Concurrent Chemoradiation and Durvalumab for Locoregionally Advanced Nasopharyngeal Carcinoma

Description

Nasopharyngeal carcinoma (NPC) of the undifferentiated histology is endemic in southern China and southeast Asia including Hong Kong, Taiwan, Singapore and Malaysia, with a peak annual incidence of up to 30 per 100,000 persons. According to global cancer registry, NPC ranked 11th most common among all malignancies in China in 2008 with an incidence of 2.8/100,000 person-years in men and 1.9/100,000 person-years in females. It is highly associated with prior infection with Epstein-Barr virus and thus it is a highly immune-related malignancy. Treatment strategy is mainly based on the disease stage according to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system. In general, stage I-II diseases are treated with radiation therapy alone while stage III-IV diseases are treated with concurrent chemoradiation with or without adjunct chemotherapy (induction or adjuvant). Intensive pretreatment workup including blood hematology and biochemistry, dedicated head and neck imaging with computed tomography and magnetic resonance imaging and positron-emission tomography with integrated computed tomography (PET-CT) and plasma Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) are essential in high-risk locoregionally advanced diseases to confirm non-metastatic diseases, since the treatment protocol and overall prognosis between locoregionally advanced (stage III-IVA) disease differ significantly from metastatic disease.

Despite intensive radical treatment in the contemporary radiotherapy era with concurrent chemoradiation with or without adjunct chemotherapy, between 15% and 30% of these patients with stage III-IVA disease develop metastatic diseases at distant sites. Further systemic chemotherapy following radical concurrent chemoradiation may not bring survival benefits, attributed by the compromised physique following intensive radical concurrent chemoradiation and the prolonged treatment-related toxicities brought by adjuvant chemotherapy. The recent Hong Kong NPC Study Group NPC-0502 study failed to show survival benefit in patients with post-treatment detectable plasma EBV DNA after a further 6 cycles of adjuvant chemotherapy compared to those who just observed after radical concurrent chemoradiation. On the other hand, induction chemotherapy followed by concurrent chemoradiation may be the more preferred regimen due to the perceived efficacy of eradication of tumor micro-metastasis and early shrinkage of primary tumor and bulky neck nodes, which allow a more radical radiotherapy dose and better coverage of both the primary tumor and neck nodes. Very recently, a China multi-centre phase III randomised-controlled trial demonstrated an improvement in recurrence-free survival and overall survival (OS) with induction chemotherapy gemcitabine plus cisplatin followed by concurrent chemoradiation versus concurrent chemoradiation alone. Nevertheless, new treatment strategies must be developed to improve treatment outcomes of these high-risk patients with stage III-IVA disease, which has become the major research focus in the past decade. A recent meta-analysis demonstrated that induction chemotherapy followed by concurrent chemoradiation improved overall survival compared to concurrent chemoradiation in the era of modern radiotherapy with intensity-modulated radiation therapy (IMRT).

Immune checkpoint inhibitors are now comprehensively and extensively tested in combination with radiotherapy (RT) as well (NCT01935921, NCT01860430). It has been recently known that RT increases the expression of the major histocompatibility complex (MHC). In turn, the MHC class-I restricted tumor antigen-specific cells elicited by RT will upregulate interferons in the tumors. This radiation-induced local inflammation and tumor-specific effector T cells will provide an additional mechanism for tumor control by modification of the tumor vasculature. In addition, RT will increase dendritic cell surface antigen presentation to T cells and production of cytokines leading to recruitment and activation of leucocytes from peripheral blood and extravasation to tumor parenchyma. These are part of the mechanisms of abscopal effect, a phenomenon where the tumors at the sites far away from the irradiated sites also regress after localized radiotherapy. Having learnt from the pivotal PACIFIC trial on the use of consolidation therapy with durvalumab (anti-PD-L1 monoclonal antibody) which confirmed the efficacy and safety of combination of chemoradiation and immunotherapy for stage III non-small-cell lung cancer, it is prime time to consider incorporation of immune checkpoint inhibitors into concurrent chemoradiation for other solid tumors like head and neck squamous cell carcinoma and NPC. In concurrent +/- adjuvant setting for locoregionally advanced NPC, there are at least two clinical trials on immune checkpoint inhibitors for locoregionally advanced disease. The first one is a phase II single-arm study using nivolumab in combination with concurrent chemoradiation with or without by adjuvant nivolumab for up to 3 months at different dose schedules (NCT03267498). A phase III multi-center randomized-controlled trial (RCT) in China on the use of a locally-manufactured PD-1 monoclonal antibody (SHR-1210) every 4 weeks for 12 cycles starting at 4-6 weeks after concurrent chemoradiation for stage III-IVA NPC versus no adjuvant therapy is currently under way (NCT03427827). It is highly expected and eagerly awaited that immunotherapy with immune checkpoint inhibitors will bring a new insight on the adjuvant treatment for NPC.

In view of the above with promising synergy between radiation therapy and immune checkpoint inhibitors, the investigators propose a phase II RCT on adding durvalumab in combination with induction chemotherapy followed by concurrent chemoradiation and adjuvant durvalumab for previously untreated locoregionally advanced NPC. In parallel, the investigators will also perform collateral tumor and serum biomarker studies which will be correlated with the treatment response. The investigators will collect fresh tumour biopsies at pretreatment, then serially after induction chemotherapy and after concurrent chemoradiation to investigate the change in microenvironment of the tumour and the surrounding inflammatory cells before and after durvalumab. In addition, the investigators will also measure the change in number and intensity of PD-L1-positive circulating tumour cells before and after durvalumab and evaluate their correlation with treatment response.

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