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A Discussion on Biologic Agents in
Gastric Cancer Treatment
Yoon-Koo Kang, MD
Professor of Medicine
Asan Medical Center
University of Ulsan College of Medicine
Seoul, Korea
Opening the Door to Targeted Therapy in
Gastric Cancer
• Phase 3 trial results with 2 biologic agents recently
reported
• With ToGA trial, trastuzumab plus chemotherapy
became new standard of care
– Highly important to select patients mostly likely
to benefit from trastuzumab
Selecting Patients for Trastuzumab
Therapy in Gastric Cancer
• In ToGA, 22% of patients were HER2+1
– Real-life HER2+ rate estimated to be 10% to 15%
• ToGA subgroup analysis suggested patients with
HER2 IHC 2+/FISH+ or IHC 3+ benefit most from
trastuzumab treatment2
• HER2 testing algorithm recommended
FISH = fluorescence in situ hybridization; HER2 = human epidermal growth factor receptor 2; IHC =
immunohistochemistry
1. Chung H et al. Eur J Cancer Suppl .2009; 7:364.
2. Van Cutsem E et al. J Clin Oncol. 2009; 27[Suppl15S]:Abstract 4509.
Recommended HER2 Testing Algorithm in
Metastatic Gastric and Gastroesophageal
Junction Cancer
Patient tumor sample
IHC
0
1+
2+
3+
FISH
Important to test secondary and
resected tumors, as they may
differ in HER2 expression
–
+
Eligible for trastuzumab
Trastuzumab EU SmPC: http://www.ema.europa.eu/humandocs/PDFs/EPAR/
Herceptin/emea-combined-h278en.pdf.
AVAGAST: A Randomized, Double-Blind,
Placebo-Controlled, Phase-3 Study
Locally advanced
or metastatic
gastric cancer
Capecitabine*/cisplatin (XP)
+ placebo q3w
R
Capecitabine*/cisplatin (XP)
+ bevacizumab q3w
Stratification Factors:
1. Geographic region
2. Fluoropyrimidine backbone
3. Disease status
*5-FU also allowed if capecitabine contraindicated
Capecitabine 1000 mg/m2 oral bid, d1–14, 1-week rest
Cisplatin 80 mg/m2 d1
Bevacizumab 7.5 mg/kg d1
Maximum of 6 cycles of cisplatin
Capecitabine and bevacizumab/placebo until disease
progression
Kang Y-K et al. J Clin Oncol. 2010;28[18S]:Abstr LBA4007.
AVAGAST Primary Endpoint: Overall Survival
XP + placebo
1.0
XP + bevacizumab
0.9
Survival rate
0.8
HR = 0.87
0.7
95% CI 0.73–1.03
0.6
P = .1002
12.1
0.5
10.1
0.4
0.3
0.2
0.1
0.0
0
3
6
9
15
18
21
24
98
104
54
50
15
19
0
0
Study month
Number at risk
XP + Placebo
XP + Bev
12
387
387
343
355
271
291
204
232
146
178
CI = confidence interval; HR = hazard ratio
Kang, et al. J Clin Oncol. 2010;28[18S]:Abstract LBA4007.
AVAGAST Secondary Endpoints: PFS and ORR
1.0
XP + bevacizumab
XP + placebo
(n = 387)
(n = 387)
143 (46%)
111 (37%)
ORR
P = .0315
Survival rate
0.8
XP + placebo
0.6
6.7
XP + bevacizumab
5.3
0.4
HR = 0.80
95% CI 0.68–0.93
P = 0.0037
0.2
0
0
3
6
9
12
Study month
PFS = progression-free survival; ORR = overall response rate
Kang et al. J Clin Oncol. 2010;28[18S]:Abstract LBA4007.
15
18
21
24
AVAGAST: Areas for Further Study
• Although bevacizumab did not meet primary endpoint of OS,
secondary endpoints of PFS and ORR were significantly
improved
– Further study warranted for bevacizumab in gastric cancer
• Efficacy of bevacizumab varied by geographic region
– OS was longest in Asia, but benefit was the smallest
– OS was shortest in Pan-America, but benefit was the largest
Multiple Targets and Agents in Gastric Cancer
Panitumumab
Cetuximab
Trastuzumab
EGFR
HER2
Gefitinib
Ras
Erlotinib
SOS
Grb2
PI-3
kinase
Raf
MEK
STAT
Receptor MoAb
internalisation
Bevacizumab
Lapatinib
MAPK
Akt
mTOR1
mTOR2
Everolimus
Signal transduction
cascade blocked
Apoptosis
Proliferation
Gene
transcription
/cell cycle
Angiogenesis
Invasion/metastasis
VEGF
Ramucirumab
Conclusions
• Numerous targeted agents are being investigated in gastric
cancer
• To date, trastuzumab is the only targeted agent shown to
improve OS in patients with advanced gastric cancer
• Important to test HER2 status in all patients with advanced
gastric cancer