Avastin combo improves survival in advanced breast cancer

5 May 2016

Adding bevacizumab (Avastin) to letrozole (Femara) improved progression-free survival in estrogen receptor-positive metastatic breast cancer (ER+MBC) but not other outcomes, an open-label, multicenter phase 3 trial showed.

While median progression-free survival increased by 4.6 months in patients who received combined therapy versus letrozole alone, there was no significant difference in overall survival, Maura N. Dickler, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues reported.

In addition, there was a marked increase in grade 3 to 4 toxicities, particularly hypertension (24% versus 2%) and proteinuria (11% versus 0%), the researchers said, emphasizing that the role of bevacizumab in this setting will need to be clarified with research on predictive markers.

Clinical trial details

For the open-label CALBG/Alliance 40503 trial, a total of 350 women with ER+MBC were enrolled from May 2008 to November 2011. Median age was 58 years, 62% had measurable disease, 25% had bone-only metastases, 45% had de novo metastatic disease, and and 44% had a disease-free interval longer than 2 years.

Nearly half of the patients received prior hormone therapy such as an aromatase inhibitor or tamoxifen and 40% received prior chemotherapy. A total of 343 women were randomly assigned 1:1 to letrozole (2.5 mg orally per day) with or without bevacizumab (15 mg/kg intravenously once every 3 weeks).

"Given the positive results of CALGB 40503 on our primary end point [progression-free survival], we will refine subgroup selection by using patient and tumor characteristics to potentially identify factors in both the control and experimental arms that are predictive of benefit from ET alone or with bevacizumab," Dickler and colleagues wrote. "Results may inform the design of new trials to test bevacizumab or other classes of targeted therapies added to ET."

CareAcross-girl-at-sea

Lack of overall survival benefit

At a median follow-up of 39 months, the addition of bevacizumab resulted in a 25% reduction in the hazard of progression and a prolongation in median progression-free survival from 15.6 months with letrozole to 20.2 months with letrozole plus bevacizumab in the Cancer and Leukemia Group B (CALGB) trial, now known as Alliance 40503.

Given the toxicity of bevacizumab and the lack of overall survival benefit demonstrated in this trial, it is unlikely to be adopted for all patients with hormone receptor positive metastatic breast cancer, said Jennifer K. Litton, MD, of the University of Texas M.D. Anderson Cancer Center in Houston. However, added Litton, who was not affiliated with the study, "there is likely agreement that there is a subset of breast cancer patients who may benefit from bevacizumab, but as of yet there is no reliable biomarker to identify those patients."

The good news is that since this study launched, a definitive change in the ER+MBC treatment landscape has led to the availability of endocrine therapy combinations such as mTOR inhibitors and cyclin-dependent kinase inhibitors, Litton pointed out. What's more, there are other endocrine therapies with oral formulations in development "that provide improvement over endocrine therapy alone and often with significantly less toxicity than bevacizumab," she told.

Not sufficient result to change standards of care

"Broadly, these data challenge the assumption that progression-free survival is a surrogate for overall survival in metastatic breast cancer or that progression-free survival alone can be used in all settings to identify superior treatment options," Dickler and colleagues wrote. "Given the extent of data for bevacizumab across multiple stages and settings in breast cancer, it is clear that the statistically significant improvement in progression-free survival that our trial was designed to detect is not, in itself, sufficient to change standards of care. Were it associated with improved survival, a different (and lesser) toxicity profile, or different (and lesser) costs, then perhaps our assessment would change."

Although several trials have demonstrated the safety and feasibility of combining ET with bevacizumab, which is a humanized monoclonal antibody to vascular endothelial growth factor receptor (VEGFR), until now its impact on outcomes has been uncertain, the researchers said. The phase 3 Letrozole/ Fulvestrant and Avastin Study (LEA) demonstrated that progression-free survival increased with the addition of bevacizumab but the difference (14.4 versus 19.3 months) didn't reach statistical significance.

Source: MedPage Today

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