Bevacizumab Plus Second-Line Chemotherapy Extends Survival in Advanced Colorectal Cancer Patients

Dirk Arnold, MD

Bevacizumab plus chemotherapy as a second-line treatment for metastatic colorectal cancer improved survival among patients whose disease had progressed after first-line combination therapy with bevacizumab, according to the results of a phase III trial.

The results of the study were presented on Sunday at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

"We know that bevacizumab nicely works, in addition to chemotherapy, in the first-line setting on the basis of two phase III trials," said Dirk Arnold, MD, director, Hubertus Wald Tumor Center, University Cancer Center of University Clinic Eppendorf in Hamburg, Germany and lead author of the study. "We also know that bevacizumab works second-line when patients are not pretreated with bevacizumab. There was a thinking in Europe and also mainly in the US whether it makes sense to continue with this drug throughout both treatment lines."

Although many oncologists in the US already provide such therapy, Arnold said that the FDA has not clearly defined the role of bevacizumab in this particular patient population with regard to second-line treatment. However, in Europe, regulations have defined the use of bevacizumab in combination with chemotherapy for either first-line or second-line treatment, but not both, according to Arnold. This trial was the first to prospectively study these claims.

In the randomized trial, 820 patients with inoperable metastatic colorectal cancer were treated with either oxaliplatin- or irinotecan-based chemotherapy plus bevacizumab. If the disease progressed, patients were randomized to receive the opposite chemotherapy regimen plus either bevacizumab or a placebo. Arnold explained that switching chemotherapy regimens between first-line and second-line treatments is considered the standard of care. The primary endpoints of the trial were overall survival (OS), progression-free survival (PFS), and safety.

There was a significant benefit observed in both OS and PFS in patients who received bevacizumab in the second-line compared with the placebo arm. Patients who received second-line bevacizumab combination therapy had a median OS of 11.2 months compared with 9.8 months in those who received chemotherapy alone (hazard ratio [HR], 0.81; 95% confidence interval [CI] 0.69-0.94; unstratified log-rank test, P=.0062). The median PFS in the bevacizumab plus chemotherapy arm was 5.7 months compared with 4.1 months in the chemotherapy alone arm (HR=0.68; 95% CI 0.59-0.78; unstratified log-rank test, P<.0001). The overall response rate was 5.4% in the bevacizumab plus chemotherapy arm compared with 3.9% in the chemotherapy alone arm (unstratified Chi-Square Test, P=.3113).

Additionally, adverse events did not increase when patients continued using bevacizumab beyond first progression. For example, neutropenia between grade 3-5 was experienced in 13% of patients in the chemotherapy alone arm compared to 16% in those who received chemotherapy and bevacizumab. Similarly, comparable results were seen in other side effects pertaining to the use of bevacizumab, including hypertension, diarrhea, and thromboembolic events. This suggests that bevacizumab is relatively well-tolerated in these patients.

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Arnold noted that the trial shows that even though a patient may develop resistance to one form of chemotherapy that does not necessarily mean the patient will also become resistant to an anti-angiogenic therapy such as bevacizumab. Arnold said this line of thinking is likely to be tested in other tumor types outside of colorectal cancer.

"This study confirms that the continuation of bevacizumab beyond progression, while changing chemotherapy, is beneficial for patients, as it translated into an improvement in overall survival in metastatic colorectal cancer patients," Arnold said. "This clearly provides a new treatment option in second-line in patients who have been pretreated with a bevacizumab combination regimen."

Arnold D, Andre T, Bennouna J, et al. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study). J Clin Oncol. 2012;30(suppl; abstr CRA3503).

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