New targeted drug prolongs survival in advanced stomach cancer


Charles Fuchs, MD, MPHCharles Fuchs, MD, MPH

A targeted drug that reduces blood flow to tumors prolonged the survival of patients with advanced stomach cancer after standard treatments failed, according to results of large multicenter clinical trial led by scientists at Dana-Farber Cancer Institute.

Patients receiving the antibody drug ramucirumab also experienced a longer delay before the cancer progressed than those who were given a placebo in the randomized, controlled phase 3 trials, the investigators reported in the Lancet.

Because of the antibody’s selective action, patients receiving ramucirumab generally had modest side effects, though they had slightly increased rates of high blood pressure compared to the control patients.

“It’s really impressive that an antibody which had very little side effects could provide a survival benefit,” said Charles Fuchs, MD, MPH, of Dana-Farber, first author on the report of results from the REGARD trial.

The clinical trial involved 355 patients with cancer of the stomach or the junction of the stomach and esophagus. The patients were treated at 119 medical centers in 29 countries.

 

Stomach cancer is the second leading cause of cancer mortality worldwide, though in the United States its burden is much less, with an estimated 21,600 cases and 10,990 deaths projected for 2013. Advanced stomach cancer is typically treated with chemotherapy, but there is no approved second-line treatment if the cancer continues to progress.

“We realized that we need better treatments for stomach cancer because for the most part, the current paradigm for using routine chemotherapy just isn’t enough,” said Fuchs, director of Dana-Farber’s Center for Gastrointestinal Cancer. “We need to develop targeted agents for this disease that really focus on our understanding of the biology.”

Unlike standard toxic chemotherapeutic agents that kill cancer cells or prevent them from dividing, ramucirumab targets protein signals in the circulation that trigger the formation of new blood vessels to support tumors’ growth and spread. Ramucirumab is designed to block signaling through the VEGF Receptor-2 (VEGFR-2), reducing new blood vessel formation (angiogenesis) and starving the tumors of nutrients. Blocking VEGFR-2 in animal models slowed the growth of stomach cancer in mice.

In the clinical trial of ramucirumab, 355 patients with advanced gastric cancer received the antibody drug every two weeks plus best supportive care, and 117 patients received a placebo along with best supportive care.

The study ended in July 2012, and analysis revealed a significant 22 percent reduction in mortality with ramucirumab. In addition, patients treated on the ramucirumab arm achieved a median overall survival of 5.2 months compared with 3.8 months in the placebo group.  

The drug delayed progression of the cancer by 52 percent. The rate of freedom from cancer progression at 12 weeks was 40 percent in patients treated with ramucirumab compared to 16 percent for the placebo group. The researchers considered that the disease was under control for a median of 4.2 months with ramucirumab and for 2.9 months in the placebo group.

“What we found is that the patients who received the antibody had a significant improvement in their survival as well as reducing the rate of cancer progression,” Fuchs said. “The results were encouraging and we hope that the drug will ultimately be approved for routine use for patients with stomach cancer.” He added that clinical trials are underway to find out if adding ramucirumab to chemotherapy “can get even better results.”

Adverse effects were common in both groups, and the incidence of serious side effects was comparable. However, hypertension occurred in 7.6 percent of patients on ramucirumab compared with 2.6 percent on placebo. The drug did not appear to cause effects sometimes seen with anti-angiogenic drugs such as increased bleeding blood clots, and perforations of the stomach and intestines, according to the report.

The research was funded by Eli Lilly and Company and ImClone Systems, a wholly-owned subsidiary of Lilly. 

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