Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials

Summary

Background

Platinum-based doublet chemotherapy regimens, preferentially gemcitabine plus cisplatin, are generally considered the first-line standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma. However, no consensus has been reached regarding treatment following progression after first-line therapy. Camrelizumab (SHR-1210) is a humanised anti-programmed death-1 (anti PD-1) antibody. We present safety and preliminary antitumour activity of camrelizumab alone as second-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma and combined with gemcitabine and cisplatin as first-line therapy in this patient population.

Methods

We report the results from two single-arm, phase 1 trials. Both trials included patients aged 18–70 years with histologically or cytologically confirmed nasopharyngeal carcinoma and confirmed metastatic disease or locoreginal recurrence, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients who received at least one previous line of treatment were enrolled at five academic hospitals in China into the dose-escalation and expansion trial to receive camrelizumab monotherapy intravenously at escalating doses of 1 mg/kg, 3 mg/kg, and 10 mg/kg, and a bridging dose of 200 mg per dose once every 2 weeks (monotherapy trial). Treatment-naive patients were enrolled from a single centre in China to receive six cycles of camrelizumab 200 mg (day 1), gemcitabine 1 g/m² (days 1 and 8), and cisplatin 80 mg/m² (day 1) every 3 weeks followed by camrelizumab 200 mg maintenance once every 3 weeks (combination trial). The primary endpoint of both trials was the safety and tolerability of the study treatment. Analyses were done per protocol. Both trials are registered with ClinicalTrials.gov, number NCT02721589 (camrelizumab monotherapy trial) and NCT03121716 (camrelizumab combination trial). Both trials are ongoing, but are no longer enrolling patients.

Findings

In the camrelizumab monotherapy trial, between March 31, 2016, and Sept 20, 2017, 121 patients were assessed for eligibility, of whom 93 patients were enrolled across the dose-escalation and expansion cohorts and received at least one dose of camrelizumab (safety population). 15 (16%) of 93 patients had treatment-related adverse events of grade 3 or 4, the most common of which were elevated conjugated bilirubin concentration (three [3%] of 93 patients), stomatitis, anaemia, and increased concentrations of aspartate aminotransferase, alanine aminotransferase, and total bilirubin, each of which occurred in two (2%) patients. Eight (9%) patients had a treatment-related serious adverse event. No dose-limiting toxic effects were observed during the dose-escalation phase. 31 (34%; 95% CI 24–44) of 91 evaluable patients on camrelizumab monotherapy had an overall response with a median follow-up of 9·9 months (IQR 8·1–11·7). In the camrelizumab combination trial, between April 18, 2017, and Aug 15, 2017, 24 patients were assessed for eligibility, of whom 23 patients were enrolled and treated (safety population). 20 (87%) of 23 patients had grade 3 or 4 treatment-related adverse events: neutropenia (13 [57%] of 23 patients), anaemia (11 [48%] patients), leucopenia (11 [48%] patients), thrombocytopenia (seven [30%] patients), oedema (two [9%] patients), hyponatraemia (two [9%] patients), hypochloraemia (one [4%] patients), and rash (one [4%] patient). Two patients had treatment-related serious adverse events. No treatment-related deaths occurred in these trials. 20 (91% [95% CI 72–97]) of 22 evaluable patients had an overall response with a median follow-up time of 10·2 months (IQR 9·7–10·8).

Interpretation

Camrelizumab is a well tolerated, potential treatment option for patients with recurrent or metastatic nasopharyngeal carcinoma. The combination of camrelizumab plus gemcitabine and cisplatin has a manageable toxicity profile and promising preliminary antitumour activity for this disease in treatment-naive patients. Randomised controlled trials are needed to further establish the role of immune checkpoint inhibition for nasopharyngeal carcinomas.

Funding

Hengrui Medicine Co, Chinese National Natural Science Foundation project, Science and Technology Program of Guangdong, Pearl River Nova Program of Guangzhou.

Introduction

Nasopharyngeal carcinoma is one of the most common head and neck cancers in southeast Asia and north Africa.1, 2 In endemic areas, the predominant histological subtypes are non-keratinising differentiated or undifferentiated carcinoma (WHO classes 2 and 3), whereas the squamous-cell carcinoma subtype (WHO class 1) is more common in patients from North American and European countries.³ Nasopharyngeal carcinoma remains an important cause of cancer-related death worldwide with an incidence of approximately 50 000 deaths annually.2, 4

Nasopharyngeal carcinoma is a highly chemosensitive tumour. Standard-of-care therapy for patients with previously untreated recurrent or metastatic nasopharyngeal carcinoma is platinum-based chemotherapy.⁵ In a randomised, phase 3 study,⁶ we showed superiority of gemcitabine plus cisplatin compared with fluorouracil plus cisplatin in this setting, with 116 (64% [95% CI 57–71]) of 181 patients achieving an overall response with gemcitabine plus cisplatin versus 76 (42% [35–49]) of 181 patients achieving an overall response with fluorouracil plus cisplatin and a median progression-free survival of 7·0 months (IQR 4·4–10·9) in the gemcitabine plus cisplatin group versus 5·6 months (3·0–7·0) in the fluorouracil plus cisplatin group. However, patients with recurrent or metastatic nasopharyngeal carcinoma who are refractory to first-line platinum-based chemotherapy have few treatment options. There remains an unmet need for more effective first-line and salvage treatment options for this type of cancer. In recent years, immune checkpoint inhibitors, exemplified by the humanised monoclonal antibodies pembrolizumab and nivolumab, which target programmed cell death-1 (PD-1), and atezolizumab, durvalumab, and avelumab, which target programmed cell death-ligand 1 (PD-L1), have been extensively studied in various tumour types.⁷ However, to date none of these drugs have obtained approval for patients with recurrent or metastatic nasopharyngeal carcinoma.

One essential feature of nasopharyngeal carcinoma, predominantly WHO class 2 and 3 subtypes, is the association with Epstein-Barr virus infection, intensive lymphocyte infiltration, and increased PD-L1 expression.3, 8, 9 We have previously shown that latent membrane protein 1 induced by Epstein-Barr virus synergistically upregulate PD-L1 expression with interferon-γ in nasopharyngeal carcinoma cells in vitro.¹⁰ In nasopharyngeal carcinoma clinical histological samples, the prevalence of PD-L1 expression ranges from 89% to 95%.9, 10, 11 This feature of nasopharyngeal carcinoma makes patients potentially suitable for immunotherapy treatment.¹⁰ To date, pembrolizumab and nivolumab have been approved for the treatment of patients with relapsed or refractory metastatic squamous-cell carcinoma of the head and neck (non-nasopharyngeal) after previous platinum-based therapy, as per the results of the KEYNOTE-012¹² and CheckMate-141¹³ studies. However, only two small phase 2 trials have shown the moderate antitumour activity of nivolumab¹⁴ and pembrolizumab¹⁵ for recurrent or metastatic nasopharyngeal carcinoma. Therefore, further investigation of immunotherapy drugs in this setting is needed.

Camrelizumab (SHR-1210) is a high-affinity, fully humanised, IgG4-κ PD-1 monoclonal antibody that blocks binding of PD-1 to its ligands. In this report, we present results from two phase 1 trials assessing the safety and preliminary antitumor activity of camrelizumab monotherapy as second-line therapy or in combination with gemcitabine plus cisplatin as a first-line therapy for patients with recurrent or metastatic nasopharyngeal carcinoma.