A Randomized Phase Ii Study of Paclitaxel-Carboplatin-Bevacizumab (Pcb) with or Without Nitroglycerin Patches (Ntg) in Patients (Pts) with Stage Iv Non-Squamous-Non-Small Cell Lung Cancer (Ns-Nsclc)(Nvalt 12), Impact of Circulating Vascular Endothelial Growth Factor (Vegf) Levels

Abstract

ABSTRACT Aim: NTG added to standard chemotherapy has been shown to improve clinical outcome. NTG is hypothesized to increase tumor blood flow and may augment drug delivery to the tumor and diminish tumor hypoxia causing a decrease in VEGF. High circulating VEGF is a prognostic factor for unfavourable outcome. We showed that adding NTG to PCB (PCB + N) did not improve progression free survival (PFS), response rate (RR) and overall survival (OS) in pts with stage IV NS-NSCLC (NCT01171170; Dingemans, ASCO 2014). Here we present impact of baseline VEGF on clinical outcome. Methods: In this open-label multicenter phase II trial chemo-naive pts with stage IV NS-NSCLC were randomized 1:1 to PCB or PCB + N. Pts were treated with P 200 mg/m2 day (d) 1-C AUC 6 d1-B 15 mg/kg d1 every 3 weeks (wks) or PCB + NTG 15 mg/24 h for 5 d (d -2 to +3) every cycle for 4 cycles and B + N until progression. The study was powered (80%) to detect a decrease in the hazard of progression of 33% at a = 0.05 with a two-sided log rank test. As pre-planned exploratory analysis baseline, wks 3 and 6 free circulating VEGF levels by ELISA were assessed. Results: 223 pts were randomized; 112 PCB and 111 PCB + N; Median (95% CI) PFS in PCB was 6.8 months (m) (5.6-7.3) and 5.0 m (4.2-5.8) in PCB + N, HR 1.22 (0.91-1.63). OS was 11.6 m (8.7-14) in PCB and 9.5 m (7.8-11.9) in PCB + N, HR 1.12 (0.76-1.67). Baseline median VEGF (n = 178) was 111 pg/ml (inter-quartile range 55-218), equal between 2 arms. High VEGF levels (n = 89) at baseline was associated with worse OS (p = 0.02) and PFS (p = 0.0003). For pts with above median VEGF at baseline, OS and PFS were not different for PCB and PCB + N, for pts with below median VEGF there was a trend for worse PFS HR 1.46 (0.95 – 2.24) and OS HR1.55 (0.97-2.49) in the pts treated with PCB + N. In both arms VEGF became undetectable or very low at 3 and 6 wks. Conclusions: Adding NTG to first line PCB does not improve PFS and OS in pts with stage IV NS-NSCLC. As the mechanism of action of NTG is presumably through the VEGF pathway, decrease of VEGF levels by B may preclude an additional effect of NTG. Disclosure: A.C. Dingemans: advisory board Roche; H.J.M. Groen: advisory board roche E.F. Smit: advisory board roche; J.G. Aerts: advisory board roche. All other authors have declared no conflicts of interest.