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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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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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
© Universitätsklinikum Leipzig AöR: Universitäres Krebszentrum Leipzig (UCCL), Prof. Dr. Florian Lordick
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
© Universitätsklinikum Leipzig AöR: Universitäres Krebszentrum Leipzig (UCCL), Prof. Dr. Florian Lordick
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
© Universitätsklinikum Leipzig AöR: Universitäres Krebszentrum Leipzig (UCCL), Prof. Dr. Florian Lordick 17th ESO-ESMO M
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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
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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
© University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick 17th ESO-ESMO M
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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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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
© University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick
R
A
N
D
O
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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
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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)
© Universitätsklinikum Leipzig: UCCL - Onkologie, Prof. Dr. med. F. Lordick
Wilke et al., Lancet Oncol 2014; [published online 18 September]
R
A
N
D
O
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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)
© Universitätsklinikum Leipzig: UCCL - Onkologie, Prof. Dr. med. F. Lordick
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
© Universitätsklinikum Leipzig: UCCL - Onkologie, Prof. Dr. med. F. Lordick
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
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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)
© University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick
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)
© University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick
Kang YK et al. Lancet 2017 Dec 2;390(10111):2461-2471
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)
© Universitätsklinikum Leipzig (2013): UCCL - Onkologie, Prof. Dr. med. F. Lordick
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
© Universitätsklinikum Leipzig (2013): UCCL - Onkologie, Prof. Dr. med. F. Lordick
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)
© Universitätsklinikum Leipzig (2013): UCCL - Onkologie, Prof. Dr. med. F. Lordick
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
© Universitätsklinikum Leipzig (2013): UCCL - Onkologie, Prof. Dr. med. F. Lordick
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%
17th ESO-ESMO M
astercl
ass in
Clin
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ncology
2nd-line Gastric Cancer– Docetaxel - COUGAR
© Universitätsklinikum Leipzig: UCCL - Onkologie, Prof. Dr. med. F. Lordick
Ford et al. Lancet Oncol 2014; 15: 78-86
EORTC QLQ C30
EORTC STO 22
17th ESO-ESMO M
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Clin
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Ramucirumab 2nd-line (REGARD)
© Universitätsklinikum Leipzig: UCCL - Onkologie, Prof. Dr. med. F. Lordick
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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© Universitätsklinikum Leipzig AöR: University Cancer Center Leipzig (UCCL), Prof. Dr. F. Lordick 55
PD-L1 als Response Biomarker ?
Muro K, et al. The Lancet Oncol 2016 Jun;17(6):717-26
17th ESO-ESMO M
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Nivolumab effective in GC
© University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick
Kang YK et al. Lancet 2017 Dec 2;390(10111):2461-2471
17th ESO-ESMO M
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ncology
Nivolumab effective in GC
© University Cancer Center Leipzig (UCCL): Prof. Dr. Florian Lordick
Kang YK et al. Lancet 2017 Dec 2;390(10111):2461-2471
Limited role of PD-L1 expression
17th ESO-ESMO M
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Clin
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