Antiangiogénesis en cáncer gástrico

Transcripción

1 Antiangiogénesis en cáncer gástrico Dr. Carles Pericay Corporació Sanitària Parc Taulí

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3 1ª línea: ensayos fase III Ensayo Fase III Autor Año N N Países Rama Resp (%) mslp (m) msg (m) P (SG) Neutrop G3/4 (%) Mortal. (% <60d) V325 Ajani JA E, NA, AP, SA DCF FP4w ,6 3,7 9,2 8,6 0, ML SPIRITS REAL-2 AIO Kang YK Koizumi W Cunning ham E Al Batran SE E, NA, CA, SA, AU Japan UK GE, SUI XP FP3w CS S1 ECF ECX EOF EOX FLO FLP ,7 46,4 42,4 47,9 34,8 24,5 5,6 5,0 6,0 4,0 6,2 6,7 6,5 7,0 5,8 3,9 10,5 9, ,9 9,9 9,3 11,2 10,7 8,8 0,008 (NI) 0,04 0,06 (NI) 0, ,7 51,1 29,9 27,6 11,6 14, ,2 5,6 5,7 6,1 5,4 2,0 Estudio francés Dank M E, NA IFL FP4w 31,8 25,8 5,0 4,2 9,0 8,7 NS 24,8 51,6 NR

4 ESQUEMAS DE QUIMIOTERAPIA (n=846) N (%) EOX 191 (23%) FOLFOX 161 (19%) CX 143 (17%) CAPOX 138 (16%) DCF 39 (5%) DC 37 (4%) CF 34 (4%) FOLFIRI 9 (1%) DCX 27 (3%) ECX 13 (1%) Otros 69 (8%) Respuestas: 25-54% SLP: 4-7 meses SG: meses

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8 INHIBICIÓN LIGANDO VEGF Bloqueo VEGF Inhibición señal VEGF(s) Bevacizumab Aflibercept Ziv-aflibercept Neovastat AC anti-vegfr-2 Bloqueo unión de ligando Bloqueo activac y señal RC Ramucirumab INHIBIDOR TK VEGFR-2 Bloquea la actividad y señal TK del RC Sorafenib Sunitinib Pazopanib Vandetanib Axitinib Regorafenib Cediranib Brivanib alaninate Motesanib Linifanib Tivozanib

9 Angiogenic signaling network

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11 AVAGAST fase III: CX + bevacizumab CX + BEVACIZUMAB CX + PLACEBO P HR (IC 95%) SLP 6.7 meses ( ) RR 46% 37% 0.03 SG 12.1 meses ( )

12 BEVACIZUMAB Cáncer Gástrico Avanzado

13 FOLFOX + Ramucirumab en 1ª línea

14 FOLFOX + Ramucirumab en 1ª línea RAMUCIRUMAB Cáncer Gástrico Avanzado

15 Phase III trials in second-line AGC

16 Mechanism of action of Ramucirumab Javle M, et al Clin Cancer Res 2014

17 Fuchs CS et al, Lancet 2014; 383: 31-39

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19 Wilke H et al, Lancet Oncol 2014; 15:

20 OS: R+P:9.6 m vs P: 7.4 m HR P:0.017 PFS: R+P: 4.4m vs P: 2.9 m HR:0.635 p< Wilke H et al, Lancet Oncol 2014; 15:

21 Análisis de subgrupos para SG N N Category Subgroup (RAM+PTX) (PBO+PTX) HR Overall Combined Geo. Region a Region ASIA Region Time to PD on 1st-line Therapy < 6 months months Disease Measurability Non-measurable Measurable Gender Male Female Age Group (yrs) < ECOG PS Histologic Subtype Intestinal Diffuse Mix/Miss./Unk Number of Metastatic Sites > Primary Tumor Location Gastric GEJ Prior Gastrectomy Yes No Peritoneal Metastases Yes No a Region 1: Europe, United States, and Australia; Region 2: Brazil, Chile, Mexico, and Argentina; Region 3: Japan, South Korea, Hong Kong, Taiwan, and Singapore. 0.2 Favors RAM+PTX Favors PBO+PTX 1

22 Region RAM+PTX PB+ PTX Delta HR 95% CI msg (m) mslp (m) RR (%) Asia a 0.73, 1.34 EU/NA/AUS + Central/South Am a 0.59, 0.91 Asia a 0.47, 0.83 Resto a 0.52, 0.79 Asia 33.9% 20.2% 13.7% 2.24 b 1.18, 4.24 Resto 24.9% 14.0% 10.9% 2.09 b 1.28, 3.41

23 Brazo tratamiento RAM + PTX (N=327) PBO + PTX (N=329) TOXICIDAD Cualquier Grado (%) Grado 3 (82%) Cualquier Grado (%) Grado 3 (63%) Fatiga Neutropenia Cáncer Gástrico RAMUCIRUMAB Avanzado Neutropenia febril Neuropatía Hipertension Muertes por toxicidad Ajuste dosis: Profilaxis con FSC-G - Ramucirumab vs Paclitaxel

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25 Phase III Apatinib vs. Placebo: OS 195 d vs 140 d (p<0.016) PFS: 78 d vs 53 d (p<0.0001) Quin S et al, J Clin Oncol 2014

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28 Cáncer Gástrico Avanzado APATINIB

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32 REGORAFENIB Cáncer Gástrico Avanzado

33 Ramucirumab en 2ª línea: 2 estudios fase III positivos Fuchs, Lancet 2014; Wilke, Lancet Oncol 2014

34 2ª línea de tratamiento

35 BEVACIZUMAB Cáncer Gástrico Localizado

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45 Changes in QoL Scales/Items as Predictors of Best Overall Response QoL scales/items a that met prespecified criteria for meaningful change a Black bars are functioning scales, red bars are symptom scales/items Abbreviations: BOR=best overall response; QLQ-C30=EORTC Quality-of-Life Questionnaire v3.0; QoL=quality of life 45

46 Changes in QoL Scales/Items by Best Overall Response Abbreviations: CR=complete response; NE=not evaluable; PD=progressive disease; PR=partial response; QLQ-C30=EORTC Quality-of-Life Questionnaire v3.0; QoL=quality of life; SD=stable disease 46

47 698P A Dose-Response Study of Ramucirumab Treatment in Patients with Gastric Cancer/Gastroesophageal Junction Adenocarcinoma: Primary Results of 4 Dosing Regimens in the Phase 2 Trial I4T-MC-JVDB Jaffer A Ajani 1 ; Adrian Udrea 2 ; Tomasz Sarosiek 3 ; Michael Shenker 4 ; Carys Morgan 5 ; Joanna Pikiel 6 ; Elzbieta Wojcik 7 ; Daniel Swinson 8 ; Mano Joseph 9 ; Alexander Luft 10 ; Tomas Salek 11 ; Christophe Tournigand 12 ; David Ferry 13 ; Yawei Zhang 13 ; Amanda Long 13 ; Wen-Ling Kuo 13 ; Ling Gao 13 ; Francesca Russo 14 ; John Kauh 15 ; Wasat Mansoor 16 Figure 3. PFS and OS of 8 mg/kg Q2W vs. 12 mg/kg Q2W (Non-Stratified) Trough 1 University of Texas MD Anderson Cancer Center, Houston, Texas, United States; 2 MedisProf SRL, Cluj-Napoca, Romania; 3 Magodent, Warszawa, Poland; 4 Centrul de Oncologie Sf. Nectarie SRL, Craiova, Romania; 5 Velindre Cancer Centre, Cardiff, United Kingdom; 6 COPERNICUS Podmiot Leczniczy, Gdańsk, Poland; 7 NZOZ Centrum Medyczne HCP, Poznań, Poland; 8 St James's University Hospital, Leeds, United Kingdom; 9 New Cross Hospital Deanesly Centre, Wolverhamptom, United Kingdom; 10 Leningrad Regional Clinical Hospital, St. Petersburg, Russian Federation; 11 Narodny Onkologicky Ustav, Bratislava, Slovakia; 12 APHP, CHU Henri Mondor, Creteil Cedex, France; 13 Eli Lilly and Company, Bridgewater, New Jersey, United States; 14 Eli Lilly Italy, Florence, Italy; 15 Former employee of Eli Lilly and Company, Bridgewater, New Jersey, United States; 16 Christie Hospital NHS Foundation Trust, Manchester, United Kingdom BACKGROUND Ramucirumab (RAM), either as monotherapy or in combination with paclitaxel, is approved for the treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma with disease progression after prior platinum and/or fluoropyrimidine chemotherapy Approved at 8 mg/kg every 2 weeks (Q2W) based on results of 2 phase III trials Exposure-response analyses from these trials indicated efficacy of RAM correlated with exposure JVDB is an open-label RAM monotherapy study that examined pharmacokinetics (PK) and safety of the standard regimen and 3 experimental regimens predicted to result in higher exposures across the population METHODS Figure 1. Study Design 1:1:1:1 Randomization (N = 164) Stratified by: Body weight (< 60 kg vs. 60 kg) ECOG PS (0 vs. 1) Arm 1 (Standard) 8 mg/kg Q2W (28-day cycles) (n = 40) Arm 2 12 mg/kg Q2W (28-day cycles) (n = 42) Arm 3 6 mg/kg QW (28-day cycles) (n = 41) Treat Until: Disease progression Toxicity requiring cessation of treatment Death Withdrawal of consent Other withdrawal criteria Arm 4 Abbreviations: D=day; ECOG PS=Eastern 8 mg/kg D1D8 Cooperative Oncology Group Performance Status; QW=every week; Q3WQ2W=every 2 weeks; Q3W=every 3 weeks (21-day cycles) (n = 41) PFS Post- Discontinuation Follow-up and Study Completion OS Mean Ramucirumab Concentration (µg/ml) Mean Ramucirumab Concentration (µg/ml) Time (weeks) Peak 8 mg/kg Q2W 12 mg/kg Q2W 6 mg/kg QW 8 mg/kg D1D8 Q3W Time (weeks) CONCLUSIONS The RAM trough concentrations associated with the 3 experimental dosing regimens were higher than that observed with the standard regimen (Figure 1) The maximum RAM peak concentration was observed with the 12 mg/kg Q2W dosing regimen (Figure 1) The greatest improvement in median PFS and OS compared to the standard regimen was 1 month (12 mg/kg Q2W vs. 8 mg/kg Q2W) (Figure 2, Table 4) RAM was well tolerated in this patient population, with similar rates of adverse events across all of the arms (Table 3) Despite higher RAM exposures observed with the alternative regimens, safety profiles were comparable to the standard regimen TRT A = 8mg/kg Q2W TRT B = 12mg/kg Q2W Abbreviations: HR=hazard ratio; OS=overall survival; PFS=progression-free survival; Q2W=every 2 weeks; TRT=treatment 2017 ESMO Annual Meeting; Madrid, Spain; September 8 12, 2017 Corresponding Author: Francesca Russo, russo_francesca@lilly.com Sponsored by Eli Lilly and Company and/or one of its subsidiaries

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51 CONCLUSIONES 1.-La angiogénesis no ha demostrado un beneficio claro en el tratamiento del CGA en primera línea 2.-La angiogénesis (Ramucirumab) ha demostrado un beneficio claro en el tratamiento del CGA en segunda línea en monoterapia y en combinación 3.-Las moléculas tirosín-kinasas no parecen aportar beneficio en este grupo de pacientes (salvo Apatinib) 4.-El beneficio de Ramucirumab se consigue independientemente de la edad 5.-La calidad de vida se mantiene en los pacientes tratados con Ramucirumab 6.-Los metaanálisis demuestran un beneficio de los pacientes tratados con antiangiogénicos

52 MUCHAS GRACIAS