Magnitud del beneficio clínico en cáncer de pulmón. Bartomeu Massutí Hospital General Universitario Alicante

Transcripción

1 Magnitud del beneficio clínico en cáncer de pulmón Bartomeu Massutí Hospital General Universitario Alicante

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3 Contenido Comentarios terminológicos Beneficio vs costes; evaluación economica Resultados globales en cáncer de pulmón Estrategias tratamiento dirigido en cáncer de pulmón Evaluación beneficios terapias anti EGFR y anti ALK Impacto global del cáncer de pulmón Aprobación fármacos en cáncer de pulmon Conclusiones

4 Clinical benefit Google Scholar Clinical benefit: Clinical benefit cancer: Clinical benefit cancer lung: But really what does it means clinical benefit?

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6 Profundizando en el beneficio clínico Beneficio individual? Beneficio social? Costes? Coste oportunidad: implica consecuencia de elección; reflejo de las opciones no elegidas Definición del valor en cuidados de salud

8 Técnicas de evaluación económica Análisis Coste/Beneficio (ACB) Análisis Coste/Efectividad (ACE) (unidades objetivas) Análisis Coste/Utilidad (ACU) (unidades subjetivas) Fundamento ético de la eficiencia Valores individuales, base de los valores sociales Utilitarismo, base de la evaluación económica Variables Costes: Coste de oportunidad Efectos: Cambios en el estado de salud: Beneficio? Relación Coste Efecto: El ACB y el ACE

9 Análisis coste/beneficio Evaluación de acciones alternativas en términos de sus consecuencias, con el fin de maximizar los beneficios sociales netos del uso de los recursos, o el bienestar social Un proyecto debe llevarse a cabo si y sólo si sus beneficios sociales exceden a los costes sociales, es decir, si su beneficio social neto es positivo VAN = [( Bi Ci ) /(1 + d)i ]

11 Datos epidemiológicos Europa EU 27: Mortalidad total cáncer: Hombres: Mujeres: Mortalidad cáncer pulmón: Hombres: Mujeres: J. Ferlay et al. / European Journal of Cancer 49 (2013) M.Malvezzi et al / Ann Oncology 2013; doi: /annonc/mdte010 De Angelis:Lancet Oncol (13)

12 Evolución mortalidad hombres/mujeres

13 Los costes del cáncer en Europa: 126 billones (40% asistencia sanitaria) Lancet Oncol 2013; 14:

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17 Quimioterap. plateau 1 Evolución terapéutica en Cáncer Pulmón avanzado: S XXI Segunda línea terapéutica 1L Bevacizumab + CP vs CP 3 1L CPem vs CG 4 1LM swicht Pem vs placebo 5 1L Erlotinib EGFR MUT+ 6 1L Gefitinib vs CP en EGFR MUT+ 7 1L Erlotinib vs QT EGFR Mut 1LM Cont Pem vs Plac / M Pem_Bev Crizotinib ie ALK + 1LM Erlotinib vs placebo CP = carboplatin paclitaxel CPem = cisplatin pemetrexed CG = cisplatin gemcitabine 1. Schiller, et al. NEJM 2002; 2. Sheppard, et al. NEJM 2005; 3. Sandler, et al. NEJM Scagliotti, et al. JCO 2008; 5. Ciuleanu, et al. Lancet 2009; 6. Rossell, et al. NEJM Mok, et al. NEJM 2009; 8. Cappuzzo, et al. Lancet Oncol 2010; 9. Sandler, et al. JTO 2010

18 Evolution of lung cancer classification over time M Reck, DF Heigener, T Mok, JC Soria, KF Rabe, 2013

19 Mutation driven therapy presently benefits only a subgroup of the overall population BIOMARKERS FRANCE: driver mutations in 10,000 patients with non-squamous NSCLC Of the alterations detected, only EGFR Mut and EML4-ALK can currently be targeted therapeutically Results expressed in % on available analyses Barlesi, et al. ASCO 2013

20 El impacto y las limitaciones de los tratamientos dirigidos sobre dianas JAMA. 2014;311(19): doi: /jama

22 Mutaciones de EGFR Exon G719X % P-loop Deleciones % Hélice C Inserciones % Dominio T790M quinasa L858R 42.7% 21 A-loop K Mitsudomi, et al. Int J Clin Oncol 2006; Riely, et al. Clin Cancer Res 2006

23 EGFR mutations IPASS: SUPERVIVENCIA LIBRE DE PROGRESIÓN Probabilidad de SLP POBLACIÓN GLOBAL 5.8 m 5.7 m Months At risk : Gefitinib Carboplatin / At risk : paclitaxel Gefitinib Probability of progression free survival MUTACIÓN EGFR POSITIVA Gefitinib (n=132) Carboplatino / paclitaxel (n=129) Months HR (95% CI) = ( ) p< HR (95% CI)= 0.48 ( ) P< Primary Cox analysis with covariates HR <1 implies a lower risk of progression on gefitinib Mok T. et al. NEJM 2009 Sep 3;361(10):

24 Mutaciones de EGFR NEJ002 OPTIMAL WJTOG3405 ICOGEN Zhu et al. Lancet Oncol 2011 Mitsudomi T et al. Lancet Oncol Shi Y et al. Lancet Oncol maemondo et al NEJM 2012

25 Mutaciones de EGFR

26 EGFR M+ NSCLC Presence of EGFR mutation (M+) defines a distinct subtype of NSCLC, sensitive to EGFR TKIs 1 : Common sensitizing mutations (Del19, L858R) account for ~ 90% of cases EGFR TKIs are standard first line treatment in EGFR M+ NSCLC, showing improved PFS and ORR in 7 randomized trials 2 8, but no difference in OS vs platinum doublet chemotherapy 8 15 Trial PFS HR OS HR EURTAC Erlotinib 0.47 (0.28, 0.78) ind 0.93 (0.64, 1.35) OPTIMAL Erlotinib 0.16 (0.10, 0.26) inv 1.04 (0.69, 1.58) ENSURE Erlotinib 0.42 (0.27,0.66) ind n/a IPASS Gefitinib 0.48 (0.36, 0.64) inv 1.00 (0.76, 1.33) NEJ002 Gefitinib 0.30 (0.22, 0.41) ind 0.89 (0.63, 1.24) WJTOG3405 Gefitinib 0.49 (0.34, 0.71) inv 1.25 (0.88, 1.78) FIRST SIGNAL Gefitinib 0.54 (0.27, 1.1) inv 1.04 (0.50, 2.18) 1. NCCN Guidelines: Non-Small Cell Lung Cancer. V ; 2. Mok et al. N Engl J Med. 2009;361:947; 3. Maemondo et al. N Engl J Med. 2010;362:2380; 4. Mitsudomi et al. Lancet Oncol. 2010;11:121; 5. Rosell et al. Lancet Oncol. 2012;13:239; 6. Zhou et al. Lancet Oncol. 2011;12:735; 7. Wu et al. J Thorac Oncol. 2013;8:suppl 2 (P ); 8. Han et al. J Clin Oncol. 2012;30:1122; 9. Fukuoka et al. J Clin Oncol. 2011;29:2866; 10. Yang et al. Eur J of Cancer (suppl1;s633); 11. Inoue et al. Ann Oncol. 2013;24:54; 12. Mitsudomi et al. J Clin Oncol. 30, 2012 (suppl; ab7521); 13. TARCEVA (erlotinib) prescribing information, 2013; 14. Zhou et al. J Clin Oncol. 30, 2012 (suppl; ab7520); 15. Yoshioka H, et al. ASCO 2014, abstract 8117

27 LUX Lung 3+6: Combined OS analysis: common mutations (n=631) Estimated OS probability Afatinib n=419 Chemo n=212 Median, months HR (95%CI), p-value 0.81 ( ), p= No of patients Afatinib Chemo Time (months) Presented by: James Chih Hsin Yang

28 Combined OS analysis: mutation categories Del19 L858R 1.0 Afatinib n=236 Chemo n=119 Median, months Afatinib n=183 Chemo n=93 Median, months Estimated OS probability HR (95%CI), p-value 0.59 ( ), p= Estimated OS probability HR (95%CI), p-value 1.25 ( ), p= Time (months) No of patients Afatinib Chemo Time (months) No of patients Afatinib Chemo Presented by: James Chih Hsin Yang

29 Posible impacto poblacional terapias anti EGFR POBLACIÓN GLOBAL 18.1 m 12.5 m EGFR M m 27.2 m EGFR M m 13.2 m Takano T et al JCO 2008

30 Efectos secundarios: Calidad de Vida Los pacientes que reciben un ITK frente a EGFR tienen una mejoría significativa en Calidad de Vida. IPASS study La quimioterapia se asocia a una mayor tasa de toxicidad grado 3-4, más eventos adversos serios asociados al tratamiento, mayores reducciones de dosis y discontinuación del tratamiento. OPTIMAL study Mok et al.nejm 2009 Zhou et et al. Lancet Oncol

31 Modelización análisis económico 1ª línea anti EGFR / ASCO ) first line erlotinib vs. first line chemotherapy 2) first line erlotinib and mixed second line treatments vs. first line chemotherapy and second line erlotinib. First line treatment with erlotinib vs. chemotherapy resulted in an increase of 0.60 life years or 0.44 quality adjusted life years (QALYs). 1) Mean total costs were $59,300 in the erlotinib arm and $17,800 in the chemotherapy arm, yielding an incremental cost effectiveness ratio (ICER) of $98,338 with a 53% probability of being cost effective at a willingness to pay (WTP) of $100,000/QALY 2) ICER was $50,002/QALY, with a 66% probability of being cost effective. The main cost drivers in the model were the time spent in the PFS health state and drug costs. Conclusions: Treatment with erlotinib in first line EGFR positive NSCLC results in increased costs but also substantial increases in QALYs, demonstrating that this personalized approached to treatment may be cost effective.

32 EURTAC: Cost-utility calculation (France) Euros 2012 Mean Cost of first line treatment 1 st line erlo 1 st line chemo Difference 28,491 10,773 17,717 95% CI (25,441.76;31,946.42) (9,743.85;12,277.38) (14,526.33;20,933.25) Cost of Erlotinib ,00 Administration Cost of Erlotinib 326,46 0,00 Cost of Chemo Doublet 0, Administration Cost of Chemo Doublet 0, Mean cost of progression after 1st line 38,947 66,163 27,216 95% CI (33,853; 44,865) (58,805; 75,127) ( 36,676; 17,961) Mean Supportive Care Cost Mean Total Cost 67,438 76,937 9,498, 95% CI (62,181; 73,295) (69,224; 86,140) ( 18,832;269) Mean total QALYs % CI (0.95;1.24) (0.83;1.11) ( 0.06;0.31) Cost per QALY Gained NEGATIVE 32

33 Cost savings in one way sensitivity analysis Survival follow up Time horizon 1 year +4 years Cost of Supportive Care 20% +20% Cost of Administration 1st line % +20% Cost of Chemotherapy % +20% Cost of Erlotinib +20% 20% Cost savings of Erlotinib versus chemo first line O16: Economics TKIs A Vergnenegre

34 Results: scatter plot of ICER, probability to be under = 90.2% % Incremental Cost ,50 0,00 0,50 1,00 1,50 2, Incremental QALY 9.6% % Erlotinib versus chemo first erlotinib versus chemo first line 34 O16: Economics TKIs A Vergnenegre

35 Incremental cost/utility ratio according to the 3 countries France Italy Spain Cost difference -9,498-7,806-7,466 Utility difference ICER negative negative negative 35 O16: Economics TKIs A Vergnenegre

36 Translocación de ALK Cromosoma 2p32.2 Proteina transmembrana con actividad TK En adultos, la expresión normal se limita al sistema nervioso Grande E et al. Mol Cancer Ther 2011 Bai et al. Mol Cell Biol 1998 Mossé et al. CCR 2009.

37 Translocación de ALK TPM4 TFG NPM ALK MSN ATIC EML4 CLTC KIF5B Soda et al Nature 2007 Rivoka et al Cell 2007 Choi et al Cancer Res 2008 Takeuchi CCR 2009

38 Fase I Crizotinib en translocación ALK: Fase I respuesta N=133 TRO (95% CI) 60.8% (52 68) Duración media de la respuesta 49 sem Tiempo medio de respuesta 8 sem Tasa de control de la enf sem 8 y %, 70.6% Camidge et al. The Lancet Oncol 2012; 13:

39 Fase I Fase I Crizotinib: SLP SUPERVIVENCIA LIBRE DE PROGRESIÓN SLP mediana = 9.7 meses (95% CI: 8.2, 14.7) 50 eventos (42%; 40 eventos PE) 69 pacientes (58%) censurados, 59/69 (86%) en el seguimiento por SLP Camidge et al. The Lancet Oncol 2012; 13:

40 Subgrupo Fase I: Crizotinib 1ª línea Study 1001: PFS with First line Crizotinib (n=24) Median PFS=18.3 months (95% CI: 8.3 not reached) 60 PFS (%) Censored patients 95% Hall Wellner band 40 No. at PFS time (months) risk Camidge DR, et al. Lancet Oncol 2012;13: [Supplementary Material]

41 Fase I Crizotinib: Supervivencia global Fase I SUPERVIVENCIA GLOBAL Supervivencia Global NO ALCANZADA Supervivencia Global a 1 a 87.4% Supervivencia Global a 2 a 74% Shaw et al. Lancet 2011

42 Crizotinib vs QT 2ª línea PROFILE 1007 ( 347) ALK + 1 línea de QT previa Basada en platino Pemetrexed 500 mg/m2 o Docetaxel 75 mg/m2 A cada 21 días Crizotinib 250 mg/12h Objetivo Principal: SUPERVIVENCIA LIBRE DE PROGRESIÓN Shaw et al NEJM 2013

43 Crizotinib vs QT 2ª línea: RR PROFILE 1007 Crizotinib (173) Quimioterapia (174) Supervivencia Libre de Progresión 3 m 2.6 m 7.7 m 4.2 m 7.7 m RESP. 1 (1%) 0 (0%) COMPLETA RESP. PARCIAL 112 (65%) 34 (20%) EN. ESTABLE 32 (18%) 63 (36%) PROGRESIÓN 11 (6%) 60 (34%) NO EVALUABLE 17 (10%) 17 (10%) TRO 65% frente 20% TCE 94% frente 66% Shaw et al NEJM 2013

44 PROFILE 1007 Crizotinib vs QT 2ª línea: CDV CALIDAD DE VIDA Cambio en Calidad de Vida desde la basal Tiempo hasta el deterioro en Calidad de Vidad Shaw et al NEJM 2013

45 Mean Change from Baseline Efecto Crizotinib en síntomas y CDV PROFILE CALIDAD DE VIDA Clinically meaningful improvement in QOL Global QOL Mean Change from Baseline Fatigue Cough Dyspnea Clinically meaningful improvement in symptoms 25 p Kim et al Abst 7533 ASCO 2012 Cycle

46 Modelización efecto Crizotinib en Supervivencia La Supervivencia Global pacientes ALK + es superior en los pacientes tratados con crizotinib. Los pacientes ALK + no tratados con crizotinib tienen un pronóstico similar a los pacientes wild type. Shawn et al. Lancet 2011

47 Evaluación coste beneficio Crizotinib February 24, 2014 as /JCO

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50 Value based pricing: wider considerations There is a basic NHS cost per QALY threshold Costs and QALYs (through weighting) to take into account: diseases with greater burden of illness as reflected in QALY loss from a condition greater therapeutic innovation and improvement (size of QALY gain) wider societal benefits (e.g. productivity and carer time) Basic threshold adjusted to reflect the opportunity cost of displaced activities weighted using same methods Price negotiated on the basis of the cost per weighted QALY compared to the new threshold (from 2014)

51 Elicitation of societal preferences Discrete choice experiment (DCE) survey using online UK panel to elicit societal preferences for: Burden of illness (QALY loss from condition) Therapeutic improvement (size of QALY gain from treatment) End of life (e.g. NICE weights QALY gain more where expected survival is 24 months and survival gain 3 months or more)

52 Overview of results Regression results: QALYs matter but at a decreasing rate no support for TI BOI matters but is weak and inconsistent EOL is significant Coefficients change for different variants of normal life expectancy

53 Weights for BOI Model (1): Assuming the value of a QALY is constant MRS (1) of 1 more unit of BOI is QALYs Model (2) Allowing value of a QALY to vary Warning: This is additive and not proportionate to the size of QALY gain QALY gain MRS (2)

54 A Coordinated Cancer Care Team 22

56 Aprobaciones FDA en CBP g y p g pp Drug Trial Design Approval Endpoints First-Line Inoperable/Metastatic NSCLC Vinorelbine monotherapy Open-label, randomized, active-controlled trial vs. 5FU/leucovorin OS, ORR Vinorelbine in combination with cisplatin Open-label, randomized, active-controlled trial vs. cisplatin OS, ORR Docetaxel in combination with cisplatin Open-label, randomized, active-controlled trial, docetaxel/cisplatin vs. OS, TTP, ORR vinorelbine/cisplatin Gemcitabine in combination with cisplatin (1) Open-label, randomized, active-controlled trial vs. gemcitabine (2) Open-label, randomized, active-controlled trial, gemcitabine + cisplatin vs. etoposide + cisplatin OS TTP, ORR Bevacizumab in combination with Open-label, randomized, active-controlled trial vs. paclitaxel/ carboplatin OS paclitaxel/carboplatin 1 Paclitaxel in combination with cisplatin Open-label, active-controlled, dose-ranging, randomized, three-arm trial, paclitaxel (135 mg/m 2 )/cisplatin vs. paclitaxel (250 mg/m 2 )/cisplatin vs. TTP, ORR, OS Pemetrexed in combination with cisplatin 1,2,3 Maintenance Therapy Pemetrexed in patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy 1 Erlotinib in patients whose disease has not progressed after four cycles of platinum-based etoposide/cisplatin Open-label, active-controlled, randomized trial; pemetrexed/cisplatin vs. gemcitabine/cisplatin Randomized, double-blind, placebo-controlled trial Randomized, double-blind, placebo-controlled trial first-line chemotherapy Second-Line NSCLC Docetaxel Randomized, placebo-controlled trial, docetaxel vs. best supportive care OS, TTP, ORR Erlotinib Randomized, placebo-controlled trial, erlotinib vs. best supportive care OS, TTP, ORR Pemetrexed 1,2 Randomized, open-label trial vs. docetaxel Durable ORR, Decreased Toxicity Third-Line NSCLC Erlotinib Randomized, placebo-controlled trial Erlotinib vs. best supportive care OS, TTP, ORR Gefitinib 2,4 Single-arm trial Durable ORR Partially or Completely Obstructing Endobronchial Tumor NSCLC and Microinvasive Endobronchial NSCLC in Nonsurgical Candidates Porfimer sodium and photodynamic therapy Randomized, open-label, active-controlled trial vs. YAG laser Improvement in disease-related symptoms 1 OS OS OS

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58 Trends in end points and outcomes in NSCLC Trials Sacher A: Published Ahead of Print on March 3, 2014 as /JCO

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60 Desafíos y riesgos integración biomarcadores en EC y en práctica clínica Lancet Oncol 2014; 15: e184 93

61 Ceritinib en pacientes pretratados con Crizotinib y translocación ALK: Fase I N Engl J Med 2014;370: DOI: /NEJMoa

62 Respuesta y SLP con Ceritinib N Engl J Med 2014;370: DOI: /NEJMoa

63 Ramucirumab Docetaxel vs Placebo Docetaxel 2nd line Ph III REVEL The Lancet Published Online June 2, S (14)60845 X

64 Ramucirumab Docetaxel vs Placebo Docetaxel 2nd line Ph III REVEL The Lancet Published Online June 2, S (14)60845 X

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67 Rossi A, Cancer treat Rev, 2013

68 Conclusiones Alto impacto socio económico del cáncer de pulmón Cáncer de pulmón área de investigación prioritaria en cáncer La evaluación coste beneficio y coste eficiencia en cáncer de pulmón moduladas por impacto de la enfermedad y baja supervivencia Supervivencia y CDV factores determinantes para definición beneficio Limitaciones EE CC clásicos para evidenciar beneficios en tratamientos individualizados. Criterios específicos de evaluación e implicaciones éticas para subpoblaciones minoritarias; consideración cribado Valor y precio de los fármacos determinantes en la evaluación económica Alianzas sociales

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