A randomized phase II study comparing paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches in patients with stage IV nonsquamous nonsmall-cell lung cancer: NVALT12 (NCT01171170)aEuro

Background: Nitroglycerin ( NTG) increases tumor blood flow and oxygenation by inhibiting hypoxia- inducible- factor ( HIF)- 1. A randomized phase II study has shown improved outcome when NTG patches were added to vinorelbine/ cisplatin in patients with advanced nonsmall- cell lung cancer ( NSCLC). In addition, there is evidence that the combination of bevacizumab and HIF- 1 inhibitors increases antitumor activity. Patients and methods: In this randomized phase II trial, chemo- naive patients with stage IV nonsquamous NSCLC were randomized to four cycles of carboplatin ( area under the curve 6)- paclitaxel ( 200 mg/ m2)- bevacizumab 15 mg/ kg on day 1 every 3 weeks with or without NTG patches 15 mg ( day - 2 to + 2) followed by bevacizumab with or without NTG until progression. Response was assessed every two cycles. Primary end point was progression- free survival ( PFS). The study was powered ( 80%) to detect a decrease in the hazard of tumor progression of 33% at a = 0.05 with a two- sided log- rank test when 222 patients were enrolled and followed until 195 events were observed. Results: Between 1 January 2011 and 1 January 2013, a total of 223 patients were randomized; 112 control arm and 111 experimental arm; response rate was 54% in control arm and 38% in experimental arm. Median [ 95% confidence interval ( CI)] PFS in control arm was 6.8 months ( 5.6- 7.3) and 5.1 months ( 4.2- 5.8) in experimental arm, hazard ratio ( HR) 1.27 ( 95% CI 0.96- 1.67). Overall survival ( OS) was 11.6 months ( 8.8- 13.6) in control arm and 9.4 months ( 7.8- 11.3) in experimental arm, HR 1.02 ( 95% CI 0.71- 1.46). In the experimental arm, no additional toxicity was observed except headache ( 6% versus 52% in patients treated with NTG). Conclusion: Adding NTG to first- line carboplatin- paclitaxel- bevacizumab did not improve PFS and OS in patients with stage IV nonsquamous NSCLC.