**2. Angiogenesis inhibitors**

Most early studies on anti-angiogenic agents explored their clinical efficacy as single drugs for treating cancer in the relapsed or recurrent setting. However, the outcome of those studies was generally disappointing. Later, anti-angiogenic agents were combined with cytotoxic agents, mainly pemetrexed/cisplatin.

Bevacizumab is a monoclonal antibody that binds VEGF-A. Bevacizumab was tested in combination with the standard-of-care, cisplatin and pemetrexed, as a firstline treatment. An open-label, randomized phase 2/3 study that added bevacizumab to cisplatin and pemetrexed in chemotherapy-naïve patients showed a beneficial effect [12]. In that study, 448 patients were randomized to either pemetrexed/cisplatin with bevacizumab or chemotherapy alone. Patients were treated for up to 6 cycles. OS was statistically prolonged in the bevacizumab arm; the median OS was 18.8 months, versus 16.1 months for chemotherapy alone (HR: 0.77, 95% CI: 0.62–0.95).

Nintedanib is a multi-target angiokinase inhibitor, with activity against the receptors for VEGF (receptors 1, 2, and 3), PDGF, and fibroblast growth factor. A phase II study on patients with MPM showed that the addition of nintedanib to pemetrexed/ cisplatin improved PFS (median 9.4 vs. 5.7 months; hazard ratio [HR]: 0.54; 95% CI: 0.33–0.87; p = 0.010). Moreover, the nintedanib arm showed a trend toward improved OS (median 18.3 vs. 14.2 months; HR: 0.77; 95% CI: 0.46–1.29; p = 0.319), compared to placebo. These positive effects were observed in patients with epithelioid histology. However, the findings were not confirmed in the subsequent phase 3 study [13].

*Recent Advances in Systemic Therapy for Malignant Pleural Mesothelioma… DOI: http://dx.doi.org/10.5772/intechopen.102511*

Recently, ramucirumab, an anti-VEGF receptor-2 antibody, was tested in a double-blind, placebo-controlled, phase 2 trial for patients with pretreated MPM. In that trial, 161 patients were randomly assigned to gemcitabine (1000 mg/m2 intravenously, on days 1 and 8 every 3 weeks) or gemcitabine plus ramucirumab (10 mg/ kg, intravenously, on day 1 every 3 weeks) [14]. The OS was prolonged in the ramucirumab arm (HR: 0·71, 70% CI: 0·59–0·85; p = 0·028); the median OS was 13·8 months (70% CI: 12·7–14·4) with gemcitabine plus ramucirumab and 7·5 months (70% CI: 6·9–8·9) with gemcitabine plus placebo. Hypertension was more common in the gemcitabine plus ramucirumab group, but no events were related to bleeding.
