NPC is endemic in Singapore and southern China, where the southern Chinese have the highest incidence of NPC worldwide.~Nasopharyngeal cancer usually presents as locally advanced stage III or IV disease with T3-4 or N2-3 nodal status.The standard of care of patients with locally advanced NPC is concurrent cisplatin chemotherapy with radiation therapy. However, a significant proportion of patients (about 30% in most randomised phase III studies) still relapse, compromising their survival from NPC. This is particularly so in patients with stage IVA, T4 or N3 NPC. Emerging evidence suggests induction chemotherapy improves patient survival in this group of patients when integrated with concurrent chemoradiation. A meta-analysis also showed that the addition of induction chemotherapy improved overall survival, and reduced locoregional and distant failure.~Dysregulation of the vascular endothelial growth factor (VEGF)/VEGF receptor-2 axis is a feature of many cancers including NPC. Elevated VEGF expression promotes disorganised tumour neovascularisation with hyperpermeable, tortuous capillaries.9, 10 Leakiness of vessels increases interstitial fluid pressure that collapses vessels with the collective effect of compromising blood flow and perfusion, limiting the delivery of therapeutic drugs. Furthermore, tumour expression of VEGF promotes immune tolerance directly and through hypoxic mechanisms.11 The VEGF/VEGFR-2 axis can be inhibited humanised monoclonal antibody bevacizumab, which binds to VEGF-A and prevents ligand-receptor engagement.~As NPC is associated with EBV antigen expression and is characterised by a prominent inflammatory infiltrate (inflammatory immune phenotype), there has been great interest in studying the effect of immune checkpoint inhibitors in NPC. Recently, the addition of 2 antiPD1 monoclonal antibodies, toripalimab 12 and camrelizumab 13, to cisplatin and gemcitabine was studied in 2 phase III trials conducted in mainland China. Both studies demonstrated that addition of antiPD1 therapy to cisplatin/gemcitabine chemotherapy improved the response rate, PFS and the duration of response in treatment naïve patients with metastatic or recurrent NPC.~The investigators have conducted a prior study evaluating pembrolizumab with and without bevacizumab. Preliminary analysis showed a higher response rate for addition of bevacizumab to pembrolizumab compared to pembrolizumab alone arm with no new safety signal. Importantly, the adverse effects of anti-angiogenic and anti PD1 therapy in humans are non-overlapping with cytotoxic chemotherapy. In view of this, we are conducting an open label, phase II randomised controlled trial comparing induction cisplatin, gemcitabine, bevacizumab and pembrolizumab with the standard arm (induction cisplatin and gemcitabine) in patients with stage III-IVA locally advanced EBER positive nasopharyngeal carcinoma.
The investigators hypothesize that the addition of bevacizumab and pembrolizumab to induction cisplatin and gemcitabine is tolerable and improves metabolic complete response (mCR), relapse free survival (RFS) and overall survival (OS) compared to induction cisplatin and gemcitabine in patients with locally advanced nasopharyngeal cancer (NPC)