Roxanne Nelson

June 03, 2012

June 3, 2012 (Chicago, Illinois) — A new study has confirmed that continuing bevacizumab (Avastin) treatment beyond first progression, while modifying chemotherapy, can be beneficial for patients with metastatic colorectal cancer.

In the first randomized study to prospectively investigate the impact of continuing bevacizumab beyond first progression, there was a significant improvement in both overall and progression-free survival.

"Preclinical observational studies have shown us that it may make sense to continue bevacizumab from one treatment line to another treatment line, and that this may increase the benefit for the patient," said lead author Dirk Arnold, MD, director of the Hubertus Wald Tumor Center, University Cancer Center of University Clinic Eppendorf, in Hamburg, Germany.

The trial clearly met its end point of overall survival, with a statistically significant improvement in overall survival (hazard ratio [HR], 0.81), he explained. Median survival was longer with chemotherapy plus bevacizumab than with chemotherapy alone (11.2 vs 9.8 months).

Median "progression-free survival was also improved in the second-line setting" with chemotherapy plus bevacizumab (5.7 vs 4.1 months; HR, 0.68; P < .0001), said Dr. Arnold.

In addition, the response rate was better with chemotherapy plus bevacizumab than with chemotherapy alone (5.4% vs 3.9%; P = .3113).

The results of the trial were presented here at the 2012 Annual Meeting of the American Society of Clinical Oncology.

Needed Evidence

Many oncologists in the United States are already extending bevacizumab beyond first progression; this study gives justification for that, said Bruce J. Roth, MD, professor of medicine in the division of oncology at Washington University School of Medicine in St. Louis, Missouri.

"We could think of a dozen reasons why continuation of an antiangiogenic strategy would be beneficial," Dr. Roth told Medscape Medical News. "Quite frankly, if the drug cost $1.25 a month, we wouldn't even be having this discussion."

Dr. Roth moderated a press briefing in which highlights of the study were reported prior to the presentation; he was not involved in the trial.

"It raises the level of awareness of what the financial impact of continuation is, and whether it is worth these months of second-line therapy," he said. "It's hard to know where that breakpoint is. But this study provides a scientific benefit for that strategy."

Although the study was well designed and demonstrates the benefit of continuation, it doesn't address the magnitude of that benefit, Dr. Roth pointed out. "That's...for individual physicians and their patients to decide."

Previous studies have hinted at the benefit of continuing bevacizumab in patients with advanced colorectal cancer. One large observational study reviewed 1445 metastatic colorectal cancer patients after they progressed on a variety of chemotherapy regimens plus bevacizumab. Patients who changed chemotherapy after progression but continued on bevacizumab had an overall survival of 31.8 months, compared with 19.9 months for those who changed chemotherapy regimens but discontinued bevacizumab. Multivariate analysis showed that bevacizumab was "strongly associated" with improved survival.

"The importance of the current trial is in the proof of concept in the clinical setting, showing us that what the scientists have been telling us for 30 years is actually true," said Philippe Bishop, MD, vice president of clinical development and angiogenesis franchise head at Genentech. "Putting the brakes on this angiogenesis access to the blood supply that feeds the tumors is actually beneficial to patients."

Dr. Bishop noted that he is unaware of any other biologics that have demonstrated a survival advantage in this setting, except in the case of bevacizumab-naïve patients. "This gives doctors a new option to choose from when deciding how to manage their patients," he said.

"This is a very important trial, not only from the scientific perspective, but from the medical practice perspective," Dr. Bishop explained. "Previously, physicians had indirect evidence. I think that those who are already using it in this setting now have more definitive proof to justify what they have been seeing in the clinic; those who were waiting to see the data now have what they need to make those decisions."

Study Details

Bevacizumab administered in combination with fluoropyrimidine-based chemotherapy is the standard first-line treatment for metastatic colorectal cancer and second-line treatment in bevacizumab-naïve patients.

In this international study, Dr. Arnold and colleagues randomized 820 patients with unresectable, histologically confirmed metastatic disease who had progressed within 3 months of discontinuing first-line bevacizumab plus chemotherapy to either second-line fluoropyrimidine-based therapy plus bevacizumab (2.5 mg/kg per week equivalent) or placebo.

The choice of oxaliplatin- or irinotecan-based chemotherapy as second-line therapy depended on the regimen used in the first-line setting. The primary end point was overall survival; secondary end points included progression-free survival, response rate, and safety.

Treatment was well tolerated in both study groups, and adverse events associated with bevacizumab were comparable with those observed in previous studies. Bevacizumab-related adverse events were no worse when the agent was continued past progression.

"This clearly provides a new second-line treatment option for patients who have already been treated with a combination bevacizumab regimen," said Dr. Arnold. "Furthermore, these findings might serve as a potential new model for treatment approaches across multiple lines in metastatic colorectal cancer and across other tumor types, which is being investigated."

The study was funded by Genentech. Dr. Arnold reports being a consultant or advisor for Amgen, Merck Serono, and Roche Diagnostics; receiving honoraria from Amgen, Merck Serono, and Roche Diagnostics; and receiving research funding from Roche Diagnostics. Some of his coauthors report financial relationships with industry, as noted in the abstract.

2012 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract CRA3503. Presented June 3, 2012.

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