Gastric Cancer: Time to Revisit Angiogenesis

Get Permission

David H. Ilson, MD, PhD

Progress in the treatment of gastric cancer has lagged behind advances in other solid tumor malignancies. A modest but clear survival benefit with the use of adjuvant therapy combined with surgery has been achieved, including the use of postoperative adjuvant chemotherapy as shown in large-scale trials from Asia, the use of pre- and postoperative chemotherapy from British trials, and the application of combined postoperative chemotherapy and radiotherapy in American trials. For esophageal and gastroesophageal junction adenocarcinoma, combined chemoradiotherapy followed by surgery is emerging as a standard of care in the United States.

Progress in the treatment of metastatic gastric cancer, however, has been minimal. The combination of a fluorinated pyrimidine with a platinum agent remains the chemotherapy standard despite decades of research in newer systemic therapies. The advent of oral fluorinated pyrimidines and the use of oxaliplatin have improved therapy convenience and potentially lessened toxicity, but overall survival in advanced gastric cancer has not been significantly improved over the past few decades. Taxanes and irinotecan are used in second-line treatment, with a modest but very limited survival improvement achieved.

Targeted Agents

The development of targeted therapies in gastric cancer has also been slow. Trastuzumab (Herceptin) has been the only targeted agent shown to improve survival when added to chemotherapy.1 The benefit is limited to the 10% to 20% of patients with HER2-positive or HER2-amplified tumors. Currently available epidermal growth factor receptor (EGFR)-targeted agents have repeatedly failed to improve outcome in advanced disease, either in combination with chemotherapy or as single agents.2-4

Furthermore, no biomarker has emerged to potentially identify a subgroup of patients likely to benefit from EGFR-targeted therapies. Esophagogastric adenocarcinoma seems to lack the driving mutations seen in other cancers, with activating mutations in KRAS and EGFR virtually absent.

Recent studies from genomic analyses of esophagogastric cancer indicate that amplification rather than mutation of key pathways may be a more common driver of carcinogenesis.5 The search for amplified genes to target with new agents will hopefully lead to the identification of candidate biomarkers to ensure the greatest benefit from new agents.

Antiangiogenic Agents

Angiogenesis is a key pathway in esophagogastric cancer, with increased levels of blood and tissue vascular endothelial growth factor (VEGF) correlating with a more advanced stage of disease and with a poorer prognosis. Unfortunately, the negative trial results for targeted agents have also extended to angiogenesis in gastric cancer. The global AVAGAST trial of the VEGF-A–targeted agent bevacizumab (Avastin) combined with chemotherapy failed to show a survival benefit in first-line treatment.6

However, enthusiasm for further study of antiangiogenic therapies in gastric cancer may now change with publication of the REGARD trial,7 as reviewed in this issue of The ASCO Post. Ramucirumab, a monoclonal antibody that binds to and blocks ligand binding and activation of VEGFR2, was evaluated in this phase III double-blind placebo-controlled trial in patients with metastatic gastric and gastroesophageal junction adenocarcinoma progressing on first-line platinum or fluorinated pyrimidine chemotherapy.

Overall survival in the REGARD trial was modestly but significantly improved with ramucirumab, with the hazard ratio for a benefit (0.78) in the ballpark of benefit seen for trials comparing second-line chemotherapy to best supportive care (0.66–0.67).8,9 Progression-free survival and disease control were also improved with ramucirumab, although no significant tumor responses were seen. Toxicity of therapy above placebo was limited to grade 3 hypertension, an expected class effect for antiangiogenic therapy.

Supportive Data

The positive results for the REGARD trial are supported by the recent press release report of results from the RAINBOW trial. This trial also indicated a survival benefit for the combination of ramucirumab plus paclitaxel vs paclitaxel alone as second-line therapy. Ramucirumab therefore appears be active both as monotherapy and when added to chemotherapy.

Ramucirumab represents the first targeted agent to demonstrate single-agent activity in a non–biomarker-selected population in advanced gastric cancer, and it is the first antiangiogenic therapy to show a survival benefit in this disease. This, in concert with the favorable toxicity profile, indicates that this agent will likely become a part of second-line therapy options in advanced gastric cancer. First-line data in combination with FOLFOX (leucovorin, fluorouracil, oxaliplatin) are still pending as of this publication.

Biomarkers for antiangiogenic therapy have yet to be established in gastrointestinal cancers. VEGF-A levels, in conjunction with levels of the receptor neuropilin, may be potential candidate biomarkers in gastric cancer. The AVAGAST bevacizumab phase III trial indicated that patients with either relatively high VEGF-A levels or relatively low neuropilin levels achieved a survival benefit with the addition of bevacizumab.10 These biomarkers also appeared to have prognostic value, with inferior survival in these patients.

Future Progress

Appropriate biomarker-driven patient selection for new therapies will be the key to new drug development. The benefits of newer and likely costly therapies will certainly be modest, and likely to have an actual impact on a relative minority of patients when unselected populations are treated. The dramatic success of biomarker selection of patients with EGFR-mutated or ALK gene-rearranged non–small cell lung cancer, and more recently in BRAF-mutant melanoma, needs to be duplicated in esophagogastric adenocarcinoma. ■

Dr. Ilson is Attending Physician at Memorial Sloan-Kettering Cancer Center, New York.

Disclosure: Dr. Ilson reported no potential conflicts of interest.


1. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2 positive advanced gastric or gastroesophageal junction cancer (TOGA): A phase 3 open label randomized controlled trial. Lancet 376:687-697, 2010.

2. Waddell T, Chau I, Cunningham D, et al: Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated esophagogastric cancer (REAL-3): A randomized open label phase 3 trial. Lancet Oncol 14:481-489, 2013.

3. Lordick F, Kang YK, Chung HC, et al: Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomized open label phase 3 trial. Lancet Oncol 14:490-499, 2013.

4. Dutton SJ, Blazeby JM, Petty RD, et al: Patient reported outcomes from a phase III, randomized, double-blind placebo controlled trial of gefitinib versus placebo in esophageal cancer progressing after chemotherapy: Cancer Oesophagus Group (COG). J Clin Oncol 30(suppl 34):Abstract 6, 2012.

5. Dulak AM, Schumacher SE, van Lieshout J, et al: Gastrointestinal adenocarcinomas of the esophagus, stomach, and colon exhibit distinct patterns of genome instability and oncogenesis. Cancer Res 72:4383-4393, 2012.

6. Ohtsu A, Shah MA, Van Cutsem E, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer, a randomized double blind placebo controlled phase III trial. J Clin Oncol 29:3968-3976, 2011.

7. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet October 3, 2013 (early release online).

8. Kang JH, Lee SI, Lim do H, et al: Salvage chemotherapy for pretreated gastric cancer: A randomized phase III trial comparing chemotherapy plus best supportive care versus best supportive care. J Clin Oncol 30:1513-1518, 2012.

9. Cook N, Marshall A, Blazeby JM, et al: Cougar-02: A randomized phase III study of docetaxel versus best supportive care in patients with relapsed esophagogastric cancer. J Clin Oncol 31(suppl):Abstract 4023, 2013.

10. Van Cutsem E, de Haas S, Kang YK, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol 30: 2119-2127, 2012.

Related Articles

Anti–VEGFR-2 Antibody Ramucirumab Prolongs Survival in Previously Treated Advanced Gastric or Gastroesophageal Cancer

Vascular endothelial growth factor (VEGF)– and VEGF receptor-2 (VEGFR-2)–mediated signaling and angiogenesis seem to have an important role in the pathogenesis of gastric cancer. In the phase III REGARD trial reported in Lancet, Charles S. Fuchs, MD, MPH, of Dana-Farber Cancer Institute, Boston,...