Cáncer Gástrico: Tratamiento de 2ª línea. Dr. Javier Sastre Servicio de Oncología Médica. HC San Carlos (Madrid)

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1 Cáncer Gástrico: Tratamiento de 2ª línea Dr. Javier Sastre Servicio de Oncología Médica. HC San Carlos (Madrid)

2 Evolución de la supervivencia en cáncer gástrico metastásico Mediana SG en el tratamiento del CG metastásico BSC (1) FAMTX (2) C+S1 (3) CF (4) IF (5) EOF (6) DCF (4) ECF (6) ECX (6) XP (7) EOX (6) Herceptin + X/FC* (8) HER2 IHC 2+ / FISH+ and IHC meses Meses Referencias: 1.Murad A.M, et al. Cancer 1993; 72: Vanhoefer U, et al. J Clin Oncol 2000; 18: Ajani JA, et al. ASCO Gastrointestinal Cancers Symposium 2009; Abstract 8. 4.Van Cutsem E, et al. J Clin Oncol 2006; 24: Dank M, et al. Ann Oncol 2008; 19: Cunningham D, et al. N.Engl.J Med 2008; 358: Kang Y.K, et al. Ann Oncol 2009; 20: Bang et al. The Lancet, 20th Aug 2010

3 Segunda línea de cáncer gástrico: Cuestiones Existen fármacos activos en 2ª línea? Se incrementa la SLP o SG en 2ª línea con estos fármacos? LA RESPUESTA A AMBAS CUESTIONES ES SI Fase III CT (CPT-11 o Docetaxel) + BSC vs BSC (Kang JCO 2012) Fase III CPT-11 vs BSC (Thuss-Patience Eur J Cancer 2011) Fase III COUGAR-02 Docetaxel vs BSC (Ford Lancet Oncol 2014) Fase III WJOG 4007 CPT-11 vs Paclitaxel (Hironaka JCO 2013) Fase III REGARD Ramucirumab vs Placebo (Fuchs Lancet 2013) Fase III RAINBOW Ramucirumab + Paclitaxel vs Paclitaxel (ASCO GI 2014) Fase II Apatinib vs Placebo (Li JCO 2013)

4 Objetivo principal: SG Asumiendo una mediana de SG de 4m para BSC reducir la probabilidad de muerte en un 43% Factores de estratificación ECOG: 0 vs 1 Nº líneas previas: 1 vs 2 Salvage chemotherapy: Docetaxel 60 mg/m 2 every 3 weeks or Irinotecan 150 mg/m 2 every 2 weeks.

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6 Kaplan-Meier estimates for overall survival in randomly assigned patients. mos: 5.3m vs 3.8m HR 0.65, p=0.007 Significativamente mas pacientes recibieron tratamiento adicional en la rama de QT (40% vs 22%, p= 0.011), si bien no está demostrado el beneficio de los agentes utilizados) Kang J H et al. JCO 2012;30: by American Society of Clinical Oncology

7 Forest plot of overall survival Factores pronóstico para SG PS 0 Intervalo libre de QT > 3 meses 1 línea previa de QT 2012 by American Society of Clinical Oncology Kang J H et al. JCO 2012;30:

8 Objetivo principal: SG SG estimada del grupo control 2.5m y el objetivo es incrementar la msg a 4m. Tamaño muestral 120 pts. Cierre prematuro del estudio por bajo reclutamiento. CPT-11: 250 mg/m 2 cada 3 semanas. Thuss-Patience Eur J Cancer 2011

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10 Docetaxel 75 mg/m 2 c/3sem BSC Objetivo principal: SG Asumiendo una msg de 4m para el grupo control con BSC, incrementar la msg a 6 meses con docetaxel (HR 0.64)

11 Objetivo principal: SG msg 5.2m msg 3.6m HR 0.67 P= 0.01

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13 The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please Standard forest plot of the hazard ratio (HR) for death comparing second-line chemotherapy with best supportive care. Kim H S et al. Ann Oncol 2013;24:

14 Objetivo principal: SG Asumiendo una SG de 5m en el grupo de taxol, incrementar la mediana de SG con irinotecan a 7.5m Taxol: 80 mg/m 2 1,8,15 c/4sem CPT-11: 150 mg/m 2 c/2 sem 2013 by American Society of Clinical Oncology Hironaka S et al. JCO 2013;31:

15 Kaplan-Meier curves of (A) overall and (B) progression-free survival by American Society of Clinical Oncology Hironaka S et al. JCO 2013;31:

16 REGARD Study Design S C R E E N R A N D O M I Z E 2:1 Ramucirumab 8 mg/kg q2wk + BSC (n = 238) Placebo q2wk + BSC (n = 117) Treatment until disease progression or intolerable toxicity N = 355 Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial Gastric or GEJ adenocarcinoma Tumor assessment, survival, and safety follow-up Stratification factors: geographic region, weight loss ( 10% vs. <10% over 3 months), location of primary tumor (gastric vs. GEJ) Global: 6 continents, 30 countries, 120 study centers Crossover was not allowed Abbreviations: BSC=best supportive care; GEJ= gastroesophageal junction

17 Study Endpoints Primary endpoint Overall survival (OS) Secondary endpoints Progression-free survival (PFS), including 12-wk PFS rate Objective response rate and duration of response Safety Quality of life Pharmacodynamic and immunogenicity profile

18 Statistical Considerations Sample size: 268 events from 348 patients to give 80% power, based on assumed HR=0.69 Corresponding to an improvement in median OS from 5.0 months (placebo/bsc) to 7.25 months (ramucirumab/bsc) Primary analysis: stratified log-rank test with 2-sided α=0.05 Hierarchical testing: PFS could be formally tested if there was a statistically significant difference between groups in OS 355 patients were randomized (Oct 2009 Jan 2012) Data cut-off: 25 July 2012; Database lock: 26 Sept 2012 (278 OS events)

19 REGARD: Patient Characteristics Ramucirumab (N=238) Placebo (N=117) Age: Median (range) (yrs) 60 (30-86) 60 (24-87) Gender: Male, n (%) 169 (71.0) 79 (67.5) Race, n (%) White 181 (76.1) 91 (77.8) Asian 39 (16.4) 17 (14.5) Black/Other 18 (7.6) 9 (7.7) ECOG PS*, n (%) 0 67 (28.2) 31 (26.5) (71.8) 85 (72.6) Weight Loss Prior 3 Months, n (%) 10% 41 (17.2) 20 (17.1) <10% 197 (82.8) 97 (82.9)

20 Geographic Region N. Am/Europe/Australia/NZ 165 (69.3) 80 (68.4) Asia 18 (7.6) 8 (6.8) Latin Am/India/S. Africa/Middle East 55 (23.1) 29 (24.8) Location of Primary Tumor Gastric 178 (74.8) 87 (74.4) GEJ 60 (25.2) 30 (25.6) Histologic Subtype Intestinal 52 (21.8) 35 (29.9) Diffuse 96 (40.3) 46 (39.3) Unknown/NA 90 (37.8) 38 (32.5) Primary Tumor: Present 174 (73.1) 86 (73.5) Number of Metastatic Sites (68.5) 71 (60.7) 3 75 (31.5) 46 (39.3)

21 Peritoneal Metastases: Yes 64 (26.9) 45 (38.5) Measurable Disease: Yes 218 (91.6) 106 (90.6) Prior Therapy First-line 199 (83.6) 103 (88.0) Adjuvant 39 (16.4) 14 (12.0) Progression-free Interval on Prior Therapy <6 months 154 (64.7) 83 (70.9) 6 months 81 (34.0) 34 (29.1) * One patient randomized to the placebo arm had an ECOG PS of 2. This term includes patients who received neoadjuvant therapy.

22 REGARD: Overall Survival HR (95% CI) = (0.603, 0.998) Log rank P-value (stratified) = Ramucirumab Placebo Patients / Events 238 / / 99 Median (mos) (95% CI) 5.2 (4.4, 5.7) 3.8 (2.8, 4.7) 6-month OS 42% 32% 12-month OS 18% 11% No. at Risk Ram Plcb

23 REGARD: Progression-free Survival Progression Free Survival Ramucirumab Placebo Censored HR (95% CI) = (0.376, 0.620) Log rank P-value (stratified) < Ramucirumab Placebo Patients / Events 238 / / 108 Median (mos) (95% CI) 2.1 (1.5, 2.7) 1.3 (1.3, 1.4) 12-week PFS 40% 16% No. at Risk Months Ram Plcb

24 Post-discontinuation Treatment Slightly higher rates of post-study chemotherapy were observed in placebo arm Ramucirumab (N=238) Placebo (N=117) n (%) n % Patients with any PDT* 75 (31.5) 46 (39.3) Chemotherapy 69 (29.0) 44 (37.6) Biologic therapy 6 (2.5) 1 (0.9) Radiotherapy 4 (1.7) 6 (5.1) Surgery 2 (0.8) 0 0 *PDT=Post-discontinuation Treatment Each patient may have received more than one regimen. *Treatments used in 2% of patients in either arm are shown.

25 A summary of adverse events generally associated with anti-angiogenic agents and therapeutic antibodies Ramucirumab (N=236) Placebo (N=115) Category of event Any Grade Grade 3 Any Grade Grade 3 (%) (%) (%) (%) Hypertension Bleeding/Hemorrhage Arteriothromboembolic Venous thromboembolic Proteinuria GI perforation Fistula (GI and non-gi) Infusion-related reaction Cardiac failure

26 RAINBOW PHASE III : STUDY DESIGN Primary end-point: Overall survival C D D P / F P F A I L U R E R 1 1 Ramucirumab 8 mg/kg d 1&15 + Paclitaxel 80 mg/m 2 d 1,8,15 c/28d N= 330 Placebo d 1,& 15 + Paclitaxel 80 mg/m 2 d 1,8,15 c/28d N= 335 Important inclusion criteria: Metastatic or LA unresectable gastric or GEJ adenocarcinoma Progression after first-line P + FP based chemotherapy Stratification factors: Geographic region Measurable vs non measurable disease TTP on 1st line (< 6m vs > 6m) Treatment progression or unaceptable toxicity

27 RAINBOW: STATISTICAL CONSIDERATIONS Sample size 510 events from 663 patients at 90% power, based on assumed HR 0.75 (anticipated mos 9.33m for RAM-TAX vs 7.0m for P+TAX) 665 patients randomized between Dec 2010-Sep Data cut-off on July 2013 after observation of 516 OS events Primary analysis Stratified log-rank test with 2-sided a=0.05

28 RAINBOW: OVERALL SURVIVAL Patients / Events mos months (95% CI) 6-months OS 12-months OS RAM + TAX 330 / ( ) 72% 40% PBO + TAX 335 / ( ) 57% 30% D 2.3 months HR ( ) Stratified log-rank p value=

29 RAINBOW: Progression-free survival Patients / Events mpfs months (95% CI) 6-months OS 9-months OS RAM + TAX 330 / ( ) 36% 22% PBO + TAX 335 / ( ) 17% 10% Response rate 28% 16% P= Disease Control Rate 80% 64% D 1.54 months HR ( ) Stratified log-rank p value< P=

30 Treatment Emergent-adverse events ocurring in >20% of patients and > 5% higher in the RAM+TAX arm Adverse event RAM + TAX PBO + TAX Fatigue Neutropenia Neuropathy Decreassed appetite Abdominal pain Leukopenia Diarrhea Vomiting Peripheral edema > Grade 3 > Grade

31 Adverse events of special interest Adverse event RAM + TAX PBO + TAX Bleeding GI hemorrhage Hypertension Proteinuria Renal failure Venous thromboembolic Arterial thromboembolic Cardiac failure GI perforation > Grade 3 > Grade

32 Apatinib for chemotherapy-refractory gastric cancer A randomized placebo-controlled phase II trial Objetivo principal: SLP Se estima una SLP con placebo < 2 meses y con apatinib de 4.5m o un incremento de 2.5m Todos los pacientes han recibido al menos 2 líneas de quimioterapia previa 2013 by American Society of Clinical Oncology Li J et al. JCO 2013;31:

33 Kaplan-Meier estimates of progression-free survival and overall survival in the intent-to-treat population for the three treatment groups. msg Apatinib 850mg: 4.83m HR 0.37 msg Apatinib 425mg: 4.27m HR 0.41 msg Placebo: 2.50m mslp Apatinib 850mg: 3.67m HR 0.37 mslp Apatinib 425mg: 3.20m HR 0.41 mslp Placebo: 1.40m 2013 by American Society of Clinical Oncology Li J et al. JCO 2013;31:

34 Incidence of severe adverse events Adverse event Incidence (%) P Apatinib Placebo Hypertension Diarrhea Hand-foot syndrome Li J et al. JCO 2013;31:

35 Conclusiones La quimioterapia de 2ª línea en cáncer gástrico metastásico incrementa la SLP y SG. La administración en monoterapia de taxotere, CPT-11 o taxol pueden ser considerado como las pautas de elección. Los fármacos antiangiogénicos, especialmente ramucirumab, han demostrado incrementar la supervivencia global tanto en monoterapia como asociado a taxol y podrían constituir un nuevo estándar de tratamiento en un futuro inmediato.