Nitroglycerin (NTG) plus whole intracranial radiotherapy for brain metastases (BM) in non-small cell cancer patient (NSCLC): A randomized open label, phase II clinical trial.

9114 Background: Hypoxia has been associated with chemo-radioresistance secondary to Vascular Endothelial Growth Factor Receptor induced by Hypoxia Induced Factor (HIF). Nitroglycerin (NTG) can reduce HIF-1 in cell lines, and this may have anti-angiogenic, pro-apoptotic, and anti-efflux effects. Particularly, EGFR mutated (EGFRm) tumor cell lines have been shown to overexpress both VEGF and HIF. In this phase II study, we evaluated the effect of transdermal NTG on intracranial objective response rate (iORR), intracranial progression-free survival (ICPFS), and overall survival (OS) of NSCLC patients with BM. Methods: We performed an open-label, phase II clinical trial among ninety-six histologically confirmed NSCLC patients with BM. Patients were randomized 1:1 to receive NTG plus WBRT (30 Gy in 10 fractions) or WBRT alone. iORR and ICPFS were evaluated by MRI by two independent, blinded radiologists. Nitroglycerin was administered using a transdermal 36 mg patch, which released 10 mg in 24 hours with a rest interval of 12 hours from Monday-Friday throughout WBRT administration (10 days). Results: Fifty patients were allocated to the control group, while 46 were allocated to the experimental group (NTG); among these 26 (55.3%) had EGFRm in the control group and 21 (44.7%) had EGFRm in the NTG arm. In terms of the iORR, patients in the NTG group had a significantly higher response when compared to controls (56.6% vs. 43.5%; p = 0.024). Additionally, patients who received NTG in addition to WBRT had an independently prolonged ICPFS compared with those who received WBRT alone (27.7 vs. 9.6; HR: 0.470 [95%CI: 0.24-0.89]; p = 0.021). PFS was also positively impacted (HR: 0.519 [95%CI: 0.27-0.98]; p = 0.043). The benefit in terms of iORR and ICPFS (HR: 0.38 [95%CI: 0.16-0.91]; p = 0.030) was particularly important in the EGFRm patient subgroup. No differences were observed in OS. A significantly higher rate of vomiting presented in the NTG arm of the study ( p= 0.016). Conclusions: The concurrent administration of NTG and chemo-radiotherapy improves iORR and ICPFS among NSCLC patients with BM. The benefit is particularly significant in the EGFRm patient subgroup. Clinical trial information: NCT04338867.