• Can we screen and identify patients with gastric cancer whose tumors overexpress HER2?
• Does trastuzumab improve survival when added to chemotherapy in HER2-positive metastatic gastric cancer?

Dr. Van Cutsem’s study, the Trastuzumab in Gastric Cancer (ToGA) trial, is an international collaboration conducted across Europe, Asia, and Central and South America. The study included 3,807 patients with locally advanced unresectable or metastatic gastric cancer who were screened for HER2 overexpression. Central testing was performed using immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). Positive patients were defined as either IHC 3+ or FISH+. HER2 positivity was identified in 810 patients (22%) and 584 were treated on protocol. The study treatment arms were:

1. Cisplatin 80 mg/m² day 1, plus infusional 5-FU 800 mg/m²/day for five days, or capecitabine 1000 mg/m² BID for 14 days, cycled once every three weeks.
2. Chemotherapy plus trastuzumab 8 mg/kg loading dose followed by 6 mg/kg, every three weeks.

Chemotherapy with either 5-FU or capecitabine was selected by the treating physician.

The primary endpoint was overall survival. Secondary endpoints included progression-free survival, response rate, and safety. Half of the patients were treated in Asia and one-third in Europe, three-quarters had an intestinal histology, and one-fifth had prior gastrectomy. The majority had metastatic disease (97%) that was measurable (90%), and most had more distal gastric primaries. The majority of patients were treated with capecitabine (87%-88%).

Median overall survival was significantly improved for patients receiving trastuzumab: 13.8 months compared to 11.1 months for chemotherapy alone (HR 0.74, p=0.0046) (Figure 1). Progression- free survival was also improved with trastuzumab (6.7 months compared to 5.5 months, HR 0.71, p=0.0002) (Figure 2), and response was superior with trastuzumab (47% compared to 35%, p=0.0017) (Figure 3). Nearly all subgroups of patients benefited from the addition of trastuzumab, including gastric or gastroesophageal (GE) junction primary, and patients treated with capecitabine or 5-FU. Adverse events were comparable in the treatment arms, with the exception of a greater incidence of asymptomatic decline in left ventricular ejection fraction to less than 50% (5.9% for trastuzumab compared to 1.1% for chemotherapy alone).

The Chemotherapy Question
Two-drug chemotherapy based on 5-FU and cisplatin is the global standard of care for metastatic GE cancer. Toxicity varies widely dependent on the dose and schedule of administered 5-FU, with a weekly or twice weekly infusion schedule² or a more protracted low-dose infusion³ tending to lessen toxicity compared to bolus or 4-5 day infusions. Lowering the dose of cisplatin to 60-80 mg/m² also lessens gastrointestinal, renal, and hematologic toxicity.^3,4 Adding a third agent to 5-FU and cisplatin—epirubicin on the ECF regimen3 and docetaxel on the DCF regimen⁵—may modestly improve response and survival; however, toxicity is greater and three-drug regimens may not be the ideal backbone for adding a targeted agent. The regimen most commonly used on the ToGA trial, capecitabine plus cisplatin, performed well both as a control arm (median overall survival: 11.8 months) and in combination with trastuzumab, with acceptable rates of toxicity, consistent with other phase III trials employing capecitabine.^4,6 Whether or not more cumbersome and toxic three-drug regimens will permit the addition of targeted agents remains to be established in ongoing phase II and III trials.

The Targeted Therapy Question
The trial by Dr. Van Cutsem and colleagues is the first trial to validate the addition of a targeted agent to chemotherapy in gastric cancer, in particular identifying a subpopulation of HER2- positive patients likely to benefit most from the addition of a new agent. Other targeted agents awaiting completion of phase III trials include bevacizumab, cetuximab, panitumumab, and lapatinib.

The conclusions of the study’s authors were:

• Trastuzumab is the first biologic therapy to show a survival benefit in advanced gastric cancer.
• Trastuzumab in combination with chemotherapy is a new treatment option for patients with HER2-positive advanced gastric adenocarcinoma.

Analysis
The positive results of the ToGA trial establish trastuzumab as a new and active therapy option in esophagogastric cancers overexpressing HER2. As in breast cancer, oncologists will now have to test esophagogastric cancer for overexpression of HER2. Another landmark achieved on the ToGA trial is the median survival exceeding one year, a first for a multinational phase III trial in advanced esophagogastric cancer. The challenge is to move forward with trials of adjuvant trastuzumab in HER2-positive esophageal and gastric cancers in the potentially curative setting.

References

1. Van Cutsem E, Kang YK, Chung HC, et al. Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. J Clin Oncol. 2009;27(Sup 15S):204.
2. Al Batran S, Hartmann J, Probst S, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008;26:1435-42.
3. Webb A, Cunningham D, Scarffe JH, et al. A randomised trial comparing ECF with FAMTX in advanced oesophago-gastric cancer. J Clin Oncol. 1997;15:261- 7.
4. Kang Y, Kang W, Shin D, et al. Capecitabine/cisplatin versus 5-fluorouracil/ cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009;20:605-8.
5. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as firstline therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24:4991-7.
6. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced gastric cancer. New Engl J Med. 2008;358:36-46.