The age of targeted therapy has arrived in esophagogastric cancer

Gastric cancer, the second leading cause of cancer-related mortality worldwide, has eluded progress in recent years. Adjuvant therapy employing either perioperative chemotherapy or chemoradiotherapy imparts only a modest 10% to 15% survival improvement in surgically treated patients. Systemic chemotherapy in metastatic disease achieves response in only 35% to 45% of patients, with a median survival of less than one year. Combination chemotherapy beyond fluorouracil has failed to achieve the incremental advances seen in colorectal cancer with the advent of irinotecan and oxaliplatin. Depending on which regimen is chosen to treat metastatic gastric cancer, therapy toxicities can be substantial. The majority of patients diagnosed with esophagogastric cancer will ultimately succumb to metastatic disease.

The theme of the 2009 ASCO Annual Meeting was personalized therapy with the goal of tailoring therapy more specifically to patients based on traditional clinical and potentially more sophisticated biochemical parameters. This includes using three basic strategies: optimizing therapeutic outcomes by applying treatments only to patients identified as most likely to benefit, lessening toxicity by use of supportive care measures, and selecting the optimal drug, dose, and schedule of treatment.

The ToGA trial

Personalized therapy has finally arrived in advanced gastric cancer with the report of the ToGA trial by Eric van Cutsem, MD, and colleagues. The ToGA trial is a landmark phase-3 trial of trastuzumab (Herceptin, Genentech) added to standard chemotherapy as first-line treatment in advanced esophagogastric cancers testing HER2-positive.

The HER2 receptor — validated as a critical target in HER2 over expressing breast cancers — is over expressed in 10% to 20% of esophageal and gastric adenocarcinomas. Trastuzumab inhibits HER2 mediated signaling, prevents HER2 activation by blocking extracellular domain cleavage, and may activate antibody-dependent cellular cytotoxicity. In HER2-positive breast cancer, trastuzumab is effective as a single agent and adds to the effectiveness of chemotherapy in metastatic disease and in the adjuvant setting.

David H. Ilson

Van Cutsem and colleagues undertook an ambitious, global trial with the screening of 3,807 patients with gastric or gastroesophageal junction adenocarcinoma for over expression of HER2. The criteria for positivity were either an immunohistochemistry score of 3+ or FISH positivity in immunohistochemistry 0-2+ patients, with patients immunohistochemistry 0-2+/FISH negative considered HER2 negative. HER2-positivity was identified in 810 patients (22.1%).

Patients with locally advanced /unresectable or metastatic disease were randomly assigned chemotherapy with cisplatin (80 mg/m² every three weeks) combined with either continuous infusion 5-FU (800 mg/m² per day × five days every three weeks) or capecitabine (1,000 mg/m² twice daily for 14 days every three weeks) at the investigator’s discretion. Half of the patients were assigned trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every three weeks), in a multicenter, open-label, phase-3 design.

Patients were stratified by locally advanced vs. metastatic disease, gastric vs. gastroesophageal junction cancer primary, measurable vs. nonmeasurable disease, performance status, and treatment with 5-FU vs. capecitabine. The primary endpoint was to improve overall survival from 10 months to 13 months, with secondary endpoints including response rate, time to tumor progression and safety.

Demographics of the treatment arms were well balanced. Ninety-seven percent of patients had metastatic disease and 90% had measurable disease. Slightly more than half of the patients were treated in Asia and a third in Europe; 80% or more had gastric primary tumors with an intestinal histology in 75% of patients.

The trial achieved the primary endpoint of improved overall survival with addition of trastuzumab to chemotherapy with an increase in survival from 11.1 months to 13.8 months (HR=0.74; P=.0046). Progression-free survival was also improved from 5.5 months to 6.7 months (HR=0.71; P=.0002) and overall response rate improved from 35% to 47% (P=.0017). Nearly all subgroups benefited from the addition of trastuzumab to chemotherapy, including gastric vs. gastroesophageal junction cancers and whether patients received 5-FU or capecitabine. Similar numbers of patients received second-line treatment.

There were no differences in hematologic or nonhematologic toxicity, with the exception of a greater rate of asymptomatic drop in left ventricular ejection fraction to < 50% in 5.9% of patients on the trastuzumab arm compared with 1.1% on the chemotherapy alone arm.

Implications of data

The strongly positive results of the ToGA trial establish trastuzumab as a new and active therapy option in esophagogastric cancers over expressing HER2. The results offer new hope in a research field that has lagged behind the advances and new drug development seen in colorectal cancer. Now, as in breast cancer, oncologists will have to test gastric cancers for over expression of HER2.

The ToGA trial is also the first multinational trial to achieve a median survival exceeding one year in advanced gastric cancer, a barrier not previously breached by systemic chemotherapy alone. The identification of an active and well-tolerated molecularly targeted therapeutic agent in gastric cancer marks the start of the age of use of targeted agents in gastric cancer. The challenge to the research community is to now rapidly implement trials of adjuvant trastuzumab in HER2-positive esophageal and gastric cancers in the potentially curative setting.

A new bar in gastric cancer has been set and the search for other novel agents in esophagogastric cancer has been given new enthusiasm and hope. Moreover, the respectable performance of the two drug standard chemotherapy arm, achieving a median survival of 11.1 months, as well as the highly favorable toxicity profile, argue that two drug chemotherapy backbones will likely be the preferred platform to study in combination with targeted agents, rather than the more toxic three drug regimens adding either epirubicin or docetaxel to 5-FU/cisplatin.

Results of other targeted agents in phase-3 trials in combination with chemotherapy in advanced gastric cancer, including bevacizumab (Avastin, Genentech), cetuximab (Erbitux, ImClone), panitumumab (Vectibix, Amgen), and lapatinib (Tykerb, GlaxoSmithKline), are anxiously awaited.

David H. Ilson, MD, PhD, is an Attending Physician at Memorial Sloan-Kettering Cancer Center and a member of the HemOnc Today Editorial Board. Dr. Ilson has a direct financial interest in trastuzumab.

For more information:

• Van Cutsem E. J Clin Oncol. 2009;27(Sup 15S): 204.