TERAPIA ADIUVANTE, TERAPIA ADIUVANTE, NEOADIUVANTE E DELLA NEOADIUVANTE E DELLA

MALATTIA AVANZATA NEL MALATTIA AVANZATA NEL CARCINOMA GASTRICOCARCINOMA GASTRICO

Sara LonardiSara Lonardi

Oncologia Medica 1Oncologia Medica 1

Istituto Oncologico VenetoIstituto Oncologico Veneto

PadovaPadova

GC mortality in Italy derived from population based cancer registries

AIRTUM, 2013

Carcinoma gastrico: chemioradioterapia adiuvante

Macdonald, N Engl J Med 2001

556 resected stage IB-IV M0 gastric cancer

Random

Observation

5FU/LV + RT

Carcinoma gastrico: chemioradioterapia adiuvante

Relapse-free Survival by treatment arm

Overall Survival by treatment arm

HR 1.35 (95% CI: 1.09-1.66)P=0.005mOS 36 vs 27 months

HR 1.52 (95% CI: 1.23-1.86)P<0.001mRFS 30 vs19 months

Macdonald, N Engl J Med 2001

Carcinoma gastrico: chemioradioterapia adiuvante

Major critic: surgery inadequate

Macdonald, N Engl J Med 2001

Carcinoma gastrico: chemioterapia adiuvante – nuovi studi

Reference Stage Treatment N of patients

5-yr survival

P

Bajetta, 2002 pT3-4/N+ EAP x 2 → 5FU x 2Surgery alone

135136

5248

NS

Bouché, 2005 II-IV M0 PF x 5Surgery alone

138140

46.641.9

NS

Nitti, 2006 IB-IV M0 FAMTX or FEMTX x 6Surgery alone

194203

4344

NS

De Vita, 2007 IB-IIIB ELFE x 6Surgery alone

113112

4843.5

NS

Di Costanzo, 2008 IB- IV M0 PELF x 4Surgery alone

130128

47.648.7

NS

Cascinu, 2007 II-IV M0 PELFw x 85FU bolus x 6

201196

5250

NS

Carcinoma gastrico: chemioterapia adiuvante –metanalisi

Reference N. of studies

N of patients

HR 95% CI Reduction of Mortality

Bajetta, 2008 15 3514 0.82 NR 7%

Boku, 2008 14 3293 0.81 0.73-0.89 7%

GASTRIC, 2010 16 3710 0.83 0.76-0.91 6.5%

Carcinoma gastrico: chemioterapia adiuvante –metanalisi

GASTRIC, JAMA 2010

Chemioterapia adiuvante: XELOX

Chemioterapia adiuvante: fattibilità

CT adiuvante e perioperatoriastudi di fase III

Autore Sakuramoto 2007(ACTS-CG)

Cunningham 2006(MAGIC)

Ychou 2011(FNCLCC/FFCD)

Stato Giappone UK Francia

Stadio II/III II/III III

N. Pz 529/530 250/253 113/111

Strategia Adiuvante Perioperatoria Perioperatoria

Tratt sperimentale

S1 post ECFx3 preop+post

FPx3 preop+post

controllo Follow-up Follow-up Follow-up

Loc gastrico/AEG NA 74%/26% 25%/75%

HR 0.68 P=0.003 0.75P=0.009 0.69P=0.02

Braccio di controllo :chirurgia

5-year OS in advanced GC (aGC): a sad starting point!

What are the aims of CT in this setting?

• Symptomatic control

• Improve of QoL or avoid its deterioration

• Delay tumor progression

• Prolong survival

Should pts with aGC receive CT?

Wagner AD, JCO 2006

Effect of combination vs BSC on overall survival

Glimelius B, Ann Oncol 1994

When should pts with aGC receive CT?

Should pts with aGC receive mono or poliCT?

Wagner AD, JCO 2006

Effect of combination vs single-agent CT on OS

Recent phase III trials in aGC

Non-inferior

Study N 1st EP CT scheme mOS

REAL-2 964 OSECF vs EOF vs

ECX vs EOX9.9 vs 9.9 vs 9.3 vs 11.2

ML17032 316 PFS XP vs CF 10.5 vs 9.3

JCOG9912 704 OS S1 vs FU 11.5 vs 10.8

Superior

Study N 1st EP CT scheme mOS

V325 457 TTP DCF vs CF 9.2 vs 8.4

V306 333 TTP IF vs CF 9.0 vs 8.7

JCOG9912 704 OS IP vs FU 12.3 vs 10.8

SPIRITS 305 OS S1P vs S1 13 vs 11

TOP-002 326 OS IS1 vs S1 12.8 vs 10.5

FLAGS 1053 OS S1P vs CF 8.6 vs 7.9

START 639 OS DS1 vs S1 12.5 vs 10.8

Oxaliplatin is as effective than cisplatin

Cunningham D, NEJM 2008

Al Batran SE, JCO 2008

Oral fluoropyrimidines can replace 5-FU: Capecitabine

Okines, Ann Oncol 2009

HR 0.87(p=0.027)

DCF improves CT efficacy over CF

Van Cutsem E, JCO 2006

Best overall response rate

(A)TTP and (B) OS among pts treated with DCF or CF

BUT…

…Toxicity

Van Cutsem E, JCO 2006

Hematologic and nonhematologic toxicities

Alternative Docetaxel-containing regimen

Tebutt NC, Br J Cancer 2010

Total events

Heterogeneity: ChP = 10.76, df = 11 (P = 0.46); P = 0%

Test for overall effect: Z = 4.67 (P < 0.00001)

Total events

Heterogeneity: ChP = 10.76, df = 11 (P = 0.46); P = 0%

Test for overall effect: Z = 4.67 (P < 0.00001)

DCF regimens increase ORR compared with non- docetaxel containing CT

Cheng XL, Plos One 2013

DCF Control Risk Ratio

Study or subrgroup Events Total Events Total Weight M-H, Fixed, 95% CI Year

Sadighi S, et al 18 44 17 42 10.5% 1.01 (0.61. 1.68) 2006

Chu JH, et al 9 20 3 20 1.8% 3.00 (0.95. 9.48) 2006

Van CE, et al 81 221 57 224 34.0% 1.44 (1.08. 1.91) 2006

Roth AD, et al 15 41 10 40 6.1% 1.46 (0.75. 2.86) 2007

Li XQ, et al 22 30 19 30 11.4% 1.16 (0.82. 1.64) 2007

Zhang FL, et al 12 25 5 25 3.0% 2.40 (0.99. 5.81) 2007

Wu GC, et al 21 32 10 26 5.5% 1.71 (0.99. 2.95) 2008

Hou AJ, et al 10 19 3 17 1.9% 2.98 (0.98. 9.07) 2009

Shen YC, et al 11 24 9 24 5.4% 1.22 (0.62. 2.40) 2009

Zhao F, et al 16 31 15 32 8.9% 1.10 (0.67. 2.40) 2009

Liang B, et al 11 30 8 28 5.0% 1.28 (0.61. 2.72) 2010

Gao H, et al 18 32 9 32 5.4% 2.00 (1.06. 3.76) 2010

Total (95% CI) 549 540 100.0% 1.45 (1.24, 1.69)

165165244244

Risk Ratio

M-H, Fixed, 95% CI

Risk Ratio

M-H, Fixed, 95% CI

220.50.5 0.70.7 11 1.51.5

Favours DCFFavours DCFFavours ControlFavours Control

Forest plot of overall response rate

Overall Response Rate of triplet CT Data from randomized trials

EOXEOX

Overall Response Rate Overall Response Rate

ECXECX

ECFECF

DCFDCF

48%48%

46%46%

45%45%

35%35%

Time (months)

294290

277266

246223

209185

173143

147117

11390

9064

7147

5632

4324

3016

2114

137

126

65

40

10

00

No. at risk

11.1 13.8

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Event

FC + T

FC

Events

167182

HR

0.74

95% CI

0.60, 0.91

p value

0.0046

MedianOS

13.811.1

ToGA primary end point: OS

Bang, Lancet 2010

Targeting HER-2ToGA Trial: OS

1.0

0.8

0.6

0.4

0.2

0.0

363432302826242220181614121086420

11.8 16.0

FC + TFC

Events

120136

HR

0.65

95% CI

0.51, 0.83

MedianOS

16.011.8

4.2

0.1

0.3

0.5

0.7

0.9

Months

113

218198

40

53

124

2011

228218

196170

170141

142112

12296

10075

8453

6539

5128

10

00

3920

2813

No. at risk

Probability of survival

Exploratory analysis

Targeting HER-2ToGA Trial: OS in pts with IHC 2+/FISH+ or IHC 3+ disease(exploratory analysis)

Bang, Lancet 2010

Second-line CT is effective in aGC

COUGAR-02

Kim HS, Ann Oncol 2013

HR for death comparing 2nd line docetaxel with BSC

HR for death comparing 2nd line CT with BSC

HR for death comparing 2nd line irinotecan with BSC

Second-line CT is effective in aGC

Second-line CT is effective in aGC

HR (95% CI) = 0.807 (0.678, 0.962)

Stratified log rank p-value = 0.0169

RAM + PAC PBO + PAC

Patients / Events 330 / 256 335 / 260

Median(mos) (95% CI)

9.63 (8.48, 10.81)

7.36 (6.31, 8.38)

6-month OS 72% 57%

12-month OS 40% 30%

RAM + PAC 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0

PBO + PAC 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0

No. at risk

Censored

mOS = 2.3 months

REGARD Trial

RAIMBOW Trial

Wilke H, ASCO GI 2014

Fuchs CS, ASCO GI 2013

Which pts should receive CT?PS 2 pts present a very poor outcome

Shitara K,Gastr Cancer Res 2009

OSTTP

Chau I, JCO 2004

PS2

Liver mets

Peritoneal mets

Alkaline Phosphatase

Overall survival by prognostic index

Which pts should receive CT?Different risk groups

Does CT improve/impair QoL?QoL and efficacy outcomesin phase III trials

Al Batran SE Cancer,2010

How we will make any progress in the treatment of advanced GC ?

5-FU monotherapy5-FU monotherapy

EOXEOX

Median overall survival in advanced gastric cancerMedian overall survival in advanced gastric cancer

5-FU + LV +Oxaliplatin (FLO)

5-FU + LV +Oxaliplatin (FLO)

Capecitabine +Cisplatin (XP)

Capecitabine +Cisplatin (XP)

SP SP

Docetaxel +Cisplatin + 5FU

Docetaxel +Cisplatin + 5FU

11.2 mo11.2 mo

10.7 mo10.7 mo

10.5 mo10.5 mo

9.2 mo9.2 mo

7.0 mo7.0 mo

8.6 mo8.6 mo

13 mo13 moX/FP+ TX/FP+ T HER2 +

16 mo16 moHER2 IHC 3+ or IHC 2+/FISH +X/FP+ TX/FP+ T

Best supportive care

Best supportive care

4.0 mo4.0 mo

Shah MA, Clin Canc Res 2011

6926

6926345

115

345115

3618

3618365

166

365166

11564

11564

488221

488221

72478110

72478110up

down

updown

7520

7520

Type 2 - normalType 1 - normal

Type 3 - normal

GC: a single tumor or an heterogeneous disease?

•GC treated uniformly, despite epidemiologic, anatomic, and histopathologic distinctions between subtypes

•Proximal non-diffuse, diffuse, and distal non-diffuse gastric cancers can be distinguished by gene signatures

Targets in advanced GC

MET

FGFR2

EGFR

HER2

PI3K/mTOR

VEGF

1stL

Study Target N 1st EP CT scheme mOS (m) ORR

TOGA HER2 594 OSCX

CX + Trastu11.1

13.8 (16.0)34.5%47.3%

LOGIC HER2 497 OSCAPEOX

CAPEOX + Lapatinib10.512.2

40%53%

AVAGAST VEGF 774 OSCX

CX + Beva10.112.1

37%46%

REAL-3 EGFR553

(76%)OS

EOCmEOC-Pani

11.38.8

42%46%

EXPAND EGFR 904 PFSCX

CX-Cetuximab10.79.4

29%30%

AMG102 MET 118PFS (phase

II)ECX

ECX-Rilotu8.9

11.1

2ndL

GRANITE mTOR 656 PFSPlacebo

Everolimuns4.345.39

2.1%4.5%

REGARD VEGFR-2 355 OSPlacebo

Ramucirumab3.85.2

2.6%3.4%

RAINBOW VEGFR-2 665 OSPaclitaxel +/-Ramucirumab

7.369.63

16%28%

RAINBOWRAINBOW

TOGATOGA

AMG102AMG102

REGARDREGARD

Target therapy in GC: results

No patient selection based on PI3K/mTOR status

Targeting PI3K/mTORGRANITE-1 Trial: OS

Ohtsu A, JCO 2013

Target therapies

• Targeting right patients with targeted agents based on good biomarker in gastric cancer is important

• To better patient selection molecular selection is needed

• More knowledge

• Better technique

• Better design of trials

• Targeting right patients with targeted agents based on good biomarker in gastric cancer is important

• To better patient selection molecular selection is needed

• More knowledge

• Better technique

• Better design of trials

Take-home messages

- CT adiuvante: si, beneficio assoluto del 7%- CT-RT adiuvante: in casi selezionati (linfadenectomia)- CT perioperatoria: si, meglio tollerata

- CT per malattia avanzata: si, prima possibile (PS 2: ?)- CT a due farmaci: si, platinum-based- CT a tre farmaci: in casi selezionati (bulky, sintomatici)- CT target: si, trastuzumab in HER2 +- CT di seconda linea: si, in pazienti a buon PS

1st-line treatment algorithm in aGC

Immunohistochemistry (IHC) for Her2

FISH-Test for Her2

IHC Score 3+IHC Score 0/1+ IHC Score 2+

FISH +FISH -

Trastuzumab +Cisplatin-Fluoropyrimidine

Platin-Fluoropyrimidin(Docetaxel/Epirubicin)

Post-progression chemotherapy

ECOG PS 0-1(2) ECOG PS 3-4

Best Supportive care

Irinotecan or Taxane+

best supportive care

Second-line treatment algorithm in aGC