Secuenciacio n terape utica en ca ncer de pa ncreas

Transcripción

1 Secuenciacio n terape utica en ca ncer de pa ncreas Andrés J. Muñoz Martín MD PhD Servicio de Oncología Médica Hospital General Universitario Gregorio Marañón

2 My disclosures Consultant or advisory role: Celgene Speaking: Celgene, Shire

3 En los últimos siete años en cáncer de páncreas. En los últimos siete años se ha modificado de forma significativa el tratamiento de primera línea de pacientes con cáncer de páncreas con la aparición de dos regímenes de quimioterapia: FFX y G-A Se ha observado un incremento significativo de la supervivencia Se han observado largos supervivientes (>2-3 años) Se ha triplicado la tasa de respuestas En los últimos dos años se ha consolidado el tratamiento de segunda línea basado en la combinación de FP y oxaliplatino o naliri y se ha introducido un nuevo concepto terapéutico secuenciación Ensayos aletaorizados fase III en 3ª línea PANCRIT-1 (pacientes están viviendo más y con buena calidad de vida)

4 Diferencias de resultados mos 8.7 m NP-G vs. 6.6 m G mos 11.1m FOLFIRINOX VS. 6.8 m G Von Hoff DD, N Engl J Med. 213;369: Conroy T. N Engl J Med 211;364: Response rate 23% (29%) vs 31% Primary Endpoint (OS) & Response Rate

5 MPACT vs PRODIGE Son comparables los resultados de los dos estudios? No Por qué no son comparables? Las poblaciones incluidas son diferentes Se podrían justificar las diferencias observadas? Se podrían justificar Podemos esperar una comparación directa de los dos esquemas en un estudio randomizado? Muy probablemente no

6 Estudio Características de las poblaciones PRODIGE/ACCORD FOLFIRINOX MPACT GZT+NBP Edad (mediana y rango) 61 años (25-76) 63 años (27-86) Pacientes ancianos >76 años No Si Pacientes PS 37% 16% Pacientes PS2 1% 7% Mediana de localizaciones metastásicas Ca19.9 >59 LAN (medida indirecta carga tumoral) % % MPACT Población con características clínicas más desfavorables en cáncer de páncreas: más jóvenes y más sanos Mayor número de pacientes recibieron tratamiento de 2ª línea en el estudio de FFX: FFX 47% vs G-NABP 4%, 2ª línea impacta en supervivencia

7 Pacientes ECOG -1 MPACT Mediana de SG: 9,7 meses Tabernero et al. Beaujon Conference 214 Tabernero J et al, The Oncologist 215;2:1 8

8 ASCO 214: US Study Oncology Network, OS comparative study First line chemo n Median OS FOLFIRINOX months Gem + other drug months Gem + nabpaclitaxel months Cartwright TH et al. J Clin Oncol 214:32(15s):287s (Abs 4132)

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10 infusion (prior togeneral the administration of Abraxane and gemcitabine) once every 2Marañon, weeks for o,administered Perth,by IVHospital Universitario Gregorio Madrid, Hospital Miguel Servet, Zaragoza, Hospita Yes 72.1% Universitario 74.6% 75.4% 74% either one (1 course through Study Day 7) or two (2 course begun on Study Day 168 and continued No 27.9% 25.4% 24.6% 26% throughplacebo/ Study Day 238) 7 day courses. Patients who had two consecutive B-type natriuretic (BNP)Campus, values, Melbourne, Monash Medical Centre, Moorabbin Germans Trias i Pujol Hospital, ICO-Badalona, Barcelona, Hosp Demcizumab/ Demcizumab/ Total >1 pg/ml or one value >2Placebo pg/ml were unblinded by the Investigator through the IWRS system and if they NLR (Median) Placebo Demcizumab 15 were receiving demcizumab they were started on an ACE inhibitor or carvedilol. Subjects were assessed for Cancer Center, Ann Arbor, MI 16Kaiser Permanente, Vallejo, CA, 17Onco veland Clinic, Cleveleand, OH, University of Michigan Dem vs. Placebo 68) 71) disease(n= status every 8 weeks (N= and for safety at every(n= visit65) and through 3 (N= days 24) following the termination visit. nd Dem (N=136 Placebo N=6 YOSEMITE trial PhIIR, ESMO st Europe/Australia 161 PD es 74.6% % 75.4% % 74% 34 26% Endpoints Exploratory 1 Biomarkers Secondary Endpoints5 8 7 Survival ULN 14 Response Rate (CR+PR) (95% >ULN - < 59 X ULN 27 CI)> = 59 X ULN (41.2%) 12 (33.1%) (74.3%) 74.6% 25.4% 75.4% 24.6% 74% 26% Asthenia 9 vs. Placebo Dem vs.dem Placebo Ratio:.93 Hazard Hazard Ratio: 1.18 CI ( ) 95% CI95% ( ) Log-Rank Log-Rank p-valuep-value % 27.9% Placebo N Constipatio 8 Diarrhe Anemia Anemia 4 6 Fatigue 5 7 Meier Medians Kaplan Kaplan Meier Medians Demcizumab: 5.52 ( ) months Demcizumab: 13.2 ( ) months Placebo:NR (8.97-NR) 5.49 ( ) Placebo: months months Diarrhoea Fatigue Neutropeni Dem (N= Probability (%) Decreased appetite Nausea Nausea Alopecia Edema Edema Alopeci peripheral Vomitin Vomiting Dem (N=136) Dem (N=136) Placebo N=68) (Median) Alopecia LN atic Metastases Probability (%) mber of Metastatic 2 s (7.6%) Time (months 7 116/ /3 34 Edema peri Vomiting Overall Survival Progression-Free Survival LAPACT G-NABP response rate: 31% /31 Fatigue Abdominal Demcizumab/ Demcizumab/ Total Total Placebo/ Demcizumab/ Demcizumab/ PlaceboPlacebo Placebo Demcizumab Demcizumab (N= 24) (N= 68)(N= 71) (N= 71) (N= 65)(N= 65) (N= 24) 41/ Clinical Benefit (CR+PR+SD) (95% CI) (Median) Anemia Pyrexia CA 19-9 Placebo N=68) Response Safety (M/F) Diarrhea Dem (N=136) Cancer Characteristics Demographics Placebo/ Placebo (N= 68) % ason for discontinuation rogression 27.9% eath E 3.2 ithdraw Consent ther Cancer Treatment vestigator DecisionPrimary Endpoint ther PFS Region SDUS/Canada continued 1 6 ECOG PS PR CR going Nausea ety Population Total Demcizumab: 5.52 ( ) months Demcizumab/ Total Demcizumab P value Placebo: 5.49 ( ) months Demcizumab (N = 136) (N= 65) (N= 24) Demcizumab/ Placebo/ Placebo Placebo (N= 71) (N = 68) Probability (%) nt to Treat Placebo/ Placebo (N= 68) Best Response 5 Placebo/ Placebo Randomized: 27 pts Treated: 24 pts atic Data Cut: Nov 7, 216 Kaplan Meier Medians 116/88 Demcizumab/ Demcizumab/ Placebo Demcizumab 35/3 3 4/31 Probability (%) 41/27 Characteristics RECISTCancer Best Overall Response (n=24) Study 66Schema Subject Disposition 62 Hazard Ratio:.93 95% CI ( ) Log-Rank p-value The data cut-off for this analysis was November 7, 216. Placebo N=68) TimeTime (months (months Pyrexia Asthenia Decreas appetite Decreased appetite Neutrop Hypertensi

11 FRAGANCE (ECOG 2) ESMO 217 Hidalgo et al. ESMO 217

12 Proportion of Survival egional Cancer Centre, Barrie, ON, Canada; Roswell Park Cancer Institute, Buffalo, NY J; 1 Translational Genomics Research Institute and HonorHealth, Scottsdale, AZ Outcome of Second-Line Treatment MPACT trial Figure 1. Total OS in Pts Who Received 2L Therapy Pts at risk nab-p + Gem : nab-p + Gem Gem Time, months Events/n Median, mo (95% CI) 161/ ( ) 166/ ( ) H R.76 95% CI, P = Gem: Figure 2. OS2 From End of 1L Therapy Events/n Median, mo (95% 1. Choirean et al. Br J Cancer 216

13 2ªL Oxaliplatino OFF vs FF as 2 nd -line therapy for APC* (CONKO-3) Primary endpoint: OS Secondary endpoints: TTP, tolerability Overall survival (%) Progression-free survival (%) 1 8 OFF median 2.9 months (95% CI ) FF median 2. months (95% CI ) 6 HR.68 (95% CI.5.94) p=.19 OFF 4 2 PD following gemcitabine 1 st -line therapy KPS 7 Measureable disease R 1:1 FF No at risk Time (months) OFF FF OFF median 5.9 months (95% CI ) FF median 3.3 months (95% CI ) HR.66 (95% CI.48.91) p=.1 Stratification: Presence of metastases, duration of 1 st -line gemcitabine therapy (3, 3 6, or >6 months), KPS (7 8% or 9 1%) *>88% of patients had metastatic disease OFF differs from FOLFOX (folinic acid, fluorouracil, and oxaliplatin) with respect to the frequency of treatment administration: fluorouracil is administered weekly for the first 4 weeks, and oxaliplatin is administered on Days 8 and 22 of a 6-week cycle Time (months) No at risk OFF FF Oettle et al. JCO 214;32:2423-9

14 Overall survival probability 2ªL Oxaliplatino mfolfox6 as 2 nd -line therapy for MPC (PANCREOX) = Canadian, multicentre, open-label trial = 18 patients with APC previously treated with gemcitabine-based therapy randomized to receive: mfolfox6 5-FU/LV = No difference in PFS between treatment arms 3.1 vs 2.9 months = Inferior OS with mfolfox6 6.1 vs 9.9 months = mfolfox6 associated with more treatment-related Grade 3/4 AEs 63% vs 11% 1..5 mfolfox6 (n=54) Times (months) 5-FU/LV (n=54) Median, mo % CI HR (95% CI) 1.78 ( ) p value.24 mfolfox6 5-FU/LV 2 Gill et al. JCO 216 Gill et al. JCO 214;32(suppl):422

15 NAPOLI-1: Study Design

16 NAPOLI-1: Efficacy results

17 Proportion Proportion Estudio NAPOLI-1, análisis Q-TWiST Este enfoque facilita la comparación entre tratamientos, penalizando tratamientos con elevada toxicidad o tiempos más cortos a la progresión de la enfermedad y favoreciendo los que tienen menor toxicidad y mayor tiempo a la progresión. Quality-adjusted survival: time in TOX, TWIST, and REL as measured by AUC * 1. nal-iri+5-fu/lv (n = 117) 5-FU/LV (n = 119) Q-TWIST Increase 23,8% (>1-15%).8.6 More time in TWIST (No Tox & No PGR).4.2 TWiST REL.4.2 TWiST REL TOX Months from randomisation TOX Months from randomisation *Adjusted by utility weight during 12 months of follow-up; AUC, area under the curve Pelzer U, et al. Oncol Res Treat 216;39(S3): abstract P865 (and poster)

18 Comparación de estudios (1)

19 Comparación de estudios (2)

20 PFS 5 trials, 895 patients FPIRI: irinotecan formulations FPIRI vs. FP: HR.64; 95%CI, ; p=.5 FPOX vs. FP: HR.81; 95%CI, ; p=.2 Sonbol et al. Cancer 217

21 OS 5 trials, 895 patients FPIRI vs. FP: HR.7; 95%CI, ; p=.4 FPOX vs. FP: HR 1.3; 95%CI, ; p=.9 Sonbol et al. Cancer 217

22 No prospective randomized trial of 2L therapy after FOLFIRINOX providing risk/benefit ratio: Potential treatment sequencing approach for MPC in 217? 1 st line Nab-paclitaxel + gemcitabine 2 nd line MM FU/LV OFF mfolfox6 or CAPOX 3 rd line Platinum-based tx (depending on prior exposure) MM FU/LV (depending on prior exposure) Capecitabine FOLFIRINOX NOTE: Nab-paclitaxel is licensed for use in combination with gemcitabine as 1 st -line therapy for patients with MPC 5-FU Gemcitabine Nab-paclitaxel + gemcitabine (if no neuropathy) Nab-paclitaxel? (depending on prior exposure) Supported by RCT data Supported by retrospective data or small, single arm trials

23 Designing a continuum of care in MPC 1 st line 2 nd line 3 rd line Nab-paclitaxel + gemcitabine 8.7 m MM FU/LV 6.1 m FOLFOX/OFF = 2 nd -line MM FU/LV provides a break from neurotoxicity, paving the way for subsequent 3 rd -line treatment = Prior exposure to irinotecan (with 1 st -line FOLFIRINOX) could increase the potential for resistance to 2 nd - line MM-398 Oettle & Lehmann, Lancet216;387:57-8

24 Guía ASCO 214 Recommendations 1. There are no agents recommended for the prevention of CIPN 2. Treatment of existing CIPN, the best available data support a moderate recommendation for treatment with duloxetine Loprinzi, Practice Update 213: The benefit from duloxetine, however, was not a home run; duloxetine decreased pain, more than was associated with the placebo, by 1 point on a -to-1 point scale

25 Estudios observacionales retrospectivos de secuenciación

26 n of Survival Proportion of Survival Outcome of Second-Line Treatment MPACT trial uskoka Regional Cancer Centre, Barrie, ON, Canada; 5 Roswell Park Cancer Institute, Buffalo, NY; Summit, NJ; 1 Translational Genomics Research Institute and HonorHealth, Scottsdale, AZ r Capeaining Gem 135 Figure 1. Total OS in Pts Who Received 2L Therapy nab-p + Gem Events/n Median, mo (95% CI) 161/ ( ) Table 4. Variable Gem 166/ ( ) Any 2L the 62.5 nab-p + G H R.76 Gem 95% CI, Other 45 a P =.15 nab-p + G 35 Gem 12 5-FU- or Ca 8 nab-p + G n = 99 Gem Pts at risk 5-FU or Ca 33 Time, months nab-p + G nab-p Gem : Gem 5-FU or Ca 64 Gem: nab-p + G Gem FOLFIRINO Pts who received Figure 2. OS2 a From 5-FU- End or of cape-containing 1L Therapy 2L therapy: Total OS was nab-p + G 1. Median, mo (95% Gem Events/n significantly longer.9 for those in the nab-p + Gem vs Gem-alone CI) arms FOLFOX/O.8 nab-p + G nab-p + Gem 161/17 6.7( ) X/OFF (median, 13.5 vs 9.5 mo; P =.12) Gem.7 Gem 166/ ( ) a Other than 5.6 And combo regimens >14 months Gem alone (n = 11).5 HR.89

27 Conclusiones G-NP can face to FOLFIRINOX in the same group of patients (very fit or super-fit patients/without restrictions or limitations)? Interesting new data (data from retrospective and randomized clinical trials) 1st-line G-NP permits more 2 nd - 3 rd line treatment options than 1st-line FOLFIRINOX (1st-line treatment with G-NP does not compromise subsequent treatment options) In ECOG 2 patients (tumor load) G-NP is a new regimen with high efficacy

28 Conclusiones In second line setting the combination of naliri and 5FU is a new standard of care after gem combinations The combination of naliri and 5FU provides a break from neurotoxicity and paving the way of subsequent 3 rd -line