SAN FRANCISCO—There is currently no standard of care for patients with advanced esophagogastric cancer whose disease has progressed on first-line combination chemotherapy. However, studies presented here at the Gastrointestinal Cancers Symposium show that second-line regimens can prolong overall survival or quality of life. The question of which regimen to use will likely come down to toxicity profiles and cost, according to experts.
In the Phase III REGARD trial (Abstract LBA5), 355 patients were randomly assigned in a 2:1 fashion to receive either ramucirumab, which targets the VEGF-receptor 2, or placebo and best supportive care. To be eligible, patients had to have metastatic gastric or gastroesphageal junction adenocarcinoma that had progressed within four months of first-line therapy for metastatic disease or within six months of adjuvant therapy.
Median overall survival was 5.2 months in the ramucirumab group compared with 3.8 months in the control arm, which was a 22 percent reduction in risk of death. Secondary endpoints also favored ramucirumab, in terms of progression-free survival (2.1 vs. 1.3 months) and overall response rate (49% vs. 23%).
The most common grade 3 or higher adverse event was hypertension, affecting 7.2 percent of patients in the ramucirumab arm compared with 2.6 percent in the placebo arm, followed by fatigue (6.4% vs. 9.6%), anemia (6.4% vs. 7.8%), abdominal pain (5.9% vs. 2.6%), ascites (4.2% vs. 4.3%), decreased appetite (3.4% vs. 3.5%), and hyponatremia (3.4% vs. 0.9%).
Additionally, grade 3 or higher multi-organ failure occurred in 2.5 percent of patients in the ramucirumab arm and 0.9 percent in the placebo arm, although the researchers say this occurred in the context of disease progression and was thought to be due to the disease. Treatment-related deaths were similar in the two arms, at 10.6 percent in the ramucirumab arm and 13.0 percent in the placebo arm.
“I think what this study suggests is that this antibody, as a single agent, offers a real therapeutic option in second-line therapy in patients with stomach cancer,” said Charles Fuchs, MD, MPH, Director of the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, who presented the data. “The benefit, to my eye, looks like what is typically reported out in Phase III studies of chemotherapy in this same setting.
“More to the point, if you look at the adverse event profile for this antibody, I think it compares favorably with what we have seen in Phase III studies of standard chemotherapy.”
The benefits do appear very similar to what has been seen in patients treated with chemotherapy, agreed Hugo Ford, MD, Director of Cancer Services at Addenbrooke's Hospital in Cambridge, UK. For example, Ford presented a quality-of-life analysis on a Phase III docetaxel trial conducted in a similar patient population. In that study, overall survival was 5.2 months with chemotherapy compared with 3.6 months in the best supportive care arm, and quality-of-life data strongly favored the chemotherapy arm. (OT, 3/25/13 issue).
The toxicity seen with ramucirumab is “what you would expect from a targeted therapy,” Ford said. “They [Fuchs et al] haven't done the detailed quality-of-life analysis that we have done, but on the face of it, they may have less side effects. The question is, do the side effects that we've got [in our trial] really even matter, because much of it is asymptomatic neutropenia which people don't even notice.”
During the poster session, one senior investigator, who declined to give his name, questioned the choice of an expensive targeted agent over cytotoxic chemotherapy. “Ilson's point is the same here,” he said, referring to an exchange during an oral session in which David Ilson, MD, of Memorial Sloan-Kettering Cancer Center pointedly asked a speaker why anyone would choose their expensive targeted drug over chemotherapy when there was no survival benefit.
The multidisciplinary symposium is co-sponsored by the American Gastroenterological Association Institute, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.