Abstract:

The new results come from the ToGA study, which was conducted in 594 patients with HER2-positive disease, who were identified after nearly 4000 patients with advanced gastric cancer were screened, noted lead author Eric van Cutsem, MD, from University Hospital Gasthuisberg in Leuven, Belgium. All of the patients received chemotherapy (most commonly cisplatin and capecitabine [Xeloda], but sometimes cisplatin and 5-fluorouracil) and half were randomized to also receive trastuzumab (6 mg/kg every 3 weeks until progression). The trial was stopped early (after a median follow-up of 17 months) because of the benefit seen.

The improvement in overall survival was 2.7 months, from 11.1 months in the chemotherapy group to 13.8 months in the trastuzumab group (hazard ratio, 0.74, P = .0046).

This 2.7-month improvement in overall survival is "modest, but it is clinically meaningful in this group of patients who have a poor prognosis," said Dr. Cunningham, who was discussant for the paper. As a result, he recommended that trastuzumab plus chemotherapy should be considered for all HER2-positive patients.

Dr. Cunningham also noted that the overall survival in both groups was "impressive," and suggested this might be because a large proportion of the patients were Asian, a population that tends to have a better prognosis and might have a biologically distinct disease from Westerners. The median overall survival seen in previous studies in such patients has been around 10 months.

The ToGA study was conducted in 24 countries, spanning Europe, Asia, Australia, South and Central America, and South Africa. When asked how the results would extrapolate to patients in the United States, Dr. van Cutsem said that he predicts similar findings, and that "there is no reason to expect any differences."

"We should now test all of our advanced gastric cancer patients for HER2-positive disease," said Dr. van Cutsem. This has not been standard practice until now, because before this trial, "there was no reason to do so," he added. But these results have changed the situation — they show that testing for this receptor and using targeted therapy significantly improves the outcome for these patients, he said.

In addition to the impact on survival, trastuzumab improved all of the secondary end points, he noted, including progression-free survival (increased from 5.2 months to 6.7 months; P = .002) and overall response rate (increased from 34.5% to 47%; P = .0017), which is "statistically significant and clinically meaningful," he said.

The addition of trastuzumab did not affect safety, Dr. van Cutsem explained; the overall rate of grade 3/4 adverse events was similar in both groups. There were 3 treatment-related deaths in the trastuzumab group and 1 in the chemotherapy group. In particular, there was no concern over cardiac toxicity, he added. The incidence of cardiac failure was very rare (<1% in both groups), although asymptomatic decreases in left ventricular ejection fraction were more frequent in the trastuzumab group than in the chemotherapy group (4%–5% vs 1%).

Gastric Cancer Subtype Populations

Dr. Cunningham also noted that HER2 overexpression varied with the site of the tumor and histology. Although overall, 22% of patients were HER2-positive, overexpression was found in 35% of those with tumors at the OG junction, 33% of those with intestinal pathology, 6% of those with diffuse pathology.

In addition, he commented on the testing for HER2 that was used in the trial, which was carried out with both fluorescence in situ hybridization (FISH) and in situ hybridization (ICH) techniques. When the criteria in the ToGA trial for HER2-positive gastric cancer are limited to those used for breast cancer (i.e., FISH-positive and ICH3-positive, as recommended in 2007 ASCO guidelines), only 256 patients would have been included in the trial, but in these patients, the magnitude of benefit was even greater, with overall survival improved from 12.3 months to 17.89 months (hazard ratio, 0.58).

Future Trials

Several of the experts agreed that practice should be changed on the basis of this 1 trial, because it had been well conducted and because the results showed a clear-cut significant benefit.

To repeat this same study would be a waste of resources and would not be helpful for patients, said Jennifer Obel, MD, from NorthShore University HealthSystem in Evanston, Illinois. This is a practice-changing trial, she said, adding "I will take it into my clinic tomorrow." She told Medscape Oncology that she had already phoned her assistant to arrange HER2 testing for one of her advanced gastric cancer patients. Testing for HER2 is now commonplace; pathology labs are already geared up to carry out this testing for breast cancer. She noted that the overall survival improvement shown in the trial was significant in a disease that is "challenging to treat."

Dr. van Cutsem said the results were so clear-cut that he saw no value in repeating this trial, but would rather "move onward." The next study should look at trastuzumab as adjuvant therapy in patients with earlier gastric cancer after surgery, he suggested.

"The prognosis for these patients is still poor," Dr. van Cutsem said. "We have now raised the bar to over 1 year, but we need to raise it still further," he said.

Dr. Cunningham suggested that future studies should look at trastuzumab continuation after progression in association with second-line therapy, which is how the drug is used in breast cancer, where it has been shown to be of considerable value.

Dr. van Cutsem reports having received research funding from Roche. Dr. Obel has served as an advisor or consultant to Onyx. Dr. Schilsky has disclosed no relevant financial relationships. Dr. Cunningham reports acting as an advisor to Roche, and receiving honoraria from Merck, Roche, and Sanofi-Aventis.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract LBA4509. Presented June 2, 2009.

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