In a multicentre phase III, CONTINUUM study conducted in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, the addition of sintilimab to gemcitabine and cisplatin induction chemotherapy plus concurrent chemoradiotherapy significantly improved event-free survival (EFS). The benefit in EFS with sintilimab was reached with a significant reduction in the risk of distant metastasis and locoregional recurrence, although no significant differences in overall survival (OS) were observed at the data cut-off.
This study is the first phase III randomised trial showing the benefit of a PD1 inhibitor with a significant improvement in EFS in the definitive treatment of patients with locoregionally advanced nasopharyngeal carcinoma. The findings are published by Prof. Jun Ma of the Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center in Guangzhou, China and colleagues on 30 May 2024 in The Lancet.
Nasopharyngeal carcinoma is characterised by elevated expression of PD-L1, with 83–92% of patients exhibiting PD-L1 expression in tumour cells or tumour-associated immune cells. Compared with non-viral related head and neck cancer of other sites, nasopharyngeal carcinoma is immunogenic and has abundant lymphocyte infiltration, why it might be more responsive to anti-PD1 therapy. After three successful phase III trials, anti-PD1 therapy in combination with gemcitabine and cisplatin chemotherapy became the recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma in major guidelines.
However, although single-arm phase II studies have shown the safety of PD1 or PD-L1 blockade in combination with induction chemotherapy plus concurrent chemoradiotherapy for curative locoregionally advanced nasopharyngeal carcinoma, no phase III study has yet been reported investigating the addition of PD1 blockade in this setting. In CONTINUUM, the study team aimed to assess the efficacy and safety of adding sintilimab, a highly selective, fully humanised, monoclonal anti-PD1 antibody, to standard gemcitabine and cisplatin induction chemotherapy plus concurrent chemoradiotherapy in patients with high-risk locoregionally advanced nasopharyngeal carcinoma.
This multicentre, open-label, parallel-group, randomised, controlled, phase III study was conducted at hospitals in China. Adults aged 18–65 years with newly diagnosed high-risk non-metastatic stage III–IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3–4N0 and T3N1) were eligible. Patients were randomly assigned 1:1 using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy (sintilimab group).
The primary endpoint was EFS from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events (AEs). This study is now completed; follow-up is ongoing.
Between 21 December 2018 and 31 March 2020, 425 patients were enrolled and randomly assigned, of whom 210 to sintilimab and 215 to the standard therapy groups. At median follow-up of 41.9 months (IQR 38.0–44.8; 389 alive at primary data cut-off on 28 February 2023 and 366 had at least 36 months of follow-up), EFS was higher in the sintilimab group compared with the standard therapy group with 36-month rates of 86% (95% confidence interval [CI] 81–90) versus 76% (95% CI 70–81) with stratified hazard ratio of 0.59 (95% CI 0.38–0.92; p = 0.019).
Grade 3–4 AEs occurred in 155 patients (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (33% versus 30%), leukopenia (26% versus 22%), and neutropenia (24% versus 21%). Two patients (1%) died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3–4 immune-related AEs occurred in 20 patients (10%) in the sintilimab group.
Longer follow-up is necessary to determine whether the 10% increase in EFS at 36 months will translate into a benefit in OS. More clinical trials, especially those in other regions of the world, are needed to confirm these results before the regimen can be considered as the standard-of-care. Whether the concurrent phase of immunotherapy should be omitted still needs to be investigated.
In an accompanied comment, Dr. Nabil F. Saba of the Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University in Atlanta, GA, US wrote that because CONTINUUM was conducted in a region endemic for Epstein–Barr virus-related non-keratinising nasopharyngeal carcinoma, avoiding the generalisation of these results is imperative. With the continuum of immunotherapeutic successes, it seems now more likely than ever that further optimisation of choices and sequencing of these agents will pave the way to reaching new heights in the management of patients with locally advanced nasopharyngeal carcinoma.
This is an investigator-initiated study funded by grants from the National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. Innovent Pharmaceutical (Suzhou, China) provided free sintilimab for this study.
References
- Liu X, Zhang Y, Yang K-Y, et al. Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial. The Lancet; Published online 30 May 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00594-4
- Saba NF. Immunotherapeutics in nasopharyngeal carcinoma: a relentless CONTINUUM of success. The Lancet; Published online 30 May 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00810-9