Bevacizumab Prevents Brain Metastases Formation in Lung Adenocarcinoma

Abstract

Patients with nonsquamous non-small cell lung cancer (nsNSCLC; largely lung adenocarcinoma) are at high risk of developing brain metastases. Preclinical data suggested that anti-VEGF-A therapy may prevent the formation of nsNSCLC brain metastases. Whether non-brain metastases are also prevented, and whether bevacizumab shows a brain metastasespreventive activity in cancer patients is unknown. Data of one nsNSCLC (stage IIIB/IV, AVAiL) and two breast cancer bevacizumab trials (HER2 negative, AVADO; HER2 positive, AVEREL) were retrospectively analyzed regarding the frequency of the brain versus other organs being the site of first relapse. For animal studies, the outgrowth of PC14-PE6 lung adenocarcinoma cells to brain macrometastases in mice was measured by intravital imaging: under control IgG (25 mg/kg) treatment, or varying doses of bevacizumab (25 mg/kg, 2.5 mg/kg, 0.25 mg/kg). Brain metastases as site of first relapse were significantly less frequent in the bevacizumab arm of the AVAiL trial (HR ¼ 0.36, P < 0.001). In AVADO and AVEREL, no significant difference was seen. In mice, bevacizumab treatment led to secondary regressions of non-brain macrometastases, but did not reduce their total incidence, and did not improve survival. In a brain-seeking nsNSCLC metastasis model, treatment with bevacizumab inhibited brain metastases formation, which resulted in improved overall survival. In summary, bevacizumab has the potential to prevent brain metastases in nsNSCLC, but no preventive activity could be detected outside the brain. These data indicate that anti-VEGF-A agents might be particularly relevant for those stage III nsNSCLC patients who are at high risk to develop future brain metastases.

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

“…In fact, targeting of VEGF with bevacizumab has been shown to reduce the incidence of brain metastasis in a mouse model of non-small-cell lung cancer (NSCLC), and when combined with carboplatin and paclitaxel, is associated with a reduced frequency of brain metastases as a site of first relapse in patients with this disease 42 . Similarly, treatment with an antibody targeting VEGF receptor 2 (VEGFR2) increased the efficacy of HER2-targeted therapies against established brain metastases from HER2-positive breast cancer in a mouse xenograft model 43 .…”

Anti-angiogenetic therapies for central nervous system metastases from non-small cell lung cancer

“…In this study, a total of 112 BM events (defined as single cells, micrometastases and macrometastases), were observed in the eight control animals, while only two brain metastatic events occurred in the ten bevacizumab-treated mice (P<0.001) (20).…”

Bevacizumab in Combination with Platinum-Based Chemotherapy in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer with or without Brain Metastases: A French Cohort Study (EOLE)

“…Even though the studies are not comparable (in particular, PFS assessment was at the investigator's discretion in the EOLE study), median PFS was similar in both studies (6.7 months). A recent analysis of data from the AVAiL study went further and concluded that the BM rate as the first site of recurrence was significantly lower in the bevacizumab arm when compared to the control chemotherapy arm (2.6 vs. 5.8%; p = 0.01), with a lower risk of BM development over time (HR 0.36, p = 0.001) [22] . For the w/oBM patients analysed in the EOLE study, OS was shorter than for those reported in the BRAIN phase II study for wBM patients (16.0 months) [18] , possibly due to a greater diversity of patients and first-line chemotherapy combinations in the EOLE study.…”