Addition of sintilimab to standard IC-CCRT in the treatment of locoregionally-advanced nasopharyngeal carcinoma

The multi-center randomised phase III CONTINUUM trial aimed to investigate the efficacy and safety of the addition of sintilimab to induction chemotherapy and concurrent chemo-radiotherapy (IC-CCRT) in the treatment of locoregionally-advanced nasopharyngeal carcinoma (LANPC). This study reported that the addition of sintilimab to IC-CRT resulted in notable improvements in event-free survival. Further, the safety profile of this regimen was found to be manageable.

Current evidence supports the treatment of recurrent/metastatic nasopharyngeal carcinoma via PD-1 blockade in addition to chemotherapy. However, at present there is no evidence investigating this treatment regimen in LANPC. One of the preferred induction regimens for LANPC is induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT). However, despite the efficacy of this treatment regimen, a reported 20% of patients go on to develop recurrence or metastasis. The CONTINUUM study assessed the safety and efficacy of sintilimab with IC-CCRT in patients with stage III-IVA non-metastatic high-risk LANPC. At ASCO 2023, the current efficacy and safety data arising from the CONTINUUM study were presented.

Study design

In China, patients with stage III-IVA (excluding T3-4NO/T3N1) non-metastatic high-risk LANPC were enrolled. Patients were randomised 1:1, stratified by center and stage to either the standard treatment arm (gemcitabine and cisplatin IC plus cisplatin CCRT), or sintilimab arm (200 mg IV Q3W sintilimab plus IC-CCRT). The primary endpoint was event-free survival (EFS). Secondary endpoints included overall survival (OS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and quality of life (QoL) which was assessed using EORTC-C30. Biomarkers such as tertiary lymphoid structure (TLS), PD-L1, and gene expression were also analysed.

Results

Between December 2018 and March 2020, 425 patients were recruited, resulting in 210 patients in the sintilimab arm and 215 patients in the standard arm. The median follow-up was 42 months. In total, 94% of patients were still alive at the 36 months timepoint. The 3-year EFS rate in the sintilimab arm was 86.1% vs. 76.0% in the standard arm (HR[95%CI]: 0.59[0.38-0.92], p= 0.019). The 3-year DMFS rate was reported as 90.3% vs. 82.8% in the sintilimab vs. standard arm respectively (HR[95%CI]: 0.57[0.33-0.98], p= 0.039). LRRFS at three years was 93.4% (sintilimab arm) vs. 86.8% (standard arm) (HR[95%CI]: 0.52[0.27-0.97], p= 0.038). There was no difference in 3-year OS rates (92.9% vs. 92.8% in sintilimab vs. standard arm; HR[95%CI]: 0.95[0.49-1.87], p= 0.89). Grade 3-4 adverse events were noted in 74.2% of patients in the sintilimab arm, while this value was 65.4% in the standard treatment arm. Grade 5 adverse events were recorded in 2 patients from the sintilimab arm, whereas in the standard arm there was 1 patient. No minimum clinically important differences in patient-reported QoL were noted. The addition of sintilimab showed beneficial effects in patients with (HR[95%CI]: 0.18[0.04-0.81], p= 0.011), but not without TLS (HR[95%CI]: 0.94[0.50-1.76], p= 0.85).

Conclusion

In high-risk LANPC (stage III-IVB excluding T3-4N0, T3N1), the addition of sintilimab significantly reduced the risk of disease recurrence or death by 41%, with a 10% increase of 3-year EFS rate. While the risk of distant metastasis and locoregional recurrence is significantly reduced, OS is not significantly different and requires longer follow-up. Adverse events were higher in the sintilimab combination but were manageable. TLS could possibly serve as a predictive biomarker for the group of patients that would benefit from the combined treatment.

Reference

Ma J, et al. PD-1 blockade with sintilimab plus induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) versus IC-CCRT in locoregionally-advanced nasopharyngeal carcinoma (LANPC): A multicenter, phase 3, randomized controlled trial (CONTINUUM). Presented at ASCO 2023; Abstract LBA6002.