While targeted therapies are at the center of cancer research today, investigators are still a ways away from determining which patients will benefit from which treatments. Close behind this focus is the need to also reduce the toxicity of various treatments while either maintaining or increasing the efficacy of the given agent.
At the European Society for Medical Oncology 12th World Congress on Gastrointestinal Cancer, two studies addressed both of these issues in advanced gastric cancer. One abstract looked at prolonging survival for patients with advanced disease, while the other addressed quality of life for these patients as well as for those with gastro-esophageal junction cancer.
Negative Study, but Still Valuable
Results of the negative AVAGAST trial were first presented earlier in the year, but the study authors say there are still insights to be gained from the trial, which failed to show a statistically significant increase in survival with the addition of bevacizumab to chemotherapy as a front-line therapy.
“We found a lot of heterogeneity between subgroups, meaning some subgroups seemed to benefit more than others and others didn't benefit at all, so we're still trying to understand the data with regard to that,” said Manish A. Shah, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, speaking in a telephone interview after the meeting.
Dr. Shah was a principal investigator of the international study, representing North and South America, along with Eric Van Cutsem, MD, PhD, of the Digestive Oncology Unit at the University Hospital Gasthuisberg in Belgium; Yoon-Koo Kang, MD, PhD, of Asan Medical Center in Seoul; and Atsushi Ohtsu, MD, of the Division of Gastrointestinal Oncology/Digestive Endoscopy at the National Cancer Center Hospital East in Kashiwar, Japan.
A total of 774 patients were included in the study, which randomized participants to receive capecitabine with cisplatin and either bevacizumab or placebo every three weeks. Although progression-free survival and response rates were significantly improved when patients received chemotherapy with bevacizumab versus chemotherapy alone, at the end of the study, a modest two-month increase in overall survival was observed (10.1 vs 12.1 months).
Historically, bevacizumab added to chemotherapy would show benefits across the board, as was originally shown in colon cancer, Dr. Shah said. “Gastric cancer might be a much more heterogeneous disease with differences in benefits of bevacizumab possibly depending on the type of disease you have—whether it's intestinal or diffuse gastric cancer or if the cancer spreads into the liver or it's just peritoneal disease. We don't know these things, but we think that some subgroups did benefit from the use of bevacizumab.”
Dr. Van Cutsem echoed this point, noting the slightly improved survival rates in the subgroups of American and European patients (6.8 vs 11.5 months and 8.6 vs 11.1 months, respectively). “The overall conclusion of the study is that bevacizumab matters to the activity of this cancer,” he said.
To determine why bevacizumab was only active in certain patients, the researchers plan to study tissue samples obtained from the study participants.
“One of the unique things about this study is there was a required tissue acquisition protocol, so we had a greater than 90% yield of obtaining tissue for patients on the study. We hope to identify, using evaluations for biomarkers, perhaps some tests that might predict which patients benefit and which patients wouldn't,” Dr. Shah said. The team is also continuing to review the data to determine the best way to proceed with a next study.
“I think the way the study was performed highlights the heterogeneity of gastric cancer, which perhaps wasn't as well perceived previously. If this study was done just in certain disease classes, the study may have been positive. We have to figure that out.”
Maintaining Quality of Life
Dr. Van Cutsem was also one of the authors of another study looking at the effect of trastuzumab on quality of life when added to chemotherapy as a front-line therapy.
The study was based on results from the international Phase III ToGA (Trastuzumab for Gastric Cancer) study, which found that the addition of trastuzumab to chemotherapy was superior to chemotherapy alone. To assess whether the addition of trastuzumab had any effect on patients' quality of life, researchers, led by Dr. Ohtsu, also of the AVAGAST study, asked patients to complete standard EORTC quality-of-life questionnaires every three weeks until disease progression.
“We wanted to see if, with the benefit that was shown, quality of life was maintained, and we found that it was not worse. Patients maintained their quality of life for a longer time,” Dr. Van Cutsem said.
Global health status and functioning scores improved from baseline to the end of chemotherapy, administered at Week 19, in both treatment arms and showed a sustained effect beyond chemotherapy. To minimize bias due to selection of patients with better prognosis, an analysis was performed excluding patients whose disease had progressed prior to Week 37.
Symptom scores, including pain, appetite loss, nausea/vomiting, and constipation showed improvement in both arms for patients whose disease had not progressed at that point.
Over time, improvements were also seen for dysphagia; pain, in stomach or during eating; anxiety; and reflux symptoms. Significant average monthly decreases for eating restrictions, dry mouth, and body image scores were also observed, and around the termination of chemotherapy, scores for dry mouth, taste, body image, and hair loss had also improved in this patient population.
This data will add additional power to grant trastuzumab an indication for the treatment of gastric cancer, Dr. Van Cutsem expects.
“In Europe this is already proven in gastric cancer and in the US, the FDA is evaluating the finding because of the survival benefit. This is the first time that the biologic agent is active in gastric cancer and it also targets the HER2-positive population.”
Outlook for Targeted Therapy in Gastric Cancer
Both of these studies will likely be the basis for more trials looking at bevacizumab and other targeted therapies in gastric cancer, said Dr. Van Cutsem, noting the huge unmet need for therapies in this disease.
“What this shows is we need major efforts to try to predict markers for which patients will benefit. That is going to be crucial.
“We are at the beginning of a new era looking into the role of targeted agents. There is no reason to believe that in gastric cancer some targeted agents should not be active like in other cancers. Unfortunately, they won't cure the patients, but they may help to contribute to a benefit in the survival of patients with gastric cancer.”