Anti-VEGFR2 Inhibitor Shows No Clinical Benefit in Colon Cancer

Barbara Boughton

January 26, 2012

January 26, 2012 (San Francisco, California) — Results of a phase 3 randomized trial in metastatic colorectal cancer indicate that brivanib alaninate, an antivascular endothelial growth factor receptor 2 agent that also targets fibroblast growth factor receptors, has limited efficacy when combined with cetuximab. These findings were presented here at the 2012 Gastrointestinal Cancers Symposium (GICS).

Although preliminary clinical trials were promising, this latest international phase 3 trial of 750 patients with chemotherapy-refractive metastatic colorectal cancer indicates that not only does brivanib alaninate fail to improve overall survival when combined with cetuximab, but incidence of grade 3 adverse events was unexpectedly high, affecting 78% of patients, and those receiving the doublet therapy saw their quality of life worsen significantly.

In the trial, 750 patients were randomly assigned to receive either cetuximab plus brivanib alaninate or cetuximab plus placebo. After a median follow-up of 19 months, overall survival was not significantly different in the experimental group vs the control group (8.8 months vs 8.1 months; hazard ratio [HR], .88; P = .12).

Patients receiving the combination therapy did show improved progression-free survival (5 months vs 3.4 months; HR, .72; P = .0001) and a greater response rate than those receiving cetuximab alone (13.6% vs 7.2%; P = .004).

"Although both objective response rate and progression-free survival were improved in patients on cetuximab and brivanib alaninate, the primary endpoint of overall survival was not met," noted presenting author Lillian L. Siu, MD, from Princess Margaret Hospital and the University of Toronto, Ontario, Canada.

"Patients in the experimental arm also experienced greater frequencies of adverse events, including fatigue, gastrointestinal toxicities, hypertension, and rash, and more patients in the experimental arm discontinued their therapy due to adverse events than in the control arm," Dr. Siu said.

Although patients in the experimental arm derived some benefits from the combination therapy, in terms of a longer progression-free survival and higher response rate, they also paid a price, Dr. Siu pointed out. When patients' quality of life was assessed after therapy, those who were receiving the doublet regimen were significantly more likely than those in the placebo group to have experienced a deterioration both in their quality of life and in their physical function.

Because of adverse events from the combination therapy, fewer patients in the experimental group received at least 90% of the planned dose intensity. Specifically, 57% of those receiving the combination therapy received 90% of the planned cetuximab intensity, and 48% received 90% of the planned brivanib alaninate intensity.

In contrast, 83% of those in the control group received 90% of the planned dose intensity of cetuximab, and 87% received 90% of the dose intensity of placebo.

"This study was very well executed, but it was based on modest data on the benefits of adding brivanib alaninate to cetuximab in early-phase clinical trials," commented Herbert Hurwitz, MD, from Duke University Medical Center in Durham, North Carolina. "The increase in response rate in the experimental arm is interesting, but not really clinically significant," he added.

Dr. Hurwitz also expressed concern about the adverse effect profile of the combination regimen. "With a high rate of grade 3 and 4 toxicities, the side effects become clinically meaningful because they led patients with refractory disease to drop-out, and led to significant dose reductions not only for brivanib but also for cetuximab," he said. "Thus, not only was the value of the experimental drug compromised, but so was the value of the standard drug [cetuximab]."

Although there were progression-free survival and response rate benefits from the doublet tested in the trial, the toxicity clearly limits its use, Dr. Hurwitz stressed. "There was no meaningful crossover to confound the results, and this data will clearly not lead to regulatory approval for brivanib alaninate in colorectal cancer."

However, the drug is currently being tested in other settings, including clinical trials for hepatocellular cancer, Dr. Hurwitz noted.

The study received funding from Bristol-Myers Squibb. Dr. Siu has disclosed no relevant financial relationships. Dr. Hurwitz is a consultant or advisor to Bristol-Myers Squibb and Genentech/Roche.

2012 Gastrointestinal Cancers Symposium (GICS): Abstract 386. Presented January 21, 2012.

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