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)†.
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.


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/m(2))-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 α = 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).


CONCLUSIONS
Adding NTG to first-line carboplatin-paclitaxel-bevacizumab did not improve PFS and OS in patients with stage IV nonsquamous NSCLC.
Department of Respiratory Disease, Maastricht University Medical Center, Maastricht a.dingemans@mumc.nl.
A-M C
AM
Dingemans
Department of Respiratory Disease, University Medical Center Groningen, Groningen.
H J M
HJ
Groen
Department of Respiratory Disease, Sint Antonius Hospital, Nieuwegein.
G J M
GJ
Herder
Department of Respiratory Disease, Isala Hospital, Zwolle.
J A
JA
Stigt
Department of Respiratory Disease, VU Medical Center, Amsterdam Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam.
E F
EF
Smit
Department of Respiratory Disease, VU Medical Center, Amsterdam.
I
I
Bahce
Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam.
J A
JA
Burgers
Department of Respiratory Disease, Catharina Hospital, Eindhoven.
B E E M
BE
van den Borne
Department of Respiratory Disease, Jeroen Bosch Hospital's, Hertogenbosch.
B
B
Biesma
Department of Biostatistics, Netherlands Cancer Institute, Amsterdam.
A
A
Vincent
Department of Biostatistics, Netherlands Cancer Institute, Amsterdam.
V
V
van der Noort
Department of Respiratory Disease, Amphia Hospital, Breda Department of Respiratory Disease, University Medical Center Rotterdam, Rotterdam, The Netherlands.
J G
JG
Aerts
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab / Q000008:administration & dosage*; D016190:Carboplatin / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D005996:Nitroglycerin / Q000008:administration & dosage*; D017239:Paclitaxel / Q000008:administration & dosage*
D051793:Hypoxia-Inducible Factor 1; D000068258:Bevacizumab; D016190:Carboplatin; D005996:Nitroglycerin; D017239:Paclitaxel
VEGF; bevacizumab; nitroglycerin; nonsmall-cell lung cancer