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Tuesday, February 5, 2013

ONLINE FIRST: End of the Line for Bevacizumab in Breast Cancer?


By Robert H. Carlson


SAN ANTONIO -- Two negative trials of bevacizumab in breast cancer were reported at the CTRC-AACR San Antonio Breast Cancer Symposium, testing the antiangiogenic agent in combination with chemotherapy for patients with triple-negative disease and in combination with endocrine therapy as first-line treatment for patients with advanced breast cancer.


In the Phase III BEATRICE study, patients who received one year of bevacizumab in addition to chemotherapy for the postsurgical treatment of triple-negative breast cancer had no statistically significant improvement in invasive disease-free survival compared with patients treated with chemotherapy alone.


And the LEA study of bevacizumab plus letrozole or fulvestrant as first-line treatment for advanced breast cancer failed to demonstrate a statistically significant increase in progression-free or overall survival.


“It’s getting to the point where it’s going to be difficult to know the role of bevacizumab, if any, in breast cancer,” said Symposium Co-Chair Kent Osborne, MD, Professor of Medicine and Molecular and Cellular Biology, and Director of the Dan L. Duncan Cancer Center and the Smith Breast Center at Baylor College of Medicine, Houston, speaking at a news briefing.


“If [bevacizumab] is going to work, you’d think it would work in this situation, in the sense that we’re dealing with the stage of microscopic metastases that haven’t developed a sufficient blood supply yet. And if you could prevent that blood supply from forming you might have a more dramatic effect than with an already established tumor of likely metastatic breast cancer.”


But, he continued, “the results are obviously disappointing, and suggest that bevacizumab is going to have a very limited role, if any, in breast cancer, unless any of the ongoing trials show different results.”


No Advantage in Triple-Negative Disease

BEATRICE (“Bevacizumab Adjuvant Therapy in Triple-Negative Breast Cancer”) was an open-label, randomized Phase III trial evaluating adjuvant bevacizumab-containing therapy in triple-negative operable invasive breast cancer including 2,591 women: 1,290 received “investigator’s choice” of four to eight cycles of standard anthracycline-based and/or taxane-based chemotherapy, followed by observation; and 1,301 received investigator’s choice of four to eight cycles of standard chemotherapy plus bevacizumab at 5 mg/kg per week followed by bevacizumab monotherapy, for up to one year of total therapy.


The median age for both groups was 50. Approximately one third in each group had T1 disease, 60 percent had T2, and the remainder had T3. Approximately 95 percent in each group was hormone-receptor negative, and five percent had low levels of hormone receptor; 63 percent of patients in both groups were node negative, 25 percent had one to three nodes, and 12 percent had four or more nodes.



The study’s principal investigator David Cameron, MD, Professor of Oncology at Edinburgh University, Scotland, reported that at 32 months of follow-up, the event rates were 15.9 percent for the chemotherapy arm vs. 14.5 percent for the bevacizumab regimen arm; the rates of three-year disease free survival were 82.7 and 83.7 percent, respectively.


Cameron said the disease-free survival rates were better than anticipated when compared with historical literature. This might be due to the improved chemotherapy regimens that are standard today, he said.


“When women go on the Web and look up what is a very negative image of triple-negative breast cancer, we can at least say that in a big worldwide Phase III trial the outcomes were actually not as bad as the literature suggests.”


Osborne agreed, saying that patients appear to be doing better than expected in many recent trials, which may reflect gradual improvements through the years in basic treatments when adding a new agent.


Cameron said a pre-specified analysis will be performed to assess any potential impact of bevacizumab on overall survival.


No Overall or Progression-Free Survival Improvement with Bevacizumab-Endocrine Treatment Combination

Also reported at the meeting, the LEA (Letrozole/Fulvestrant and Avastin), the first Phase III study to explore the use of an anti-angiogenic drug in combination with endocrine therapy, failed to demonstrate a statistically significant increase in progression-free or overall survival when bevacizumab was added to endocrine therapy as first-line treatment for advanced breast cancer.



Miguel Martin, MD, PhD, Head of the Medical Oncology Service at Instituto de Investigacion Sanitaria Gregorio Marañon in Madrid, presented data for LEA on behalf of GEICAM (the Spanish Breast Cancer Research Group) and GBG (the German Breast Group).


Prior studies, he noted, suggest that high levels of vascular endothelial growth factor in breast tumors are associated with a decreased response to endocrine therapy. LEA addressed the hypothesis that anti-VEGF treatment can prevent resistance to hormone therapy in patients with unresectable locally advanced or metastatic breast cancer.


Bevacizumab given at 15mg/kg every three weeks was added to endocrine therapy with letrozole (2.5 mg/day) or fulvestrant (250 mg/4 weeks) as first-line therapy in advanced breast cancer. Patients were treated until disease progression.


Patients were postmenopausal with HER2-negative and hormone-receptor-positive breast cancer.


Overall survival was 42 months for the 189 patients who received letrozole or fulvestrant, vs. 41 months for the 191 who received hormonal treatment as well as bevacizumab.


The duration of progression-free survival was 13.8 months for the 189 patients who received letrozole or fulvestrant, vs. 18.4 months for the 191 who received hormonal treatment and bevacizumab.


The control arm behaved better than expected compared with other studies of endocrine therapy, which may be due to the good performance score of patients in that arm, he said, adding, though, that this could have skewed the statistical results against a bevacizumab benefit.


Even so, while the 31% relative reduction in progression-free survival in the bevacizumab arm was not statistically significant, Martin said the benefit should not be overlooked.


Asked for his opinion, Symposium Co-director Carlos Arteaga, MD, PhD, Associate Director for Clinical Research and Director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center, said in interview that he didn’t consider the LEA results to be very impressive: “There was no statistical improvement in outcome as a function of adding bevacizumab to hormonal therapy -- that’s kind of the end of the story.”


Arteaga noted that Martin indicated that the LEA researchers are looking for biomarkers that may identify a group that benefits from a bevacizumab-endocrine therapy combination.


“We should probably remain open-minded about the possibility they may find something in serum tests that may identify patients where this combination is going to be effective,” Arteaga said. “But again, that will not be practice-changing by any means because the study overall was not positive.”