systemic treatment in early and advanced gastric cancer · systemic treatment in early and advanced...

Systemic Treatment in Early and Advanced

Gastric Cancer

Prof. Florian Lordick

University Cancer Center Leipzig, Germany

UCCL

ESO-ESMO Masterclass

26 March 2018, Berlin

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© University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 2

Gastric Cancer – Multimodal Treatment Strategies

Lordick F. ASCO lecture 2014

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Gastric Cancer ESMO Guidelines

Smyth EC et al. Ann Oncol 2016 Sep;27(suppl 5):v38-49 17th ESO-ESMO M

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Peri-/Preoperative Therapy

CTx

Surgery

Primary endpoint: survival RANDOM

Surgery CTx

MAGIC

St. II + III

Stomach +

Cardia +

Dist. Eso

© Universitätsklinikum Leipzig AöR: Universitäres Krebszentrum Leipzig (UCCL), Prof. Dr. Florian Lordick

Cunningham D et al. N Engl J Med 2006;355:11-20

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Perioperative Therapy

23%

5-y-OS

36%

UK MAGIC 2006

Cunningham D et al. N Engl J Med 2006;355:11-20

ECF

Surgery alone

Stomach Cancer 74%

EGJ Cancer 26%

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© Universitätsklinikum Leipzig AöR: University Cancer Center Leipzig (UCCL), Prof. Dr. F. Lordick 6

FLOT-4-Study

Al-Batran SE et al. Lancet Oncol 2016 Dec;17(12):1697-1708

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FLOT-4-Study

Al-Batran SE et al. Lancet Oncol 2016 Dec;17(12):1697-1708

pCR pCR + subtotal remission

Intestinal Mixed Diffus

R0 resection rate: 85% (FLOT) versus 74% (ECF), p=0.02

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FLOT-4-Study

Al-Batran SE et al. ASCO 2017; abstract 4006

Overall Survival

ECF/ECX FLOT

mOS 35 months 50 months

[27-46] [38-na]

HR 0.77 [0.63 - 0.94]

p=0.012 (log rank)

2y 59% 68%

3y 48% 57%

5y 36% 45%

OS rate* ECF/ECX FLOT

*projected OS rates

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Radiotherapy and D1+/D2 Surgery - Trials

CRITICS (NL, Sweden)

Stage Ib-IVa

TOPGEAR (AUS, CAN, EU)

Stage Ib-IVa

R

R

CTx (ECX) Resection Radio-CTx

CTx (ECX) Resection CTx (ECX)

CTx (ECX) Resection Radio-CTx

CTx Resection CTx


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CRITICS


CRT

n=248

n=393 3x CT

n=334

3x CT

n=238

n=395 3x CT

n=318

Randomization

Completed

pre-operative

chemotherapy

n=788 Underwent

curative

surgery

Started

post-operative

treatment

Completed

treatment

n=184

n=205

100% 85% 94% 80% 61% 47%

100% 81% 93% 84% 63% 52%

Started

surgery

Surgery

n=316 n=371

Surgery

n=332 n=367

Verheij et al. ASCO 2016; abstract 4000

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CRITICS


CT CRT

5-year OS (%) 40.8 40.9

Median OS (yrs) 3.5 3.3

Verheij et al. ASCO 2016; abstract 4000

Overall Survival

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Novel Drugs

Anti-Angiogenesis Bevacizumab STO-3 (MAGIC-B)

ECX+/-Bevacizumab

Phase III negative (STO-3)

Anti-Her2 Trastuzumab/ EORTC-INNOVATION

Pertuzumab CX +/- anti-HER2

Recruiting

Immuno-Oncology PD-1/PD-L1/CTLA-4 EORTC Vestige / AIO Dante

Inhibitors and many other studies

Ongoing


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INNOVATION Study

HER2-positive

mGC or GEJ

adenocarcinoma

(N = 220)

Centrally

confirmed

Stages IB-III

R 1:2:2

XC or FLOT 3 / 4 cycles

(N = 44)

Surgery

Chemo + TP 3 cycles

(N = 88)

Chemo + T 3 cycles

(N = 88)

XC or FLOT 3 / 4 cycles

Chemo + TP 3 cycles

Chemo + T 3 cycles

T for up to 1 year

TP for up to 1 year

.

● Primary endpoint: histopathological near complete response

(<10% viable tumour cells) after neoadjuvant therapy

● Stratification: histological subtype (intestinal/non-intestinal); Korea versus Europe;

stage II versus III; node positive versus node negative

T: Trastuzumab; P: Pertuzumab

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Summary

Perioperative chemotherapy is the EU standard of care

for localized gastric cancer (N+ and/or T3-4 resectable)

Perioperative chemotherapy comprises a platinum

compound and a fluoropyrimidine, given for 8-9 weeks

pre- and postop.

Taxanes improve perioperative chemotherapy outcomes

Studies on integration of radiotherapy are ongoing

(now focus on neoadjuvant)

Anti-HER2 treatment is under investigation

Immunotherapy is under investigation

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Metastatic Gastric Cancer 1st line – Standards (I)

Wagner et al. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD004064

Chemotherapy prolongs survival

Chemotherapy improves symptom control

Established standard:

Platinum+Fluoropyrimidine combinations

Combinations more effective than 5-FU mono

Wagner et al. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD004064

© University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 17th ESO-ESMO M

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Metastatic Gastric Cancer 1st line – Standards (II)

Oxaliplatin can substitute for Cisplatin Some advantages, especially in older patients

Capecitabine or S-1 can substitute for i.v. 5-FU

A third drug increases the efficacy but also toxicity Epirubucine was used a lot in UK and NL

Docetaxel: 3-weekly DCF regimen toxic - modified DCF preferred

Al-Batran et al. J Clin Oncol 2008; 26: 1435-1442

Cunningham et al. N Engl J Med 2008; 358: 36-46

Cunningham et al. N Engl J Med 2008; 358: 36-46

Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7

Ajani et al. J Clin Oncol 2010; 28: 1547-1553

Al-Batran et al. Ann Oncol 2008; 19: 1882-7

Lorenzen et al. Ann Oncol 2007; 18: 1673-9


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Commonly Used Regimens for GC Stage 4

Doublets Cisplatin-S-1- Japan

Cisplatin-5FU - Europe

Cis-/Oxaliplatin-Capecitabine - Korea

Oxaliplatin-5FU (FOLFOX ) – U.S., Europe

Irinotecan-5FU (FOLFIRI) - France

Triplets Epirubicin-Cisplatin-5FU (ECF) and related regimens – UK, NL

Docetaxel-Cisplatin-5FU (DCF) and related regimens (FLOT) - Germany

Survival 8-11 months; Japan 11-16 months


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© University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick

Specific issues

High tumor burden / high symptom burden

Older patients

Molecular targets

Second-line therapy

Immunotherapy

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High Tumor Burden / Symptoms – Taxane-Triplet?

Time to progression

5.6 vs. 3.7 months p<0.01

Survival

9.2 vs. 8.6 months p=0.02

Response Rate

37% vs. 25% p=0.01

Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7

Docetaxel-CF vs. CF

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Better Tolerated Triplets (Modified DCF)

Lorenzen et al. Ann Oncol 2007; 18: 1673-9

GastroTax-1 regimen

Docetaxel 40mg/m2 + cisplatin 40mg/m2 2-weekly

5-FU 2000mg/m2 – folinic acid 200mg/m2 weekly

Response rate 46.6%

Time to progression (St. IV) 8.1 months

Survival (St. IV) 15.1 months

Al-Batran et al. Ann Oncol 2008; 19:1882-87

FLOT regimen

Docetaxel 50mg/m2 + modified FOLFOX 2-weekly

Response Rate 53%

Time to progression 5.3 months

Survival 11.3 months

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Older Patients

Toxicity grade 3/4

FLOT: 81.9%

FLO: 38.6% (P < 0.001)

Deterioration on

EORTC Global Health

scale > 10 points

FLOT: 47.5%

FLO: 20.5% (P < 0.01)

PFS

Al-Batran S et al., Eur J Cancer 2013; 49: 2823-2831

FLO: 5-FU-Leucovorin-Oxaliplatin

FLOT: 5-FU-Leucovorin-Oxaliplatin-Docetaxel

FLOT 65+ Study (n=142, median 70 years)

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Druggable Recepetor Tyrosine Kinases

Anti-EGFR

negative Phase-3: EXPAND, REAL3 Lordick et al. Lancet Oncol 2013

Waddell et al. Lancet Oncol 2013

Anti-MET

negative Phase-3: MetMab, RiloMet Shah et al. ASCO 2015

Cunningham et al. ASCO 2015

anti-FGFR

preliminary Phase-2: Shine Bang et al. ASCO 2015

KRAS

non druggable (?)

HER2

positiv Phase-3: ToGA

Bang et al. Lancet 2010

Genomic DNA were extracted from flash-frozen tissues or cell

pellets using a Qiagen genomic DNA extraction kit (Qiagen,

Hilden, Germany), and profiled on Affymetrix SNP 6.0 arrays

(Affymetrix, Santa Clara, California, USA)

Deng et al. Gut 2012; 61: 673-684

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HER2-positive Gastric Cancer

Significant HER2 positivity: ~16%

Proximal > distal gastric cancer

Intestinal >> diffuse gastric cancer

Bang Y, et al. Lancet 2010;376:687–97

Survival advantage with trastuzumab in HER2+ gastric cancer

CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio.

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Gastric Cancer 1st-line Treatment Algorithm

Lordick F, Janjigian YY. Nat Rev Clin Oncol 2016 Jun;13(6):348-60. HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridisation.

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Anti-HER2 Directed Drugs

from: Metzger-Filho O, et al. Clin Cancer Res 2013; 19: 5552-5556

The mechanism of action of pertuzumab and trastuzumab. Trastuzumab binds to the ECD IV of the HER2 receptor,

preventing the spontaneous formation of homodimers (HER2–HER2) and ligand-independent heterodimers

(HER2–HER3 and also HER2–HER1 and HER2–HER4). Pertuzumab binds to the dimerization domain of the HER2 receptor

(ECD II), preventing the formation of ligand-induced HER2 heterodimers.

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HER2-positive Advanced Gastric Cancer


R

A

N

D

O

M

1:1 primary endpoint: survival

Gastric

and EGJ

Stage IV

1st-line

chemo-naive

Multinational

Multicenter

Trastuzumab + Pertuzumab - Cisplatin/FP

q3w 6 cycles

Trastuzumab/Pertuzumab until progression

Trastuzumab + Cisplatin/FP

q3w 6 cycles

Trastuzumab until progression

JACOB Study

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Pertuzumab – Trastuzumab – JACOB Studie


Tabernero J et al. Ann Oncol 2017;28(Suppl 5):Abstr 616O

Pro

ba

bili

ty o

f P

FS

Time, months

1.0

0.8

0.6

0.4

0.2

0 0

388

392

6

323

306

2

363

359

4

342

339

8

297

279

14

209

175

10

266

252

12

243

221

16

175

143

22

92

76

18

149

118

20

114

95

24

67

60

26

54

47

28

36

38

34

10

14

30

27

31

32

16

23

36

6

7

42 38

4

4

40

3

2

Arm A (n=388)

Arm B (n=392)

Censored

No. at risk

Arm A

Arm B

ITT population

Arm A

(n=338)

Arm B

(n=392)

Events, n 242 262

Median, months 17.5 14.2

HR (95%CI) 0.84 (0.71, 1.00)

p-value (log-rank) 0.0565

Median duration of survival follow-up

• Arm A: 24.4 months (min–max 22.3–26.1)

• Arm B: 25.0 months (min–max 22.3–28.9)

OS

Arm A (n=388) Arm B (n=392) HR (95%CI)

mPFS, months 8.5 7.0 0.73 (0.62, 0.86)

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2nd-line Chemotherapy – Randomized Studies

Studie Medikament Überleben Verbesserung

Thuss-Patience et al.

Eur J Cancer 2011,

AIO, D (n=40)

Irinotecan

vs. BSC

4.0 mon vs.

2.4 mon

(p=0.012)

HR 0.48

∆ 1.6 months

Kang et al.

J Clin Oncol 2012,

Korea (n=202)

Irinotecan oder

Docetaxel

vs. BSC

5.3 mon vs.

3.8 mon

(p=0.007)

HR 0.657

∆ 1,5 months

Ford et al.

Lancet Oncol 2014,

COUGAR-02, UK (n=168)

Docetaxel

vs. BSC

5.2 mon vs.

3.6 mon

(p=0.001)

HR 0.67

∆ 1,6 months

Hironaka et al.

J Clin Oncol 2013

WJOG, Japan

(n=219)

Paclitaxel

vs. Irinotecan

9.5 mon vs.

8.4 mon

(p=0.38)

HR 1.13

∆ 1.1 months

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Anti-Angiogenic Approach

© Universitätsklinikum Leipzig: UCCL - Onkologie, Prof. Dr. med. F. Lordick

Clarke JM et al. Expert Opin Biol Ther 2013; 13: 1187-1196

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Ramucirumab 2nd-line (RAINBOW)


Wilke et al., Lancet Oncol 2014; [published online 18 September]

R

A

N

D

O

M

1:1

Primary endpoint: survival

N=665

Stomach

and EGJ

Stage IV

2nd-line

after Platin/5FU

170 centers

27 countries

Ramucirumab 8mg/kg q2w

Paclitaxel 80 mg/m² d1,8+15 q4w until progression

Placebo q2w

Paclitaxel 80 mg/m² d1,8+15 q4w until progression

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Ramucirumab 2nd-line (RAINBOW)


Wilke et al., Lancet Oncol 2014; [published online 18 September]

RAM +

Paclitaxel

Placebo +

Paclitaxel

HR

P-value

Response Rate 28% 16% p =0.0001

PFS (med, Mon)

6 months (%)

4.4

22%

2.9

10%

HR 0.635

p <0.0001

OS (med, Mon)

6 months

9.6

40%

7.3

30%

HR 0.807

p =0.0169

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2nd-line Therapy of Gastric Cancer


ECOG, Eastern Cooperative Oncology Group; PS, performance status. Lordick F, Janjigian YY. Nat Rev Clin Oncol 2016 Jun;13(6):348-60.

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Immunotherapy – PD1-PDL1 Checkpoints


Ribas et al. N Engl J Med 2015 Oct 15;373(16):1490-2

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PD-L1 Expression

Thompson ED et al. Gut 2017 May;66(5):794-801

H&E H&E

PD-L1 Tumor cells PD-L1 Stroma


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Pembrolizumab - anti-PD1 mAB – Keynote-059

Fuchs C, et al. JAMA Oncol 2018 [Epub ahead of print]

Keynote-059 (n=259)

Objective response rate 11.6%

MSI-high 4/7; 57.1%

Non-MSI-high 15/167; 9.0%

Median duration of response 8.4 months

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Nivolumab effective in GC (East Asia)


Kang YK et al. Lancet 2017 Dec 2;390(10111):2461-2471

ATTRACTION-2 / ONO-4538-012: Phase III randomized study to evaluate the efficacy and safety of nivolumab in patients with unresectable advanced or recurrent gastric or GEJ cancer refractory to or intolerant of standard therapy.

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Nivolumab effective in GC (East Asia)



12-months OS 12% vs 27%

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New Molecular Classification of Gastric Cancer

The Cancer Genome Atlas Research Network, Nature 2014; 11th September, 513: 202-209

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8–11 May 2019, Prague, CZ

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Back-Up

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Postoperative Therapy

© Universitätsklinikum Leipzig (2013): UCCL - Onkologie, Prof. Dr. med. F. Lordick

Surgery

Primary endpoint: survival RANDOM

Surgery CTx

Adjuvant Studies

St. II + III

Stomach

Cancer

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Postoperative Chemotherapy (Metaanalysis)


GASTRIC Group JAMA 2010; 303:1729-37

5- year survival

Surgery alone 49.6 %

Adjuvant chemotherapy 55.3 %

HR = 0.82; p < 0.001

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Postoperative Chemotherapy


Sakuramoto S et al. N Engl J Med 2007;357:1810-1820 Sasako et al. J Clin Oncol 2011; 29: 4387-4393

Overall Survival

HR = 0,669 (95% CI, 0.540 to 0.828)

P = 0,003

Japan ACTS-GC 2007

(1 year S-1)

Korea/China/Taiwan

Classic 2012

(6 mon Cape-Ox.)

BangYJ et al. Lancet 2012; 379: 315-21

Overall Survival (preliminary)

HR = 0,72 (95% CI, 0.52 to 1.00)

P < 0,0493

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Postoperative Chemotherapy – CapOx (CLASSIC)


Korea/China/Taiwan

Classic 2012

BangYJ et al. Lancet 2012; 379: 315-21

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Adjuvant Chemotherapy – CapOx (CLASSIC)

BangYJ et al. Lancet 2012; 379: 315-21 Noh SH et al. Lancet Oncol 2014; 15: 1389-96

Tumor stage and efficacy of oxaliplatin-capecitabine (CapOx)

∆ 21%

∆ 7%

∆ 9%

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Conclusion Postoperative Chemotherapy


Adjuvant chemotherapy is moderately effective

Gain in overall survival ~ 5 %

More effective in N+ disease

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Perioperative Therapy

Cisplatin/5-FU 8 weeks peri-op.

Surgery alone 24%

5-y-OS

38%

Ychou et al. J Clin Oncol 2011; 29: 1715-21

France FNCLCC 2011

Stomach Cancer 25%

EGJ Cancer 75%


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Anti-Angiogenesis perioperative

48 © Universitätsmedizin Leipzig: University Cancer Center Leipzig (UCCL), Prof. Dr. F. Lordick

STO-3/MAGIC-B (UK)

Stage Ib-Iva

N = 1063

R

ECC + Bev Resection ECC + Bev

CTx (ECC) Resection CTx (ECC)

*Chemotherapy: ECC (epirubicine, cisplatin, capecitabine)

Bev (bevacizumab)

Cunningham D et al. Lancet Oncol 2017; 18: 357–70

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STO3 – Bevacizumab perioperative treatment

Cunningham D et al. Lancet Oncol 2017; 18: 357–70

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HER2-positive Gastric Cancer

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INNOVATION Study

PI: Dorothea Wagner, Lausanne

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2nd-line Gastric Cancer– Docetaxel - COUGAR

Ford et al. Lancet Oncol 2014; 15: 78-86

OS 5.3 mon vs. 3.8 mon

HR 0.657 (p=0.007)

∆ 1.5 months

RESPONSE 7%

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2nd-line Gastric Cancer– Docetaxel - COUGAR


Ford et al. Lancet Oncol 2014; 15: 78-86

EORTC QLQ C30

EORTC STO 22

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Ramucirumab 2nd-line (REGARD)


Fuchs et al., Lancet 2014; 383: 31-9

Median: 3.8 vs. 5.2 months N=335

Stomach / EGJ

Stage IV, 2nd-line

after Platin/5FU

119 centers

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PD-L1 als Response Biomarker ?

Muro K, et al. The Lancet Oncol 2016 Jun;17(6):717-26

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Nivolumab effective in GC



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Nivolumab effective in GC



Limited role of PD-L1 expression

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systemic treatment in early and advanced gastric cancer · systemic treatment in early and advanced...

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