Antiangiogénesis en cáncer gástrico

Dr. Carles Pericay

Corporació Sanitària Parc Taulí

Ensayo

Fase III

Autor Año N N

Países

Rama Resp

(%)

mSLP

(m)

mSG

(m)

P

(SG)

Neutrop

G3/4 (%)

Mortal.

(% <60d)

V325

Ajani JA

2007

445

16

E, NA, AP,

SA

DCF

FP4w

37

25

5,6

3,7

9,2

8,6

0,02

82

57

10

8

ML

17032

Kang

YK

2009

316

12

E, NA, CA,

SA, AU

XP

FP3w

46

32

5,6

5,0

10,5

9,3

0,008

(NI)

16

19

5

3

SPIRITS Koizumi

W

2008 305 1

Japan CS

S1

54

31

6,0

4,0 13

11

0,04

40

11

3

9

REAL-2

Cunning

ham E

2008

1002

1

UK

ECF

ECX

EOF

EOX

40,7

46,4

42,4

47,9

6,2

6,7

6,5

7,0

9,9

9,9

9,3

11,2

0,06

(NI)

41,7

51,1

29,9

27,6

7,2

5,6

5,7

6,1

AIO

Al

Batran

SE

2008

220

2

GE, SUI FLO

FLP

34,8

24,5

5,8

3,9 10,7

8,8

0,08

11,6

14,7

5,4

2,0

Estudio

francés

Dank M

2008

333

9

E, NA IFL

FP4w

31,8

25,8

5,0

4,2 9,0

8,7

NS

24,8

51,6

NR

1ª línea: ensayos fase III

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: 8.6-11.2 meses

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

INHIBICIÓN LIGANDO VEGF • Bloqueo VEGF

• Inhibición señal VEGF(s)

Bevacizumab

Aflibercept

Ziv-aflibercept

Neovastat

Cediranib

Brivanib alaninate

Motesanib

Linifanib

Tivozanib

Angiogenic signaling network

AVAGAST fase III: CX + bevacizumab

CX + BEVACIZUMAB

CX + PLACEBO

P HR (IC 95%)

SLP 6.7 meses 5.3 0.004 0.80 (0-68-0.93)

RR 46% 37% 0.03

SG 12.1 meses 10.1 0.10 0.87 (0.73-1.03)

Cáncer Gástrico Avanzado

BEVACIZUMAB

FOLFOX + Ramucirumab en 1ª línea

FOLFOX + Ramucirumab en 1ª línea

Cáncer Gástrico Avanzado

RAMUCIRUMAB

Phase III trials in second-line AGC

Javle M, et al Clin Cancer Res 2014

Mechanism of action of Ramucirumab

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

Wilke H et al, Lancet Oncol 2014; 15: 1224-35

OS:

R+P:9.6 m vs P: 7.4 m

HR 0.807

P:0.017

PFS:

R+P: 4.4m vs P: 2.9 m

HR:0.635

p<0.0001

Wilke H et al, Lancet Oncol 2014; 15: 1224-35

Category Subgroup N

(RAM+PTX) N

(PBO+PTX) HR

Overall 330 335 0.807

Combined Geo. Regiona Region 1+2 221 221 0.732

ASIA Region 3 109 114 0.986

Time to PD on 1st-line Therapy < 6 months 250 256 0.871

≥ 6 months 80 79 0.615

Disease Measurability Non-measurable 63 62 1.101

Measurable 267 273 0.750

Gender Male 229 243 0.814

Female 101 92 0.672

Age Group (yrs) < 65 204 212 0.753

≥ 65 126 123 0.861

ECOG PS 0 117 144 0.778

1 213 191 0.771

Histologic Subtype Intestinal 145 135 0.705

Diffuse 115 133 0.856

Mix/Miss./Unk. 70 67 0.955

Number of Metastatic Sites ≤ 2 209 232 0.749

> 2 121 103 0.815

Primary Tumor Location Gastric 264 264 0.899

GEJ 66 71 0.521

Prior Gastrectomy Yes 133 126 0.939

No 197 209 0.753

Peritoneal Metastases Yes 163 152 0.807

No 167 183 0.758 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.

Favors RAM+PTX Favors PBO+PTX 1

0.2

Análisis de subgrupos para SG

Region RAM+PTX PB+ PTX Delta HR

95% CI

mSG

(m)

Asia 12.1 10.5 1.6 0.99a 0.73, 1.34

EU/NA/AUS + Central/South Am. 8.5 5.9 2.6 0.73a 0.59, 0.91

mSLP

(m)

Asia 5.5 2.8 2.7 0.63a 0.47, 0.83

Resto 4.2 2.9 1.3 0.64a 0.52, 0.79

RR

(%)

Asia 33.9% 20.2% 13.7% 2.24b 1.18, 4.24

Resto 24.9% 14.0% 10.9% 2.09b 1.28, 3.41

Brazo tratamiento RAM + PTX (N=327) PBO + PTX (N=329)

TOXICIDAD Cualquier

Grado (%)

Grado ≥3

(82%)

Cualquier

Grado (%)

Grado ≥3

(63%)

Fatiga 56.9 11.9 43.8 5.5

Neutropenia 54.4 40.7 31.0 18.8

Neutropenia febril 3.1 2.4

Neuropatía 45.9 8.3 36.2 4.6

Hipertension 25.1 14.7 5.8 2.7

Muertes por toxicidad 4 4.6

Ajuste dosis: - Ramucirumab vs Paclitaxel

Profilaxis con FSC-G

Cáncer Gástrico Avanzado

RAMUCIRUMAB

Quin S et al, J Clin Oncol 2014

OS 195 d vs 140 d (p<0.016) PFS: 78 d vs 53 d (p<0.0001)

Phase III Apatinib vs. Placebo:

Cáncer Gástrico Avanzado

APATINIB

Cáncer Gástrico Avanzado

REGORAFENIB

Ramucirumab en 2ª línea: 2 estudios fase III positivos

Fuchs, Lancet 2014; Wilke, Lancet Oncol 2014

2ª línea de tratamiento

Cáncer Gástrico Localizado BEVACIZUMAB

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

• QoL scales/itemsa that met prespecified criteria for meaningful change

45

Changes in QoL Scales/Items as Predictors of Best Overall Response

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

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 Ajani1; Adrian Udrea2; Tomasz Sarosiek3; Michael Shenker4; Carys Morgan5; Joanna Pikiel6; Elzbieta Wojcik7; Daniel Swinson8; Mano Joseph9; Alexander Luft10; Tomas Salek11; Christophe Tournigand12;

David Ferry13; Yawei Zhang13; Amanda Long13; Wen-Ling Kuo13; Ling Gao13; Francesca Russo14; John Kauh15; Wasat Mansoor16

1University of Texas MD Anderson Cancer Center, Houston, Texas, United States; 2MedisProf SRL, Cluj-Napoca, Romania; 3Magodent, Warszawa, Poland; 4Centrul de Oncologie Sf. Nectarie SRL, Craiova, Romania; 5Velindre Cancer Centre, Cardiff, United Kingdom; 6COPERNICUS Podmiot Leczniczy, Gdańsk, Poland; 7NZOZ Centrum Medyczne HCP, Poznań, Poland; 8St James's University Hospital, Leeds, United Kingdom; 9New Cross Hospital–Deanesly Centre, Wolverhamptom, United Kingdom; 10Leningrad Regional Clinical Hospital, St. Petersburg, Russian Federation; 11Narodny Onkologicky Ustav, Bratislava, Slovakia; 12APHP, CHU Henri Mondor, Creteil Cedex, France; 13Eli Lilly and Company, Bridgewater, New Jersey,

United States; 14Eli Lilly Italy, Florence, Italy; 15Former employee of Eli Lilly and Company, Bridgewater, New Jersey, United States; 16Christie Hospital NHS Foundation Trust, Manchester, United Kingdom

2017 ESMO Annual Meeting; Madrid, Spain; September 8 – 12, 2017 Sponsored by Eli Lilly and Company and/or one of its subsidiaries

698P

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

♦ 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

CONCLUSIONS

METHODS

Abbreviations: D=day; ECOG PS=Eastern Cooperative Oncology Group

Performance Status; QW=every week; Q2W=every 2 weeks; Q3W=every 3

weeks

Figure 1. Study Design

Figure 3. PFS and OS of 8 mg/kg Q2W vs. 12 mg/kg Q2W (Non-Stratified)

PFS

OS

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

1:1:1:1

Randomization

(N = 164)

Stratified by:

• Body weight

(< 60 kg vs. ≥ 60 kg)

• ECOG PS (0 vs. 1)

Arm 2

12 mg/kg Q2W

(28-day cycles)

(n = 42)

Arm 3

6 mg/kg QW

(28-day cycles)

(n = 41)

Arm 4

8 mg/kg D1D8

Q3W

(21-day cycles)

(n = 41)

Arm 1

(Standard)

8 mg/kg Q2W

(28-day cycles)

(n = 40)

Treat Until:• Disease

progression

• Toxicity

requiring

cessation of

treatment

• Death

• Withdrawal of

consent

• Other

withdrawal

criteria

Post-

Discontinuation

Follow-up and

Study

Completion

Trough

Time (weeks)

0 4 8 12

Mea

n R

amuc

irum

ab C

once

ntra

tion

(µg/

mL)

0

50

100

150

200

250

Peak

Time (weeks)

0 4 8 12

Mea

n R

amuc

irum

ab C

once

ntra

tion

(µg/

mL)

0

100

200

300

400

500

8 mg/kg Q2W 6 mg/kg QW 8 mg/kg D1D8 Q3W12 mg/kg Q2W

Peak

Corresponding Author: Francesca Russo, russo_francesca@lilly.com

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

MUCHAS GRACIAS