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FDA Grants Priority Review of Ramucirumab for Gastric Cancer, Phase III Findings Published—Concerns, Though, from a Lead Recruiter to the Trial

Samson, Kurt

doi: 10.1097/01.COT.0000438503.02328.5e


A Phase III study of the monoclonal antibody ramucirumab extended both overall survival and progression-free survival in patients with gastric and gastroesophageal junction cancer when initial chemotherapy failed to stop disease progression, according to the results of an international study, now available online ahead of print in The Lancet (doi:10.1016/S0140-6736[13]61719-5).

Based on the findings, the U.S. Food and Drug Administration on October 23 granted priority review of the drug, with the possibility of an approval decision early next year.

Ramucirumab is the first single-agent biologic or an anti-angiogenic therapy to improve overall and progression-free survival in advanced gastric cancer patients, according to the REGARD study, a randomized, placebo-controlled trial in 355 patients at 119 centers in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa.

All patients had advanced gastric or gastro-esophageal junction adenocarcinoma with disease progression after receiving first-line platinum-containing or fluoropyrimidine-containing chemotherapy.

“What we found is that the patients who received ramucirumab had a significant improvement in their survival as well as reduced rates of cancer progression,” said the lead author, Charles S. Fuchs, MD, MPH, Professor at Harvard Medical School and Director of the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute.



According to the study results, treatment resulted in a 22 percent increase in survival, with median survival of 5.2 months in treated patients compared with 3.8 months among those receiving placebo.

With the exception of increased rates of hypertension (8% vs. 3% in the placebo arm) and abdominal pain (6% vs. 3%), the drug was well-tolerated; there were, however, five deaths related to treatment in the ramucirumab group compared with two in those given placebo.

Perhaps most surprising is how similar the trial results were to survival with second-line chemotherapy, he said in an interview: “It's uncanny how close the data are to studies with chemotherapy agents. We found a survival benefit of 5.2 months versus 3.8 months, while treatment with docitaxel is 5.3 versus 3.6 months and survival rates with irinotecan is 5.3 compared with 3.8 months.

“Because of its lower toxicity profile, I believe it should be integrated into routine treatment for these patients.”

The REGARD researchers are now looking at the data in hopes of identifying potential biomarkers in the most responsive subjects that might set them apart from those who did not respond as well.

Ramucirumab blocks the action of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signaling and angiogenesis in tumors.

A news release from the drug's manufacturer, Eli Lilly, noted that REGARD is the second Phase III study of ramucirumab to meet its primary endpoint of improved survival in such patients. The RAINBOW trial, which is also sponsored by the company, is a global, randomized, double-blind study comparing ramucirumab and paclitaxel with placebo and paclitaxel in 665 patients across 27 countries. Lilly has reported similar low rates of adverse events in RAINBOW and has said the study met its primary endpoint of improved survival, although it has not released any specific survival data to date, saying the findings will be presented at an unspecified conference in the near future.



The ROSE trial, however, a recent Phase III trial of ramucirumab in women with locally recurrent or metastatic HER2-negative breast cancer, failed to meet its primary endpoint of significant progression-free survival.

Richard Gaynor, MD, Lilly Oncology's Vice President of Product Development and Medical Affairs, said the company is anticipating findings from other Phase III clinical trials in patients with colorectal, hepatocellular, and lung cancer, the results of which are expected in 2014.

Richard Kim, MD, a medical oncologist in the Department of Gastrointestinal Oncology at H. Lee Moffitt Cancer Center, said there is increasing evidence that ramucirumab, either alone or when combined with potent chemotherapy agents, can help such patients.

“The REGARD trial is the first study to show overall survival in this second-line setting using a targeted agent. Although the data from the RAINBOW trial investigating ramucirumab in combination with paclitaxel have not been released, Lilly has reported that the trial met its primary and secondary endpoints of improved overall survival and progression-free survival. I think that with two positive Phase III trials, ramucirumab appears to be a promising treatment option for patients with advanced gastric cancer,” he told OT.

He said that while the difference in survival between patients treated with ramucirumab and the placebo group in REGARD was only 1.4 months, that is comparable to survival rates with single-agent chemotherapy. “Even though the magnitude of benefits shown with this trial was relatively small, it was meaningful. Other than hypertension, which was expected, ramucirumab was very well tolerated as a single agent, so I think the next question is what happens when you add ramucirumab to chemotherapy agents.

“Based on the RAINBOW trial it would appear that a combination is better than chemotherapy alone, and we are eagerly awaiting the findings,” Kim continued. “The next obvious step will be to try moving ramucirumab into first-line treatment for patients where bevacizumab has failed.”

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Concerns from Jaffer Ajani

However, Jaffer A. Ajani, MD, Professor in the Division of Cancer Medicine in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, who recruited patients and participated in the trial, was less enthusiastic.

He told OT that MD Anderson recruited the highest number of patients into the REGARD trial, but that he chose not be included as an author on the Lancet paper—a decision, he said, that had nothing to do with the trial results. “The trial was well conceived and well executed, but if you look at the data closely, the positive results were delivered to the finish line on a stretcher,” he said.

“For instance, if you look at the hazard ratio, something that many people do not, you can see how limited the results actually were. The upper limit of the hazard ratio was 0.0998 with a p value of 0.047. This upper limit of the hazard ratio is important, because it was just under 1.00001, which would have made the p value insignificant. Neither of these levels is impressive. In fact the p value was close to being negative, so it is clear that the anticipated difference was not achieved.”

Ajani also noted that none of the MD Anderson patients in the study went beyond the evaluation stage because their cancers continued growing.

“Expectations for this study were high, but expectations have no place in good research,” he said. “To me the results mean ramucirumab as a single agent has only a marginal effect, and treatment will benefit only a very small number of patients. It might work better when combined with chemotherapy, but that was not explored.”

Ajani also expressed concern that the Food and Drug Administration might approve ramucirumab for gastric cancer despite the narrow hazard ratio margin. “I do not believe the agency should be approving drugs when Phase III trials have such borderline results. For one thing, it unfairly raises patient expectations.”



Fuchs, though, disagreed: “Statistics are always a problem with smaller trials, and I admit 355 patients is not the largest trial and that the survival benefits appear to be moderate. But a p value of 0.047 is significant regardless of the hazard ratio argument. Also, if you look at other ramucirumab studies in resistant cancers, with the exception of breast cancer they seem to support our findings.”

© 2013 by Lippincott Williams & Wilkins, Inc.
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