCO 2011. Abstract 7503.Erlotinib (n = 77; 35% with event)Chemotherapy (n = 76, 36% with event)HR: 0.80 (95% CI: 0.47-1.37)Log-rank P = .4170OSProbability1.00.80.60.40.200 3 6 9 12 15 18 21 24 27 30 39Time (Mos)Patients at Risk, nErlotinibChemo77766159534341353425221814141179322120059 patients in chemotherapyarm had a PFS event; 51 ofthese had second-linetreatment (EGFR TKI in 49)33 361210
    72. 72. Study EGFR TKISamplesizeResponserate (%)Median PFS(months)HRIPASS1 Gefitinib 261 71 vs 47 9.8 vs 6.4 0.48First-SIGNAL2 Gefitinib NR 85 vs 37 8.4 vs 6.7 NRWJTOC34053 Gefitinib 177 62 vs 31 9.2 vs 6.3 0.49NEJ0024 Gefitinib 198 74 vs 31 10.8 vs 5.4 0.30OPTIMAL5 Erlotinib 154 83 vs 36 13.7 vs 4.6 0.16EURTAC6 Erlotinib 174 58 vs 15 9.7 vs 5.2 0.371Mok et al NEJM 2009, 2Lee et al WCLC 2009, 3Mitsudomi et al Lancet Oncol 2010,4Maemondo NEJM 2010, 5Zhou et al ESMO 2010, 6Rosell et al ASCO 2011TKI en pacientes con mutaciones
    73. 73. LBA7500: LUX-Lung 3: A randomised, open-label, phase III study of afatinibversus pemetrexed and cisplatin as first-line treatment for patients withadvanced adenocarcinoma of the lung harboring EGFR-activating mutations –Yang JC et alPrimary endpoint• PFS*Central testing was performed for EGFR mutations(companion diagnostic TheraScreen EGFR RGQ PCRkit)Pemetrexed 500 mg/m2+ cisplatin 75 mg/m2every 21 days up to 6cycles (n=115)Daily afatinib 40mg(n=230)Key patient inclusion criteria*•Stage IIIB/IV•PS 0–1•Chemotherapy-naïve(n=345)Randomised, open-label, Phase III studyObjective: To investigate the efficacy and safety of afatinib compared withpemetrexed/cisplatin in patients with EGFR mutation positive advanced lungadenocarcinomaRYang et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7500)
    74. 74. Key efficacy data: PFSProgression-freesurvival(probability)1008060402000 3 6 9 12 15 18 21 24Progression-free survival (months)Afatinibn=230Cisplatin/pemetrexedn=115PFS event, n (%) 152 (66) 69 (60)Mean PFS (months) 11.1 6.9Hazard ratio(95% confidenceinterval)0.58 (0.43–0.78)p=0.0004AfatinibCisplatin/pemetrexed22%47%Yang et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7500)
    75. 75. ALK-Positive NSCLC andImpact of ALK InhibitionALK Rearrangementin NSCLC Rarely overlaps with EGFRand KRAS mutations Clinical testing– Break-apart FISH assay (FDA-approved test)– IHC– RT-PCRActivity of ALK Inhibitor Crizotinib in PatientsWith Advanced ALK-FISH–Positive NSCLC (N =82)Shaw AT, et al. ASCO 2011. Abstract 7507.
    76. 76. MET AMPGene Event Type Frequency, %FGFR1 Amplification 20-25FGFR2 Mutation 5PIK3CA Mutation 9PTEN Mutation deletion 18CCND1 Amplification 8CDKN2A Deletion/mutation 45PDGFRA Amplificationmutation9EGFR Amplification 10MCL1 Amplification 10BRAF Mutation 3DDR2 Mutation 4ERBB2 Amplification 2Emerging ―Druggable‖ Targets inNSCLC-Squamous SubtypeLung Cancer MolecularConsortiumLung AdenocarcinomasMutations found in 54% (280/516)Kris MG, et al. ASCO 2011. CRA7506. JohnsonBE, et al. IASLC WCLC 2011. Abstract O16.01Hammerman P, et al. IASLC WCLC 2011. AbstractPRS.1Potential ―Druggable‖ Molecular Targets?No MutationDetected KRAS22%EGFR17%NRASDoubleMutants 3%AKT1BRAF 2%MEK1HER2PIK3CA 2%EML4-ALK7%
    77. 77. Lung Cancer Mutation Consortium: 97% ofMutations Are Mutually ExclusiveKris MG, et al. ASCO 2011. Abstract CRA7506.# SingleMutationsALKALTBRAFEGFRHER2KRASMEK1METNRASPIK3CAALK (38) X 1 2 1 1AKT 1 (0) XBRAF (9) X 1EGFR (89) X 1 3HER2 (3) XKRAS (114) X 1 1MEK1 (2) X 1 1MET AMP(3)XNRAS (2) XPIK3CA (6) X
    78. 78. MolecularAdvanced-Stage NSCLC & PS 0-1EFGR mutation and ALK negativeand nonsquamous histologyEFGR mutation and ALKnegative and squamoushistologyBevacizumabappropriateBevacizumabinappropriateEGFR mutationpositiveErlotinib orgefitinibfirst lineConsider crizotinibfirst or second lineELM4-ALK positiveUpdated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.Proposed Treatment Algorithm for AdvancedNSCLC: First-line Therapy 2012Considercisplatin/pemetrexedOrcarboplatin/paclitaxel +bevacizumabConsidercisplatin orcarboplatincombined withdocetaxel orgemcitabine orpaclitaxelorcisplatin/vinorelbine± cetuximabConsidercisplatin or carboplatincombined withpemetrexed, docetaxelor gemcitabine orpaclitaxelorcisplatin/vinorelbine± cetuximabHistology: Clinical
    79. 79. META-ANÁLISIS: mantenimiento
    80. 80. Misma quimioterapiaSoon YY, et al. JCO 2009;27:3277-3283Effects HR (95% CI) p valueImproved PFS 0.75 (0.69-0.81) <.00001Improved OS 0.92 (0.86-0.99) .03
    81. 81. Switch y continuaciónBehera, et al. ASCO 2011 #7553Effects HR (95% CI) p valueImproved PFS 0.84 (0.80-0.88) <.0001Improved OS 0.87 (0.82-0.94) .0003SwitchImproved PFS 0.71 (0.66-0.77) <.0001Improved OS 0.86 (0.80-0.93) 0.00046ContinuaciónImproved PFS 0.92 (0.87-0.98) 0.007Improved OS 0.92 (0.77-1.08) 0.33
    82. 82. 13 estudios, incluyendo AVAPERL,PARAMOUNT, IFCT,…Chouahnia , et al. ASCO 2012; #e18003Effects HR (95% CI)Improved PFS 0.65 (0.58-0.73)Improved OS 0.85 (0.80-0.91)
    83. 83. ¿Quién se beneficia? Basado en respuestaEdelman 2012
    84. 84. ¿Quién se beneficia? Basado en respuestaEEHR SLPRespuestaHR SLPEEHR SGRespuestaHR SGJMEN NR NR 0.61 0.81PARAMOUNT 0.74 0.48 0.76 0.81IFCT(gemcitabina)0.68 0.44 NR 0.72
    85. 85. ¿Quién se beneficia? Según PSDesde inducción Desde mantenimientoKPS>80SGKPS<80SGKPS>80SGKPS<80SGBrodowitz 25 vs 12 m 10 m ambosbrazos22 vs 8 m 7 vs 7.7 mPS=0 PS=1IFTC(gemcitabina)0.65 0.97
    86. 86. Obasaju et al; Ann Oncol 2013;doi:10.1093/annonc/mdt123ItemsPérdida de apetitoFatigaTosDisneaDolorHemoptisisLSB: ASBI < 25HSB: ASBI > 25LSB: low symptom burdenHSB: high symptom burdenASBI: average symptoms burden index
    87. 87. LSBHSB
    88. 88. LSBHSB
    89. 89.  PS 2-3 después de la primera línea Volumen grande de lesiones diana (>7 cm) Disminución inferior al 20% con la primera línea¿Qué pacientes son los que no van a llegar a recibiruna segunda línea?Sun et al; J Thorac Oncol 2010;5:540-5
    90. 90. TKI vs PEMETREXEDOSSLPQi et al; Current Med Op&Res 2012;643-650
    91. 91. PARA CONCLUIR… Un porcentaje de pacientes no va a recibirtratamiento de segunda línea por rápidodeterioro/progresión El tratº de mantenimiento con quimioterapia ofrecela posibilidad de mantener un tratº activo hasta laprogresión
    92. 92. PARA CONCLUIR… Datos: apoyan mantenimiento en swicht y encontinuación Incremento en la SLP Incremento en SG discreto Diferentes opciones Mantenimiento: mejor en respondedores? Cambio: en pacientes con EE? Identificación de pacientes subsidiarios
    93. 93. PARA CONCLUIR… El tratamiento de mantenimiento con pemetrexedmejora significativamente la supervivencia global encomparación con placebo (HR 0.78) El perfil de toxicidad de pemetrexed fue similar alobservado en estudios anteriores, sin observarsediferencias en la calidad de vida de los pacientes

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