Bevacizumab is indicated for the management of metastatic colon cancer, first-line therapy for nonsquamous non-small cell lung cancer, recurrent glioblastoma, metastatic renal cell carcinoma, persistent/recurrent or metastatic cervical cancer, and epithelial ovarian, fallopian tube, or primary peritoneal cancer, but what role, if any, does it have in breast cancer (BC)? Individual randomized trials of bevacizumab added to standard endocrine therapy (ET) have yielded conflicting results.
To explore bevacizumab’s potential role as first-line treatment for hormone receptor-positive (HR+) metastatic BC, investigators performed a post-hoc analysis of pooled data from two randomized, multicenter, open-label, similarly designed phase III studies—LEA: GEICAM/2006-11_GBG_51 and CALGB 40503, which compared bevacizumab + ET with ET alone as first-line therapy for HR+ metastatic BC.
The primary objective of the analysis was to compare progression-free survival (PFS) between the treatment regimens. Secondary objectives included determining the effects of the drug regimens on overall survival (OS), time to treatment failure (TTF), overall response rate (ORR), clinical benefit rate (CBR), response duration (RD), and safety.
In this study, standard ET included letrozole 2.5 mg daily in both trials. However, the LEA study also administered fulvestrant 250 mg daily every 4 weeks, whereas the CALGB study utilized tamoxifen 20 mg daily. Bevacizumab was administered as 15 mg/kg body weight every 3 weeks. Premenopausal women also received ovarian suppression either with luteinizing hormone–releasing hormone agonists or by oophorectomy. Treatment was continued until disease progression, toxicity necessitating discontinuation of therapy or the patient withdrawal of consent. Patients were followed both for disease progression and for survival.
The pooled analysis included a total of 749 patients (mean age: 60.5-62 years). Forty percent of patients presented with initially advanced disease, and 59% represented recurrent disease. Sixty-six percent of patients had measurable disease. About 40% had received prior chemotherapy, and half had been given prior adjuvant ET, including 22% who had received an aromatase inhibitor. Of those with recurrent disease who had received previous ET, 11.5% in the ET-alone arm and 20.6% in the bevacizumab + ET arm were endocrine-resistant versus 84% and 82%, respectively, who were endocrine-sensitive.
After a median follow-up of 34 months, a statistically significant difference in PFS was observed in favor of the combination regimen (19 months for bevacizumab + ET vs. 14.3 months for ET monotherapy). Significant improvement was seen in those with recurrent disease and those with prior endocrine-sensitivity but not in those who had de novo metastatic BC or who were endocrine-resistant. ORR in the subset of patients with measurable disease and CBR were significantly better in the ET + bevacizumab group (61% and 77%, respectively) than ET monotherapy (40% and 64%, respectively). Benefit was seen in patients with de novo metastatic BC, in those with recurrent disease, and in endocrine-sensitive patients. The addition of bevacizumab did not affect TTF, RD, or OS.
The bevacizumab + ET arm experienced more frequent and severe adverse events compared with the ET-alone group, including grade III to IV hypertension, grade III to IV hypertension/proteinuria, and grade III to IV and elevated liver-function tests.
The investigators concluded that while bevacizumab added to ET had beneficial effects on PFS, ORR in some patients, and CBR, the combination regimen did not affect OS and was associated with significant toxicities; therefore, its use in HR+ metastatic BC is not recommended.
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