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A Discussion on Biologic Agents in Gastric Cancer Treatment Yoon-Koo Kang, MD

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

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A Discussion on Biologic Agents in Gastric Cancer Treatment Yoon-Koo Kang, MD

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  1. A Discussion on Biologic Agents in Gastric Cancer Treatment Yoon-Koo Kang, MD Professor of MedicineAsan Medical CenterUniversity of Ulsan College of MedicineSeoul, Korea

  2. 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

  3. 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.

  4. 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.

  5. AVAGAST: A Randomized, Double-Blind, Placebo-Controlled, Phase-3 Study Capecitabine*/cisplatin (XP) + placebo q3w Locally advanced or metastatic gastric cancer R Capecitabine*/cisplatin (XP) + bevacizumab q3w Stratification Factors: Geographic region Fluoropyrimidine backbone Disease status *5-FU also allowed if capecitabine contraindicatedCapecitabine 1000mg/m2 oral bid, d1–14, 1-week restCisplatin 80mg/m2 d1Bevacizumab 7.5 mg/kg d1Maximum of 6 cycles of cisplatinCapecitabine and bevacizumab/placebo until disease progression Kang Y-K et al. J Clin Oncol. 2010;28[18S]:Abstr LBA4007.

  6. AVAGAST Primary Endpoint: Overall Survival XP + placebo XP + bevacizumab 1.0 0.9 0.8 HR = 0.87 95% CI 0.73–1.03 P = .1002 0.7 0.6 12.1 0.5 Survival rate 0.4 10.1 0.3 0.2 0.1 0.0 12 0 15 18 21 24 3 9 6 Number at risk Study month 54 50 0 0 XP + Placebo XP + Bev 387 387 343 355 271 291 204 232 146 178 98 104 15 19 CI = confidence interval; HR = hazard ratioKang, et al. J Clin Oncol. 2010;28[18S]:Abstract LBA4007.

  7. AVAGAST Secondary Endpoints: PFS and ORR 1.0 0.8 0.6 0.4 0.2 0 XP + placebo XP + bevacizumab 6.7 Survival rate 5.3 HR = 0.8095% CI 0.68–0.93P = 0.0037 0 3 6 9 12 15 18 21 24 Study month PFS = progression-free survival; ORR = overall response rateKang et al. J Clin Oncol. 2010;28[18S]:Abstract LBA4007.

  8. 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

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

  10. 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

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