SESIÓN CONTROVERSIAS 7 Cáncer de Pulmón: Nuevos Fármacos SESIÓN CONTROVERSIAS 7 Cáncer de Pulmón: Nuevos Fármacos. Cuándo Usarlos Moderador: Dr. José Luis González Larriba. Hospital Clínico Universitario San Carlos. Madrid ·Sólo 2ª línea: Dra. Mª Pilar Lianes Barragán. Hospital de Mataró. Barcelona ·También en 1ª línea: Dr. Javier de Castro Carpeño. Hospital Universitario La Paz. Madrid CONCLUSIÓN: Dr. José Ramón Pérez Carrión. Hospital Quirón. Madrid

Dra. Mª Pilar Lianes Barragán Hospital de Mataró. Barcelona Sólo 2ª línea Dra. Mª Pilar Lianes Barragán Hospital de Mataró. Barcelona

QUÉ ES UNA CONTROVERSIA? (Del lat. controversĭa). 1. f. Discusión de opiniones contrapuestas entre dos o más personas. 2. f. Cuba. contrapunteo (‖ desafío en que se cantan versos improvisados). Situación de la que me había librado hasta ahora ¡¡¡¡¡¡ sin ~. 1. loc. adv. sin duda. Situación de la que me había librado hasta ahora?

Mujer con adenocarcinoma de pulmón estadio IV, sin mutación 1. Tratamiento de primera línea : lo esperable... 2. Por qué no añadir bevacizumab de entrada ? 3. Tratamiento de segunda línea : opciones

Phase III trial of Avastin in NSCLC (E4599): trial design CP  6 (n=444) PD* Previously untreated stage IIIb/IV non-squamous NSCLC (n=878) Avastin (15mg/kg) every 3 weeks + CP  6 (n=434) Avastin every 3 weeks until progression PD Primary endpoint: overall survival Avastin 15mg/kg i.v. administered every 3 weeks Carboplatin i.v. to AUC 6mg/mL and paclitaxel 200mg/m2 i.v. every 3 weeks Patients in the Avastin plus CP arm received single-agent Avastin until disease progression Last updated: December 15, 2006 E4599 was a randomised, phase III trial of CP with or without Avastin in patients with previously untreated advanced (stage IIIb/IV) NSCLC.1 In this trial, 878 patients were randomised to one of two arms: CP alone or CP plus Avastin 15mg/kg every 3 weeks. Patients received paclitaxel 200mg/m2 i.v. every 3 weeks with carboplatin i.v. to AUC 6mg/mL every 3 weeks for a total of 6 cycles unless there was evidence of disease progression or patient intolerance. Patients were not allowed to cross over from the CP-alone arm to receive Avastin in this phase III study. Patients in the CP plus Avastin arm continued to receive single-agent Avastin until disease progression or unacceptable toxicity. The primary study endpoint was overall survival. NSCLC = non-small cell lung cancer; CP = carboplatin/paclitaxel; PD = progression of disease; i.v. = intravenous Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–50. *No cross over permitted Sandler, et al. NEJM 2006

Phase III trial of Avastin in NSCLC (E4599): subgroup analyses Avastin was associated with a survival benefit in all the subgroups assessed, with the possible exception of women The effects of Avastin on survival and progression-free survival were consistent among all prespecified stratification groups measurable versus non-measurable disease prior RT versus no prior RT prior weight loss <5% versus ≥5% stage IIIb with pleural effusion versus stage IV or recurrent disease Last updated: December 15, 2006 The treatment effects of Avastin on survival and progression-free survival were consistent across the four stratification groups (measurable versus non-measurable disease, prior RT versus no prior RT, prior weight loss <5% versus ≥5% and stage IIIb with pleural effusion versus stage IV or recurrent disease). NSCLC = non-small cell lung cancer; RT = radiotherapy Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–50. Sandler, et al. NEJM 2006

Phase III trial of Avastin in NSCLC (E4599): survival treatment hazard ratios in subgroups Last updated: December 15, 2006 Non-prespecified, exploratory analyses of survival and progression-free survival were performed for the following subgroups of patient baseline characteristics: age, gender, ethnicity, performance status, number of metastatic sites and site of metastases. Avastin was associated with a survival benefit in all subgroups, with the possible exception of women; the median overall survival in the Avastin plus CP arm and the CP arm was 11.7 and 8.7 months, respectively, among men and 13.3 and 13.1 months, respectively, among women. ***NOTE: In the print version of the NEJM manuscript, the values for overall survival are reported incorrectly for the gender subgroup analysis (for both men and women, the values for overall survival in the Avastin plus CP arm and the CP alone arm are inverted). However, the online version of the manuscript reports the correct values.*** NSCLC = non-small cell lung cancer; PS = performance status; RT = radiotherapy; CP = carboplatin/paclitaxel Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–50. Sandler, et al. NEJM 2006

Diferencias por género :posibles explicaciones Avastin fue beneficioso en todos los subgrupos, con la posible excepción de la supervivencia global en mujeres Superv.global (meses) CP CP + Avastin Hombres 8.7 11.7 Mujeres 13.1 13.3 Posibles explicaciones para este hallazgo : desequilibrio entre ambos grupos respecto a factores pronósticos basales, conocidos o desconocidos desequilibrio en el uso de 2ª y 3ª líneas de tratamiento (OS mide todas las lineas) hubo mas mujeres que recibieron 2ªs lineas de tratamiento en el brazo de CP-solo que en brazo de Avastin + CP sin embargo, no hubo diferencias entre brazos en el numero de mujeres que recibieron EGFR TKIs en 2ª línea artefacto estadístico diferencias reales en relación al sexo. Last updated: December 15, 2006 Avastin was associated with a survival benefit in all subgroups, with the possible exception of women.1 In women, the hazard ratio for death was 0.98 (p=0.87)2. However, it is important to note that explorative subgroup analyses are only hypothesis generating and cannot support treatment decisions subgroup analyses are limited by small sample sizes this could be a chance finding; the exploratory analyses were not powered to reveal efficacy differences between patient subgroups the authors propose several other potential explanations for this finding, including imbalances in baseline prognostic factors or imbalances in the use of second- or third-line therapies; more women in the chemotherapy-alone arm received second-line chemotherapy than in the Avastin arm Avastin did significantly increase PFS (HR=0.71; p=0.002) and response rate (from 14% to 41%; p<0.001) in women, arguing in favour of an overall benefit from the addition of Avastin2 since these were exploratory analyses, a survival benefit for Avastin added to platinum-based chemotherapy cannot be ruled out randomised trials will provide further insight into this issue (the phase III BO17704 trial will provide an opportunity to further investigate efficacy in gender subgroups). In future Avastin studies, Roche may stratify by gender to investigate this issue. NSCLC = non-small cell lung cancer; CP = carboplatin/paclitaxel; EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–50. Brahmer JR, Gray R, Schiller JH, et al. ECOG 4599 phase III trial of carboplatin and paclitaxel ± bevacizumab: subset analysis of survival by gender. J Clin Oncol 2006;24(June 20 Suppl):373s (Abstract 7036). Sandler, et al. NEJM 2006 Brahmer, et al. ASCO 2006

AVAiL: first-line phase III trial of Avastin plus chemotherapy in NSCLC CG  6 + placebo PD No Avastin after progression Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC (n=1,050) CG  6 + Avastin 7.5mg/kg every 3 weeks PD CG  6 + Avastin 15mg/kg every 3 weeks PD Cisplatin 80mg/m2 i.v. every 3 weeks; gemcitabine i.v. 1,250mg/m2 on days 1 and 8 of each 3-week cycle. Primary endpoint: progression-free survival. Secondary endpoints: overall survival, time to treatment failure, response rate. Recruitment completed; final results expected Q1/Q2 2007. CG = cisplatin/gemcitabine

solo2o sólo. adv. m. Únicamente, solamente. “En el juego del hombre y otros de naipes, lance en que se hacen todas las bazas necesarias para ganar, sin ayuda de robo ni de compañero “

Qué es Segunda línea? Fármaco que se aplica después de la primera? Cuando la enfermedad progresa Cuando la enfermedad esta estable? Por qué cada ensayo establece criterios diferentes?

Paradigmas de la Investigación Clínica Oncológica la utilidad de los NF siempre la buscamos tratando a pacientes que hayan fracasado al menos a una primera línea de tratamiento. " cuánto antes mejor". Es decir que los tratamientos que han demostrado su utilidad en la enfermedad refractaria , han de ser más útiles si los utilizamos en primera línea

Tarceva and Iressa phase III combination trials in advanced NSCLC INTACT I: gefitinib + gemcitabine/cisplatin No difference in OS vs chemotherapy INTACT II: gefitinib paclitaxel/carboplatin 2001 2002 2003 2004 2005 TALENT: Tarceva + gemcitabine/cisplatin Talking points Combination therapy in first-line setting: phase III data (TALENT, TRIBUTE, INTACT-1 and -2) Briefly highlight that although the trials were not positive for the overall patient populations, there was a dramatic improvement in survival for the non-smoker subgroup in the Tarceva TRIBUTE trial (to be discussed in more detail in the later presentation by Dr Pérez-Soler). All patients: no difference in OS vs chemotherapy TRIBUTE: Tarceva + paclitaxel/carboplatin

INTACT 1 Giaconne JCO 2004, 22:777-784 R n 1.093 CDDP+Gem x6c + Placebo CDDP+Gem x6c + Iressa 500 mg CDDP+Gem x6c + Iressa 250 mg RR 44.8% 49.7% 50,3% NS TTP 6 m 5,5 m 5,8 m 0.76 OS 10,9 m 9.9 m 9,9 m 0.45 Iressa con CDDP y Gemzar NO mejora la eficacia en primera línea de NSCLC

JCO 2004;22:785-794 n 1.037 R CARBO+Taxol + Placebo CARBO + Taxol + Iressa 500 mg + Iressa 250 mg RR 28,7% 30% 30,4% NS TTP 5,0 m 5,6 m 5,3 m 0.56 OS 9,9 m 8,7 m 9,8 m 0.64 Iressa con CARBO + Taxol NO mejora la eficacia en primera línea de NSCLC

INTACT 2 : Survival in Adenocarcinoma Of the patients with adenocarcinoma who received chemotherapy for at least 90 days, those in the gefitinib treatment groups tended to have a longer survival time than those in the placebo group. Roy Herbst et al. JCO 2004

JCO 2005;23:5892-5899 n 1.059 R CARBO + Taxol TARCEVA 150 mg/d CARBO + Taxol PLACEBO RR 21,5% 19,3% p=0,36 TTP 5,1 m 4,9 m OS 10.6 m 10.5 m p=0,95 Tarceva con CARBO + Taxol NO mejora la eficacia en primera línea NSCLC

A randomized phase III trial comparing bexarotene/cisplatin/vinorelbine versus cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small cell lung cancer (NSCLC) Jassem, J (SPIRIT I) Negativo Los pacientes que desarrollan hipertrigliceridemia rápida (en 1 semana) responden más, con mejoría en la supervivencia (31%) A randomized phase III trial comparing bexarotene/carboplatin/paclitaxel versus carboplatin/paclitaxel in chemotherapy-naive patients with advanced or metastatic non small cell lung cancer Blumenschein GR (SPIRIT II) Negativo Los pacientes que desarrollan hipertrigliceridemia responden (p= 0.0002)

De la investigacion realizada se deduce........ 2 +1 = 2

Second-line treatment options Chemotherapy Docetaxel Pemetrexed Targeted therapy Tarceva Gefitinib Other options Best supportive care (BSC) Clinical trial

Median survival for patients with PS 0/1 in the second-line setting 10 8 6 4 2 9.4 9.4 9.1 Median survival (months) Docetaxel Pemetrexed Tarceva Ramalingam S, Sandler AB. Oncologist 2006;11:655–65

Erlotinib in previously treated non-small-cell Lung cancer Shepherd MD, Pereira JR, Ciulenau T, et al. NEJM 2005, 353:123-132 n 753 R 2:1 TARCEVA 150 mg/d PLACEBO RR 8,9 % 1 % p<0,001 TTP 2,2 m 1,8 m OS 6,7 m 4,7 m Erlotinib prolonga la supervivencia en tratamiento de segunda o tercera de NSCLC tras quimioterapia: Mujer ®, Adenocarcinoma, No fumador, Asiatico

Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung carcinoma: results from a randomised, placebo-controlled, multicenter study (Iressa Survival Evaluation in Lung Cancer Thatcher N, Chang A, Parikh P, et al LANCET 2005;366:1527-1537 n 1692 R 2:1 IRESSA 250 mg/d PLACEBO RR 8% 1,3% p=.0001 TTP 3,0 m 2,6 m p=.0006 OS 5,6 m 5,1 m p= 0.08

BR.21: overall survival in females with adenocarcinoma (second-line) Median OS (months) Tarceva (n=50) 11.8 Placebo (n=26) 3.9 1.00 0.75 0.50 0.25 Survival probability HR=0.412 (95% CI: 0.234–0.724) RR=19.0% 0 6 12 18 24 Survival (months) OSI Pharmaceuticals and F. Hoffmann-La Roche; data on file

BR.21: overall survival according to gender Male: HR=0.8; p=0.01* Female: HR=0.8; p=0.13* HR *Log-rank test 0.5 1 1.00 0.75 0.50 0.25 1.00 0.75 0.50 0.25 Female RR=14.4% Male RR=6.0% Tarceva (n=173) Tarceva (n=315) Survival distribution function Placebo (n=83) Placebo (n=160) 0 5 10 15 20 25 0 5 10 15 20 25 30 Time (months) Time (months) Shepherd FA, et al. N Engl J Med 2005;353:123–32

Docetaxel vs. Pemetrexed vs. Erlotinib Toxicidad Incidencia (%) Docetaxel 75 mg/m2 (n=176) Pemetrexed (N=265) Erlotiniba (n=485) Hematológicos Neutropenia Todos los grados 84 11 No se cita Grado 3 ó 4 65 5 Leucopenia 13 49 Anemia 91 33 9 8 a: monoterapia para CPCNP localmente avanzado irresecable o metastásico previamente tratado con quimioterapia basada en platino. Ramalingam & Sandler, 2006. The Oncologist; 11(6): 655-65.

Docetaxel vs. Pemetrexed vs. Erlotinib Toxicidad Incidencia (%) Docetaxel 75 mg/m2 (n=176) Pemetrexed (N=265) Erlotiniba (n=485) Gastrointestinal Anorexia No se cita 62 52 Diarrea Todos los grados 23 21 54 Grado 3 ó 4 8 <1 7 Rash cutáneo 20 17 75 9 Astenia 87 Disnea 41 72 Ramalingam & Sandler, 2006. The Oncologist; 11(6): 655-65.

Docetaxel vs. Pemetrexed vs. Erlotinib Esquema de Tratamiento Frecuencia Cada 3 semanas Diaria Vía de administración i.v. durante 1 hora i.v. durante 10 minutos Oral, al menos 1 hora antes ó 2 horas después de las comidas Premedicación o medicación concomitante Corticosteroide oral Dexametasona oral. Ácido fólico. Vitamina B12 i.m. Ninguna Ramalingam & Sandler, 2006. The Oncologist; 11(6): 655-65.

TITAN-SLS: Tarceva in treatment of advanced NSCLC: second-line setting Screening Period Tumour samples Stage IIIb/IV NSCLC four cycles of a first-line standard platinum-based doublet EGFR protein expression (IHC), mutations etc. SATURN Progression No progression Randomisation with stratification N=648 Study Period Tarceva 150mg/day Pemetrexed or docetaxel Until PD, death or unacceptable toxicity Until PD, death or unacceptable toxicity

SIGN study design Gefitinib vs docetaxel in 2nd-line NSCLC Multicenter, international, parallel-group, randomized (1:1 ratio) open-label phase II study 141 patients randomized from 25 centers in 12 countries (Mexico, Venezuela, Colombia, Uruguay, Panama, Guatemala, Slovenia, Croatia, Israel, Egypt, Latvia, Estonia) Primary endpoint Symptom improvement Secondary endpoints Quality of life Objective response rate Disease control rate Overall survival Safety Patients Stage IIIb / IV NSCLC Progressed on or after prior CT WHO PS 0-2 n=141 Gefitinib 250 mg/day Docetaxel 75 mg/m2 every 3 weeks CT, chemotherapy; WHO, World Health Organization; PS, performance status; Cufer et al 2006

SIGN: survival and tumor response Proportion surviving 1.0 Median, months Gefitinib Docetaxel 7.5 7.1 0.8 0.6 0.4 0.2 HR 0.97; 95% CI 0.61, 1.52; p=0.88 0.0 Time (months): 2 4 6 8 10 12 14 16 At risk: 141 114 93 75 41 20 5 Similar ORRs (~13%) and DCRs (~60%) with gefitinib and docetaxel HR, hazard ratio; CI, confidence interval; ORR, objective response rate (CR+PR); DCR, disease control rate (CR+PR+SD) Cufer et al 2006

Post-study treatments Gefitinib BSC or continue gefitinib 40% Docetaxel* 36% Other chemotherapy only 24% Docetaxel BSC or continue docetaxel 26% Gefitinib* 53% Other chemotherapy only 20% *Patients may have also received other chemotherapy BSC, best supportive care

Cost-effectiveness studies for second-line therapies Docetaxel cost-effective versus BSC (Canada, UK)1,2 Pemetrexed cost-effective versus docetaxel (UK)3 Tarceva cost-effective versus BSC (Canada, The Netherlands)4,5 cost-saving versus docetaxel (Germany, The Netherlands, Poland, Spain, UK)4,6–9 cost-saving versus pemetrexed (Germany, Poland, Spain)6–8 1Leighl NB, et al. J Clin Oncol 2002;20:1344–52; 2Holmes J, et al. Pharmacoeconomics 2004;22:581–9; 3Bhalla S, et al. J Clin Oncol 2007;25(Suppl. 18 Pt I):332s (Abs. 6540); 4Côté I, et al. Value Health 2006;9:A279; 5Pompen M, et al. Value Health 2006;9:A203; 6Gabriel A, et al. Value Health 2006;9:A278; 7Orlewska E, et al. Value Health 2006;9:A279; 8Rubio Terres C, et al. Value Health 2006;9:A283–4; 9Lewis G, et al. Value Health 2006;9:A203–4

EGFR TKIs plus Chemotherapy Combinations Hypothesis: Scheduling is important. Clinical trials (INTACTs, TRIBUTE, TALENT) suggested that continuous dosing of Gefitinib or Erlotinib is not approppriate. Intermitent dosing of TKIs may be optimal (Davies et al.). Gumerlock et al., ASCO. 2003

Por que usar ND en segunda línea?? 1 Igual eficacia de las opciones aprobadas.. 2.Por el perfil de toxicidad... 3.Porque lo importante es vivir mejor , más que el grado de respuesta... 4.Porque los pacientes con progresión o toxicidad a la primera qt tienen mínimas posibilidades de responder a qt adicional

Por que usar ND en segunda línea?? 5. Porque los pacientes sensibles a ND en primera línea, seran tambien candidatos en la segunda 6. Porque son eficaces en pacs no seleccionados 7. Porque el uso de ND no impide el uso de qt posterior