Neoadjuvant and adjuvant toripalimab for locoregionally advanced nasopharyngeal carcinoma: a randomised, single-centre, double-blind, placebo-controlled, phase 2 trial.
Patients with locoregionally advanced nasopharyngeal carcinoma with a high pretreatment plasma concentration of Epstein-Barr virus (EBV) DNA remain at high risk for recurrence after concurrent chemoradiotherapy. This study aimed to compare the efficacy and safety of neoadjuvant-adjuvant treatment with the PD-1 inhibitor toripalimab and concurrent chemoradiotherapy versus placebo and concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.
This randomised, single-centre, double-blind, placebo-controlled, phase 2 trial was conducted at Sun Yat-sen University Cancer Centre in Guangzhou, China. Adult patients (aged 18-65 years) with newly diagnosed high-risk stage III-IVa locoregionally advanced nasopharyngeal carcinoma, with a pretreatment plasma EBV DNA concentration of at least 1500 copies per mL and an Eastern Cooperative Oncology Group performance score of 0-1, were eligible. Patients were randomly assigned (2:1) using an interactive web response system (block size of six), stratified by TNM stage (III vs IVa), to neoadjuvant toripalimab (240 mg intravenously) or placebo once every 2 weeks for two cycles, followed by concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 during intensity-modulated radiotherapy and adjuvant toripalimab (240 mg intravenously) or placebo once every 3 weeks for up to eight cycles. The primary endpoint was 2-year progression-free survival in the intention-to-treat population. This study was registered with ClinicalTrials.gov, NCT03925090, and is closed to enrolment; follow-up is ongoing.
Between Dec 6, 2019, and Dec 9, 2021, 150 patients were enrolled and randomly assigned to the toripalimab group (n=100) or placebo group (n=50). 115 (77%) patients were male and 35 (23%) were female. As of data cutoff (May 31, 2024), median follow-up for progression-free survival was 37·8 months (IQR 34·2-46·5) for the intention-to-treat population analyses. 2-year progression-free survival was higher in the toripalimab group (92·0% [95% CI 86·7-97·3]) than in the placebo group (74·0% [61·8-86·2]; stratified hazard ratio 0·40 [95% CI 0·18-0·89]; log-rank p=0·019). The most common grade 3 or worse acute adverse events (occurring within 1 year of randomisation) were leukopenia (40 [40%] of 99 patients in the toripalimab group vs 22 [44%] of 50 patients in the placebo group), mucositis (28 [28%] vs ten [20%]), neutropenia (17 [17%] vs nine [18%]), anaemia (16 [16%] vs five [10%]), and weight loss (12 [12%] vs six [12%]). The most common grade 3 or worse late adverse events (occurring >1 year after randomisation) was auditory or hearing loss (eight [8%] vs four [8%]). Immune-mediated adverse events of grade 3 or worse occurred in ten (10%) patients only in the toripalimab group. One (2%) of 50 patients in the placebo group died due to septic shock caused by bacteraemia considered not treatment related. There were no treatment-related deaths in the toripalimab group.
Our findings suggested that a so-called sandwich approach involving toripalimab (in the neoadjuvant and adjuvant phases) combined with concurrent chemoradiotherapy could be a highly promising therapy for the treatment of locoregionally advanced nasopharyngeal carcinoma. Phase 3 non-inferiority trials are warranted comparing neoadjuvant and adjuvant toripalimab versus cisplatin plus gemcitabine neoadjuvant chemotherapy combined with concurrent chemoradiotherapy.
National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Science and Technology Program of Guangzhou, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Postdoctoral Innovative Talent Support Program, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, and Fundamental Research Funds for the Central Universities.
For the Chinese translation of the abstract see Supplementary Materials section.
Liu SL
，Li XY
，Yang JH
，Wen DX
，Guo SS
，Liu LT
，Li YF
，Luo MJ
，Xie SY
，Liang YJ
，Sun XS
，Yang ZC
，Lv XF
，Luo DH
，Li JB
，Liu Q
，Wang P
，Guo L
，Mo HY
，Sun R
，Yang Q
，Lan KQ
，Jia GD
，Li R
，Zhao C
，Xu RH
，Chen QY
，Tang LQ
，Mai HQ
... -
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Establishing M1 subdivision for de novo nasopharyngeal carcinoma patients receiving immuno-chemotherapy: A multicenter, retrospective cohort study.
This study aims to better manage de novo metastatic nasopharyngeal carcinoma (NPC) patients receiving palliative immuno-chemotherapy (PICT), thereby easily determining individual survival outcomes.
Patients with de novo metastatic NPC from four centers who received first-line PICT were included. We developed a nomogram for the pretherapy overall survival (OS) prediction using a logistic regression model in the training cohort (n = 296). We assessed the performance of this nomogram in a validation cohort.
A total of 592 patients were included. The median follow-up time was 29.83 months. Bone metastasis (HR, 2.46; 95 % CI, 1.01-6.21; p = 0.049) and the number of metastatic lesions > 3 (HR, 2.78; 95 % CI, 1.24-6.24; p = 0.013) were independent prognostic indicators. A new two-category M1 subdivision was generated: M1a, defined by the absence of co-existing bone metastasis and the presence of more than three metastatic lesions; and M1b, characterized by the presence of co-existing bone metastasis and the presence of more than three metastatic lesions. The 3-year OS rates of patients with M1a vs. M1b were 87.1 % vs. 60.3 % (p < 0.001). The C-indexes were 0.652 and 0.581 in the training and validation cohorts. The 1-, 2-, and 3-year areas under the curve (AUC) were 0.69, 0.68, 0.68 in the training cohort and 0.64, 0.6, 0.6 in the validation cohort. DCA curves also indicated that the nomogram has good clinical utility.
The proposed M1 subdivision provides good OS segregation for patients receiving PICT.
He SQ
，Liu GY
，Yu YH
，Wang L
，Zhang GY
，Peng DS
，Bei WX
，Chen CL
，Lv SH
，Zhao ZY
，Huang Y
，Xiang YQ
... -
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Gemcitabine plus cisplatin versus docetaxel plus cisplatin and fluorouracil induction chemotherapy combined with locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma: A single center prospective phase II clinical trial.
This prospective clinical trial aims to compare the efficacy and safety of gemcitabine plus cisplatin (GP) versus docetaxel plus cisplatin and fluorouracil (TPF) as induction chemotherapy combined with locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma (dmNPC).
146 dmNPC patients were randomly assigned in a 1:1 ratio to receive 4-6 cycles of GP (GP group) or TPF induction chemotherapy (TPF group) followed by locoregional radiotherapy (LRRT). The primary endpoint was overall survival (OS). Secondary endpoints consisted of progression-free survival（PFS）, objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (AEs).
As of data cutoff (May 31, 2024), the median follow-up time was 60.0 months (IQR 40.3-68.1). There is no significant difference in median OS (35.4 vs. 34.8 months, p = 0.2609) and PFS (15.8 vs. 14.3 months, p = 0.2318) between the GP and TPF groups. No significant differences in ORR (65.8 % vs. 71.2 %, p = 0.476) and DCR (79.5 % vs. 82.2 %, p = 0.674) were observed between GP and TPF group too. Furthermore, the 5-year OS was 40.1 % (95 % CI, 29.6 %-54.2 %) in the GP group, compared with 27.2 % (95 % CI, 17.9 %-41.3 %) in the TPF group（HR = 0.79, 95 % CI, 0.53-1.20). However, the TPF group had higher incidences of grade 3-4 AEs such as neutropenia, leukopenia, nausea, and diarrhea.
The study indicates that 4-6 cycles of TPF induction chemotherapy combined with LRRT achieves a therapeutic effect comparable to the GP regimen with controllable safety.
Shang K
，Li T
，Chen Y
，Luo X
，Wu H
，Zhou Y
，Song J
，Wu W
，Li Y
，Luo X
，Chen X
，Gong X
，Zhao C
，Li Z
，Liu L
，He Q
，Long J
，Jin F
... -
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Recursive partitioning analysis model for de novo metastatic nasopharyngeal carcinoma treated with locoregional radiotherapy following chemoimmunotherapy.
Chemoimmunotherapy is the first-line treatment of de novo metastatic nasopharyngeal carcinoma (dmNPC), with additional locoregional radiotherapy (LRRT) significantly prolonging patient survival. De novo metastatic nasopharyngeal carcinoma, however, demonstrates considerable heterogeneity, resulting in significant variability in patient outcomes. We developed and validated a prognostic tool for patients undergoing first-line chemoimmunotherapy plus LRRT and to evaluate the benefit of local therapy (LT) for distant metastases across different risk levels.
We studied 364 dmNPC patients receiving initial platinum-based chemotherapy and anti-programmed cell death protein 1 immunotherapy followed by LRRT. Patients were randomly divided into training and validation cohorts (7 : 3 ratio). The primary endpoint was progression-free survival (PFS). A prognostic model for PFS was developed using recursive partitioning analysis (RPA).
An RPA model categorized patients into five prognostic groups based on number of metastatic lesions, liver metastasis status, and post-treatment Epstein-Barr virus DNA levels. Survival analysis identified three distinct risk groups. High-risk patients had significantly poorer PFS compared with medium- and low-risk groups (2-year PFS rate: training cohort: 13.7% versus 69.4% versus 94.4%, P < 0.001; validation cohort: 7.8% versus 65.1% versus 87.3%, P < 0.001). We investigated the impact of LT for distant metastases across these risk groups and found that only patients in the medium-risk group derived benefit from LT (2-year PFS rate: 77.5% versus 64.0%; hazard ratio = 0.535, 95% confidence interval 0.297-0.966, P = 0.035). Conversely, no survival benefit from LT for distant metastases was observed in the low-risk (P = 0.218) and high-risk subgroups (P = 0.793).
Our RPA-based prognostic model integrates number of metastatic lesions, liver metastasis status, and post-treatment Epstein-Barr virus DNA levels to predict PFS in dmNPC patients undergoing chemoimmunotherapy plus LRRT. This model offers personalized treatment guidance, suggesting that patients in the medium-risk group may benefit from LT for distant metastases, while those in high- and low-risk groups may not.
Wen D
，Gu L
，Long H
，Liu S
，Luo M
，Li R
，Liu R
，Lin J
，Jin J
，Xiong L
，Tang L
，Mai H
，Liu L
，Liang Y
，Chen Q
，Guo S
... -
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