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

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Cáncer Gástrico: Tratamiento

de 2ª línea

Dr. Javier Sastre

(2)

Herceptin + X/FC*(8) _{HER2 IHC 2+ / FISH+ and IHC 3+}

16 meses

Mediana SG en el tratamiento del CG metastásico

0 5 10 15 Meses EOX (6) XP (7) ECX (6) ECF (6) DCF (4) EOF (6) IF (5) CF (4) FAMTX (2) BSC (1) C+S1 (3) EOX (6) XP (7) ECX (6) ECF (6) DCF (4) EOF (6) IF (5) CF (4) FAMTX (2) BSC (1) C+S1 (3)

16 meses

Mediana SG en el tratamiento del CG metastásico

0 5 10 15 Meses EOX (6) XP (7) ECX (6) ECF (6) DCF (4) EOF (6) IF (5) CF (4) FAMTX (2) BSC (1) C+S1 (3) EOX (6) XP (7) ECX (6) ECF (6) DCF (4) EOF (6) IF (5) CF (4) FAMTX (2) BSC (1) C+S1 (3) Referencias:

1.Murad A.M, et al. Cancer1993; 72:37–41.

2.Vanhoefer U, et al. J Clin Oncol2000; 18:2648–2657.

3.Ajani JA, et al.ASCO Gastrointestinal Cancers Symposium 2009; Abstract 8. 4.Van Cutsem E, et al. J Clin Oncol2006; 24:4991–4997.

5.Dank M, et al. Ann Oncol2008; 19:1450–1457.

6.Cunningham D, et al. N.Engl.J Med2008; 358:36–46. 7.Kang Y.K, et al. Ann Oncol2009; 20:666–673.

8. Bang et al. The Lancet, 20th Aug 2010

Evolución de la supervivencia en cáncer gástrico

metastásico

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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)

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Salvage chemotherapy: Docetaxel 60 mg/m2_{every 3 weeks or}

Irinotecan 150 mg/m2 _{every 2 weeks.}

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

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Kaplan-Meier estimates for overall survival in randomly assigned patients.

Kang J H et al. JCO 2012;30:1513-1518

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)

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Forest plot of overall survival

Kang J H et al. JCO 2012;30:1513-1518

Factores pronóstico para SG PS 0

Intervalo libre de QT > 3 meses 1 línea previa de QT

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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/m2_{cada 3 semanas.}

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Docetaxel 75 mg/m2_c/3sem

Asumiendo una mSG de 4m para el grupo control con BSC, incrementar la mSG a 6 meses con docetaxel (HR 0.64)

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Objetivo principal: SG

mSG 5.2m mSG 3.6m HR 0.67 P= 0.01

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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;24:2850-2854

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Hironaka S et al. JCO 2013;31:4438-4444

Taxol: 80 mg/m2_{1,8,15 c/4sem CPT-11: 150 mg/m}2_{c/2 sem}

Asumiendo una SG de 5m en el grupo de taxol, incrementar la mediana de SG con irinotecan a 7.5m

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Kaplan-Meier curves of (A) overall and (B) progression-free survival.

Hironaka S et al. JCO 2013;31:4438-4444

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REGARD Study Design

Ramucirumab 8 mg/kg q2wk + BSC (n = 238) R A N D O M I Z E Placebo q2wk + BSC (n = 117) S C R E E N Treatment until disease progression or intolerable toxicity Tumor assessment, survival, and safety follow-up N = 355

• Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial

• Gastric or GEJ adenocarcinoma

• 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 2:1

Abbreviations: BSC=best supportive care; GEJ= gastroesophageal junction

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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

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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)

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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) 1 171 (71.8) 85 (72.6)

Weight Loss Prior 3 Months, n (%)

≥10% 41 (17.2) 20 (17.1)

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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

0-2 163 (68.5) 71 (60.7)

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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.}

Peritoneal Metastases: Yes 64 (26.9) 45 (38.5) Measurable Disease: Yes 218 (91.6) 106 (90.6)

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Ram 238 154 92 49 17 7 3 0 0

Plcb 117 66 34 20 7 4 2 1 0

No. at Risk

REGARD: Overall Survival

HR (95% CI) = 0.776 (0.603, 0.998) Log rank P-value (stratified) = 0.0473

Ramucirumab Placebo

Patients / Events 238 / 179 117 / 99

Median (mos) (95% CI) 5.2 (4.4, 5.7) 3.8 (2.8, 4.7)

6-month OS 42% 32%

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Ram 238 213 113 65 61 45 30 18 18 11 5 4 2 1 1 1 1 0 Plcb 117 92 27 11 7 4 2 2 2 2 2 1 1 0 0 0 0 0

No. at Risk Months

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 P rogressi on Fre e S urv iv al 0.0 0.2 0.4 0.6 0.8 1.0 Ramucirumab Placebo Censored

REGARD: Progression-free Survival

HR (95% CI) = 0.483 (0.376, 0.620) Log rank P-value (stratified) <0.0001

Ramucirumab Placebo Patients / Events 238 / 199 117 / 108 Median (mos) (95% CI) 2.1 (1.5, 2.7) 1.3 (1.3, 1.4)

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Post-discontinuation Treatment

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

*Treatments used in ≥2% of patients in either arm are shown.

Slightly higher rates of post-study chemotherapy were observed

in placebo arm

*PDT=Post-discontinuation Treatment

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Ramucirumab (N=236) Placebo (N=115) Category of event Any Grade Grade ≥3 Any Grade Grade ≥3

(%) (%) (%) (%) Hypertension 16.1 7.6 7.8 2.6 Bleeding/Hemorrhage 12.7 3.4 11.3 2.6 Arteriothromboembolic 1.7 1.3 0 0 Venous thromboembolic 3.8 1.3 7.0 4.3 Proteinuria 3.0 0.4 2.6 0 GI perforation 0.8 0.8 0.9 0.9 Fistula (GI and non-GI) 0.4 0.4 0.9 0.9 Infusion-related reaction 0.4 0 1.7 0 Cardiac failure 0.4 0 0 0

A summary of adverse events generally associated with

anti-angiogenic agents and therapeutic antibodies

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RAINBOW PHASE III : STUDY DESIGN

Primary end-point: Overall survival

R

1 1 Ramucirumab 8 mg/kg d 1&15 + Paclitaxel 80 mg/m2_d 1,8,15 c/28d N= 330

Placebo d 1,& 15 + Paclitaxel

80 mg/m2_{d 1,8,15 c/28d N=} 335 Treatment progression or unaceptable toxicity

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) C D D P / F P F A I L U R E

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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 2012.

–

Data cut-off on July 2013 after observation of 516 OS

events

Primary analysis

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RAINBOW: OVERALL SURVIVAL

RAM + TAX PBO + TAX

Patients / Events

mOS months (95% CI)

330 / 256 9.63 (4.84-10.81) 335 / 260 7.36 (6.31-8.38) 6-months OS 12-months OS 72% 40% 57% 30% D 2.3 months HR 0.807 (0.678-0.962)

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RAINBOW: Progression-free survival

RAM + TAX PBO + TAX

Patients / Events mPFS months (95% CI) 330 / 279 4.40 (4.24-5.32) 335 / 296 2.86 (2.79-3.02) 6-months OS 9-months OS 36% 22% 17% 10% Response rate 28% 16% P= 0.0001

Disease Control Rate 80% 64%

P= 0.0001

D 1.54 months HR 0.635 (0.536-0.752)

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Treatment Emergent-adverse events ocurring in >20% of patients

and > 5% higher in the RAM+TAX arm

Adverse event RAM + TAX PBO + TAX

> Grade 3 > Grade 3 Fatigue Neutropenia Neuropathy Decreassed appetite Abdominal pain Leukopenia Diarrhea Vomiting Peripheral edema 11.9 40.7 8.3 3.1 6.1 17.4 3.4 3.1 1.5 5.5 18.8 4.6 4.0 3.3 6.7 1.5 3.6 0.6

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Adverse events of special interest

Adverse event RAM + TAX PBO + TAX

> Grade 3 > Grade 3 Bleeding GI hemorrhage Hypertension Proteinuria Renal failure Venous thromboembolic Arterial thromboembolic Cardiac failure GI perforation 4.3 3.7 14.7 1.2 1.8 2.4 0.9 0.6 1.2 3.4 1.5 2.7 0 0.9 3.3 0.9 0.6 0

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Li J et al. JCO 2013;31:3219-3225

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

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Kaplan-Meier estimates of progression-free survival and overall survival in the intent-to-treat population for the three treatment groups.

Li J et al. JCO 2013;31:3219-3225

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

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Incidence of severe adverse events

Li J et al. JCO 2013;31:3219-3225

Adverse event Incidence (%) P

Apatinib Placebo

Hypertension 8.5 0 0.04

Diarrhea 2.1 0 0.07

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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