Oncology: November 2008 Archives

As part of the provisional FDA approval of Avastin (bevacizumab) in metastatic breast cancer, Genentech and Roche continue to supply more data supporting use of the anti-angiogenesis mAb.

In an international, 2-part, placebo-controlled, phase 3 study of 1237 women with advanced HER2-negative breast cancer, the addition of Avastin to either taxane or anthracycline-based chemotherapy (group 1) or capecitabine (group 2) significantly prolonged the primary endpoint of progression-free survival (PFS).* These data complement findings from the E2100 and AVADO phase 3 trials of Avastin in advanced HER2-negative breast cancer.

Currently Avastin is FDA approved for use, in combination with paclitaxel, in chemotherapy-naive patients with advanced HER2-negative breast cancer. The company emphasizes that Avastin has not been shown, as yet, to increase survival or improve disease-related symptoms in breast cancer.

Genentech's chief medical officer, Hal Barron, says that the data from this latest trial, RIBBON-1, and findings from AVADO will be submitted to the FDA by the middle of next year. Data from 3 ongoing or planned trials will be provided to the FDA as well.

Avastin is also FDA approved for the first- or second-line treatment of metastatic colorectal cancer, in combination with IV 5-FU-based chemotherapy, and for the first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous NSCLC, in combination with carboplatin and paclitaxel.

5-FU = 5-fluorouracil; HER2 = human epidermal growth factor receptor 2; mAb = monoclonal antibody; NSCLC = non-small cell lung cancer.

* Time from randomization to disease progression or death.

Genentech announced today that it has submitted a supplemental Biologics License Application (sBLA) to the FDA for the use of its anti-VEGF mAb, bevacizumab (Avastin), in recurrent glioblastoma multiforme (GBM). The application will be considered for accelerated approval, according to Genentech, if accepted by the FDA.

The sBLA is based on data from a recent phase 2 trial, in which bevacizumab (with or without randomized irinotecan chemotherapy) was administered to 167 patients with recurrent, treatment-refractory GBM. Primary endpoints of the study, assessed by MR imaging, were 6-month progression-free survival (PFS) and response rate (≥50% decrease in tumor size). Median durations of treatment were 16 weeks with bevacizumab alone and 22 weeks with bevacizumab plus irinotecan.

Efficacy and safety outcomes were presented, as follows, at the annual meeting of the American Society of Clinical Oncology (ASCO) in June of this year.*

Efficacy Outcome	Bevacizumab (n = 85)	Bevacizumab + Irinotecan (n = 82)
6-month PFS, %	43	50
Overall response rate, %	28	38
Median overall survival, months	9.2	8.7
Median duration of response, months	5.6	4.3

The investigators also reported a substantial decline in the use of corticosteroids with either treatment.

Safety Outcome	Bevacizumab (n = 84)	Bevacizumab + Irinotecan (n = 79)
Grade ≥3 adverse event, %	46	66
Serious AE, %	26	43
AE leading to discontinuation, %    Bevacizumab    Irinotecan	5 0	18 18
AE leading to death, %	2.4	1.3

Two hemorrhages (grade ≥3), one outside of the CNS, were reported with bevacizumab use. The rate of grade ≥3 infection with either treatment was approximately 10%.

The current standard of initial care for GBM is surgical debulking followed by radiation therapy and concurrent temozolomide (which is followed by maintenance temozolomide). There is no standard of care for recurrent disease. Reported response rates with single-agent irinotecan in the recurrent setting are 15% or less.

The rationale for using bevacizumab in GBM is based on the high rate of VEGF expression in the tumor. Genentech reports that it plans to initate a global phase 3 study of Avastin in newly diagnosed GBM next year. 

CNS = central nervous system; mAb = monoclonal antibody; MR = magnetic resonance; VEGF = vascular endothelial-cell growth factor.

* Cloughesy T et al. A phase II, randomized, non-comparative clinnical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM).

HT to the WSJ Health Blog, which reports that the estimated cost for a course of bevacizumab treatment for GBM is nearly $40,000.