Trastuzumab Plus Platinum Chemo Heralds Breakthrough in Advanced Gastric Cancer

The data from the ToGA trial represent a true breakthrough in the treatment of HER2-positive advanced gastric or gastroesophageal junction cancer. The addition of trastuzumab (Herceptin) to chemotherapy prolonged overall survival and offered the first positive trend in gastric cancer treatment in two decades, according to experts who spoke with Oncology News International.

Alan P. Venook, MD, a gastrointestinal cancer specialist, and pathologist Jeffrey S. Ross, MD, discussed the implications of the ToGA (Trastuzumab for Gastric Cancer) trial results for clinical practice.

Trial overview

ToGA was a phase III randomized controlled trial in 594 patients undertaken at 122 facilities in 24 countries. Patients with gastric or gastroesophageal junction cancer were eligible for inclusion if their tumors showed overexpression of HER2 protein as measured with immunohistochemistry (IHC) or gene amplification by fluorescence in situ hybridization (FISH; see Related Reading).

Participants were randomly assigned in a 1:1 ratio to receive capecitabine (Xeloda) plus cisplatin or 5-fluorouracil plus cisplatin, with or without intravenous trastuzumab. Treatment was delivered every three weeks for six cycles.

Two hundred ninety-eight patients were assigned to the experimental arm and 296 to the chemotherapy-alone arm. Median follow-up was 18.6 months for the experimental arm and 17.1 months for the chemotherapy-alone arm. The primary endpoint was overall survival in all randomized patients who received study medication at least once.

According to the primary analysis results from 584 patients, median overall survival was 13.8 months in the experimental arm and 11.1 months in the chemotherapy-alone arm (hazard ratio = .74; P = .0046). Adverse events profiles were similar in both groups (see Table).

Adverse events in ToGA trial

Trastuzumab plus chemotherapy
Nausea = 67% of patients
Vomiting = 50% of patients
Neutropenia = 53% of patients
Grade 3 or 4 adverse events = 68% of patients
Cardiac events = 6% of patients

Chemotherapy alone
Nausea = 63% of patients
Vomiting = 46% of patients
Neutropenia = 57% of patients
Grade 3 or 4 adverse events = 68% of patients
Cardiac events = 6% of patients

ToGA leaders concluded that trastuzumab in combination with chemotherapy could be considered the preferred treatment option for patients with HER2-positive advanced gastric or gastroesophageal junction cancer (Lancet online, August 20, 2010).

'A real breakthrough'

"The data showing the survival benefit for adding trastuzumab to the platinumbased chemotherapy regimen was the first advance in survival for this type of cancer in decades," said Dr. Ross, a professor and chair of the pathology and laboratory medicine department at Albany Medical College in N.Y. "Even though it was a small advance, the fact there was a survival benefit when the patients were selected to receive the targeted therapy according to HER2 status was a real breakthrough, without question. Scientifically and medically, the benefit is unquestioned and of major importance."

Making the most of HER2 testing

Accurate testing for HER2 status is key to identifying candidates for trastuzumab treatment. There are special considerations for HER2 testing in gastric cancer that oncologists and pathologists need to understand so potential mistakes in test interpretation can be avoided.

A positive result for either IHC or FISH is sufficient to classify a patient with gastric cancer as HER2-positive, Dr. Ross explained. In contrast, in current practice, only breast cancer specimens with an initial, equivocal IHC result have a second test (FISH) performed.

In addition, the threshold for HER2 positivity is lower for gastric cancer. "There are slightly different criteria for reading the slides," he said. "In gastric cancer, the positive cells may be extremely infrequent and the pathologist does not have to find as much of the tissue positive, as compared with breast, to call the case positive for stomach. For breast, it's 30%, and for gastric it's 10% for surgery specimens."

Dr. Venook, a professor of clinical medicine at the University of California, San Francisco (UCSF), agreed the ToGA results offer a new standard of care in HER2-positive gastric cancer, but he also cautions that HER2-positive patients are a minority of gastric cancer cases overall, between 15% and 20%.

"It was a well-done study, and we can quibble about whether we're satisfied with a few months survival advantage," Dr. Venook said. "The point is, those are medians. You can lose track of the fact that there were some patients who did exceedingly well and got extreme benefit. If you criticize the modest overall advantage for the whole population, you still have to remember that some patients get a lot of benefit. It's a balancing act. And it's a fair question. How much benefit is enough? If you are the patient who got a big benefit, then it was worth it to you."

Worth the cost?

In a Lancet editorial, Alastair J. Munro, MD, and Paddy G. Niblock, MD, calculated that the average cost of trastuzumab was $21,276.73 per patient, and the cost per life-year gained would be around $84,449.75. "What is the justification for introducing a treatment that might enable one individual to live a few months longer but will consume, for each person treated, the total yearly health expenditures for scores of their fellow citizens?" they wrote. Dr. Munro and Dr. Niblock are from Ninewells Hospital, University of Dundee in the UK (Lancet online, August 20, 2010).

They went on to state that the ToGA results were "interesting on many levels, including the implications of this type of commercially funded study for research into cancer treatment and the political and moral consequences of the globalization of research into cancer treatment." The ToGA trial was funded by F. Hoffmann-La Roche.

The question regarding cost is a provocative one, said Dr. Venook, who is also chair of the UCSF committee on human research. "What can we afford? What advances are enough to justify the expense? As oncologists, and as a society, we struggle to know what is worth doing. The dilemma is that when you have a treatment that is helpful to a minority of patients, you incur great expenses, both monetarily and in terms of toxicity."

But drugs with high price tags are easy targets of negative editorials, he added. "Certain journals are spinning things [negatively] in terms of cost-effectiveness. It's easy to pick on expensive drugs. The point is that for some patients, they make a world of difference," he said.

Hopes for the future

While trastuzumab has shown benefits in advanced disease, clinicians are looking forward to results showing that it benefits HER2-positive patients with early-stage disease in the adjuvant setting. Adjuvant trastuzumab in HER2-positive metastatic breast cancer has demonstrated success in delaying or preventing relapse. "It is my hope, and that of many others, that the same will hold true for stomach and gastroesophageal junction cancer," Dr. Ross said.

"Metastatic recurrent disease is hopelessly fatal in the vast majority of cases, and [trastuzumab] just delays that, as ToGA showed. Now we have a targeted therapy to use earlier, and that may be curative when the cancer load is much smaller," Dr. Ross added. "The ToGA trial gives us hope that targeted therapy for stomach and esophageal junction cancer at the time of diagnosis, combined with surgery, can cure patients who, without this therapy, would be destined to relapse and die."