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

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Phase 3 trial results with 2 biologic agents recently reported

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With ToGA trial, trastuzumab plus chemotherapy became new standard of care

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Highly important to select patients mostly likely to benefit from trastuzumab

Selecting Patients for Trastuzumab Therapy in Gastric Cancer

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In ToGA, 22% of patients were HER2+ 1

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Real-life HER2+ rate estimated to be 10% to 15%

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ToGA subgroup analysis suggested patients with HER2 IHC 2+/FISH+ or IHC 3+ benefit most from trastuzumab treatment 2

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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+ FISH 3+ 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 R Capecitabine*/cisplatin (XP) + placebo q3w 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/m 2 oral bid, d1–14, 1-week rest Cisplatin 80 mg/m 2 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 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

10.1

12.1

0 3 6 9 12 Study month 15 Number at risk XP + Placebo XP + Bev 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.

98 104 HR = 0.87

95% CI 0.73–1.03 P = .1002

18 54 50 XP + placebo XP + bevacizumab 21 15 19 24 0 0

AVAGAST Secondary Endpoints: PFS and ORR 1.0

0.8

0.6

0.4

0.2

5.3

6.7

ORR XP + bevacizumab (n = 387) 143 (46%) P = .0315

XP + placebo (n = 387) 111 (37%) XP + placebo XP + bevacizumab HR = 0.80

95% CI 0.68–0.93

P = 0.0037

0 0 3 6 9 12 Study month 15

PFS = progression-free survival; ORR = overall response rate

Kang et al. J Clin Oncol. 2010;28[18S]:Abstract LBA4007.

18 21 24

AVAGAST: Areas for Further Study

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Although bevacizumab did not meet primary endpoint of OS, secondary endpoints of PFS and ORR were significantly improved

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Further study warranted for bevacizumab in gastric cancer

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Efficacy of bevacizumab varied by geographic region

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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 Cetuximab Panitumumab EGFR Trastuzumab HER2 Receptor MoAb internalisation Gefitinib Erlotinib PI-3 kinase STAT Ras SOS Grb2 Raf MEK MAPK Lapatinib Akt mTOR1 mTOR2 Everolimus Proliferation Signal transduction cascade blocked Apoptosis Gene transcription /cell cycle Angiogenesis Invasion/metastasis Bevacizumab VEGF Ramucirumab

Conclusions

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Numerous targeted agents are being investigated in gastric cancer

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To date, trastuzumab is the only targeted agent shown to improve OS in patients with advanced gastric cancer

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Important to test HER2 status in all patients with advanced gastric cancer