Avastin for breast cancer – pro
Lay Summary: Avastin has a role on metastatic breast cancer, especially in combinations with taxanes.
Bevacizumab(Avastin) was until recently FDA approved for breast cancer. It is now an off-label treatment.
A previous Phase III study of bevacizumab in metastatic breast cancer found that the addition of bevacizumab to capecitabine produced a significant increase in response rates, but this did not translate into improved progression free survival or overall survival (Miller, et al., 2005). This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab in 462 patients with metastatic breast cancer previously treated with an anthracycline and a taxane. Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional Assessment Of Cancer Treatment-Breast were comparable in both treatment groups. The investigators reported that bevacizumab was well tolerated in this heavily pretreated patient population (Miller, et al., 2005). No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab.
Results from a large, randomized clinical trial for patients with previously untreated recurrent or metastatic breast cancer — cancer that has spread from the breast to other parts of the body — show that those patients who received bevacizumab (Avastin™) in combination with standard chemotherapy had a longer time period before their cancer progressed than patients who received the same chemotherapy without bevacizumab. Preliminary results suggest that patients in the study who received bevacizumab in combination with standard chemotherapy consisting of single-agent paclitaxel had a delay in worsening of their cancer by approximately five months, on average, compared to patients treated with paclitaxel chemotherapy alone. In the E2100 study, the addition of bevacizumab (Avastin) to paclitaxel resulted in an increase in progression-free survival of more than 4 months. In the trial, patients receiving just paclitaxel had about 6.11 months before the cancer progressed. Those who were treated with both the cytotoxic agent and the new targeted therapy had progression-free survival that averaged 10.97 months. The difference in progression-free survival was statistically significant at the P <.001 level. Accordingly, Avastin had been added to the NCCN guidelines. Genetech has filed for the FDA approval for the breast cancer indication in May 2006. However, on Dec. 17th or 2007, ODAC has recommended that Avastin not be FDA approved. This was based on the newer analysis that revealed excess mortality and no increase in survival in the Avastin arm, although there was a small progression free survival advantage. Subsequently FDA rejected this recommendation and approved Avastin on 2/27/08 for first line.
On December 17th 2010, The Food and Drug Administration concluded that four studies indicate that Avastin does not benefit patients with metastatic breast cancer live longer or provide other benefits that outweigh its potentially life-threatening risks. The problem is that as several studies matures, the overall survival advantage did not materialize, Progression free survival advantage decreased and the toxicities became better appreciated. The Decision was appealed by Roche but in late June, 2011, In three unanimous votes, the six members of the FDA oncology drug panel voted that Avastin is ineffective, unsafe and should have its approval for breast cancer withdrawn. The FDA decision appears supported by recent report of teh BEATRICE trial in the 2012. Invasive disease-free survival (DFS) and preliminary overall survival (OS) results showed no significant advantage to the addition of bevacizumab compared with adjuvant chemotherapy alone. The researchers did find that outcomes were somewhat better than the literature would suggest for the group of patients not responsive to estrogen-, progesterone-, or HER2-targeted agents, with 83% to 84% without invasive cancer recurrence at 3 years.
There was significant debate on the role of Avastin for first line disease and not all compendia have followed the FDA’s withdrawal of the indication. In December 2010 the NCCN published an update to its breast cancer guidelines and compendia listing and remarkably its panel of experts decided unanimously to maintain usage of Avastin in breast cancer as a listed indication (evidence level 2A, 15-0 vote in favor). The Expert Breast Cancer Panel of the National Comprehensive Cancer Network® (NCCN®) met July 10-12, 2011 in Philadelphia, PA. At the meeting, the multidisciplinary breast cancer experts voted (24 For, 0 Against, 1 Abstain) in favor of maintaining the current position and recommendation in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Breast Cancer on the use of bevacizumab (Avastin®, Genentech/Roche) in metastatic breast cancer. The recommendation is was follows:
Bevacizumab in combination with paclitaxel is an appropriate therapeutic option for metastatic breast cancer with the evidence designation 2A.
The following footnote accompaniesdthe recommendation:
“Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first or second line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.”
As of 2016, this recommendation has been removed an Avastin is not listed by NCCN for breast cancer.
The efficacy and safety of Avastin as a second and third line treatment of patients with metastatic breast cancer were studied in a single open-label randomized study (Study 8 or AVF2119). Patients who had received prior anthracycline and taxane therapy in the adjuvant setting or for their metastatic breast cancer were randomized to receive either capecitabine alone or in combination with Avastin. The study enrolled 462 patients. The study failed to demonstrate a statistically significant effect on PFS or overall survival. The product labeling specifies that Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.
Burstein and colleagues have reported the result of a phase II trial of vinorelbine (Navelbine) in combination with bevacizumab in patients with up to two prior chemotherapy regimens for metastatic breast cancer. In this study, 56 patients received vinorelbine weekly at 25 mg/m2 with bevacizumab at 10 mg/kg every 2 weeks until disease progression. The overall response rate was 31% and 42% in those using this regimen as first-line treatment. The toxicity profile of this combination was also acceptable. Thus, it appears that bevacizumab with chemotherapy is generally well tolerated and has encouraging activity.
In regard to maintenance, this is an experimental strategy. While there is some supporting data, it remains in active clinical investigation, for example: A Study of Avastin (Bevacizumab) + Xeloda (Capecitabine)as Maintenance Therapy in Patients With HER2-Negative Metastatic Breast Cancer, NCT00929240
This randomized study will compare maintenance therapy with Avastin (bevacizumab) + Xeloda (capecitabine)versus Avastin alone, in patients with HER2-negative metastatic breast cancer who have not progressed during first-line therapy with docetaxel + Avastin.Eligible patients will receive up to 6 x 3week cycles of treatment with Avastin (15mg/mg iv on day 1 of each cycle) + docetaxel (75-100mg/m2 iv on day 1 of each cycle).Those patients who do not progress will be randomized to 3 week cycles of either a) Avastin (15mg/kg iv on day 1 of each cycle)+ Xeloda (1000mg/m2 po bid on days 1-14 of each cycle) or b)Avastin alone.The anticipated time on study treatment is until disease progression, and the target sample size is 100-500 individuals.
With gemcitabine, a study is ongoing: Gemcitabine Plus Bevacizumab in Locally Recurrent or Metastatic Breast Cancer, NCT00623233
Miller KD. E2100: A phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Clin Breast Cancer. 2003;3(6):421-422.
Miller, Kathy D., Chap, Linnea I., Holmes, Frankie A., Cobleigh, Melody A., Marcom, P. Kelly, Fehrenbacher, Louis, Dickler, Maura, Overmoyer, Beth A., Reimann, James D., Sing, Amy P., Langmuir, Virginia, Rugo, Hope S.
Randomized Phase III Trial of Capecitabine Compared With Bevacizumab Plus Capecitabine in Patients With Previously Treated Metastatic Breast Cancer
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Ramaswamy B, Shapiro CL. Phase II trial of bevacizumab in combination with docetaxel in women with advanced breast cancer. Clin Breast Cancer. 2003;4(4):292-294.
Cobleigh MA, Langmuir VK, Sledge GW, et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol. 2003;30(5 Suppl 16):117-124.
S. E. Waintraub, V. Tuchman The role of maintenance bevacizumab in patients with metastatic breast cancer treated with chemotherapy and bevacizumab upon achieving complete response or maximal radiologic response with stable disease.J Clin Oncol 26: 2008 (May 20 suppl; abstr 12022)