Key Points
Question
Can toripalimab-based chemoradiotherapy omit concurrent cisplatin while maintaining survival and improving safety in locoregionally advanced nasopharyngeal carcinoma (NPC)?
Findings
In this phase 3 randomized clinical trial including 532 patients with locoregionally advanced NPC, those patients receiving toripalimab combined with induction chemotherapy and radiotherapy without concurrent cisplatin had significantly noninferior 3-year failure-free survival (88.3% vs 87.6%) and lower incidence of all-grade vomiting (26.2% vs 59.8%) than the standard therapy group, in which concurrent cisplatin was retained.
Meaning
The toripalimab-based concurrent cisplatin–free strategy offers a promising therapeutic approach that demonstrated both high efficacy and low toxicity in patients with locoregionally advanced NPC.
Abstract
Importance
With the programmed cell death protein 1 (PD-1) blockade toripalimab, omitting highly toxic concurrent cisplatin may be feasible for nasopharyngeal carcinoma (NPC) without compromising survival.
Objective
To evaluate the efficacy and safety of toripalimab incorporated into induction chemotherapy and radiotherapy, without concurrent cisplatin, for locoregionally advanced NPC.
Design, Setting, and Participants
Open-label, multicenter, randomized phase 3 clinical trial conducted from August 2021 to July 2022 at 13 hospitals in China, enrolling 532 patients with T4N1M0 or T1-4N2-3M0 NPC; 400 (75.2%) completed the trial per protocol. The final date of follow-up was March 21, 2025.
Interventions
Patients were randomly assigned to either the standard therapy group (n = 266), receiving toripalimab with gemcitabine-cisplatin induction chemotherapy and concurrent cisplatin-radiotherapy (100 mg/m2 triweekly for 2 cycles), or the concurrent cisplatin–sparing group (n = 266), receiving the same regimen without concurrent cisplatin. The 17 cycles of toripalimab (240 mg triweekly) were distributed across the induction, radiotherapy, and adjuvant phases as 3, 3, and 11 cycles, respectively.
Main Outcomes and Measures
Coprimary end points were failure-free survival (noninferiority margin, 8%) and incidence of all-grade vomiting (superiority design). Secondary end points included overall survival, locoregional recurrence-free survival, distant metastasis–free survival, safety, tumor response, quality of life, and tolerability.
Results
In the 532 patients in the intention-to-treat population (median [IQR] age, 47 [39-54] years; 25.2% women), after a median follow-up of 37.0 (range, 4.0-50.0) months, the concurrent cisplatin–sparing group had a 3-year failure-free survival rate of 88.3% vs 87.6% in the standard therapy group, a difference of 0.7% (lower limit of the 1-sided 95% CI, −3.9%; P = .002 for noninferiority; stratified hazard ratio, 0.92 [95% CI, 0.66-1.79]; log-rank P = .73). In the safety analysis, the incidence of all-grade vomiting was significantly lower in the concurrent cisplatin–sparing group vs the standard therapy group (26.2% [68/260] vs 59.8% [156/261]; difference, 33.6% [1-sided 95% CI, 26.9%-∞]; P < .001). Patient-reported quality of life (participation rate, 87.5%) and tolerability (participation rate, 94.7%) were better in the concurrent cisplatin–sparing group, primarily in gastrointestinal, functional, and global health status.
Conclusions and Relevance
In this phase 3 randomized clinical trial, among patients with locoregionally advanced NPC, toripalimab combination therapy without concurrent cisplatin was a feasible treatment with high efficacy in failure-free survival and low toxicity.
Trial Registration
ClinicalTrials.gov Identifier: NCT04907370
This randomized clinical trial evaluates the efficacy and safety of toripalimab without concurrent cisplatin incorporated into induction chemotherapy and radiotherapy for patients with locoregionally advanced nasopharyngeal carcinoma.
Introduction
Among newly diagnosed cases of nasopharyngeal carcinoma (NPC), in excess of 70% are diagnosed as locoregionally advanced disease, which has poor prognosis and requires cisplatin-based chemoradiotherapy.1 However, high toxicity of concurrent cisplatin-radiotherapy remains a major clinical challenge.2 Although the addition of programmed cell death protein 1 (PD-1) blockade to chemoradiotherapy has further improved survival benefits for patients with locoregionally advanced NPC, toxicity has been substantially exacerbated.3,4
Concurrent cisplatin causes gastrointestinal and hematological cytotoxicity and induces irreversible damage to hearing, peripheral nerves, and kidney function.5 Patients with locoregionally advanced NPC preparing to receive concurrent cisplatin will usually have received cisplatin-based induction chemotherapy, consequently leading to more pronounced toxicity from concurrent cisplatin. Past studies in NPC showed that adding concurrent cisplatin to radiotherapy significantly increases the incidence of severe nausea, vomiting, and anorexia (by 12%-24%)6 and deteriorated quality of life (QoL).7 Additional PD-1 blockade enhanced the 3-year failure-free survival of patients with locoregionally advanced NPC by 9.6% to 10.0%.3,4 The benefits of PD-1 blockade suggest that highly toxic concurrent cisplatin could be omitted. This strategy has been explored in lung cancer and NPC through phase 2 trials, demonstrating promising efficacy and reduced toxicities.5,8,9 Toripalimab, a PD-1 blockade, is recommended by the National Comprehensive Cancer Network and the European Society for Medical Oncology as the preferred first-line regimen in combination with chemotherapy for recurrent or metastatic NPC.10,11
This multicenter, randomized, open-label, phase 3 clinical trial was initiated to assess the efficacy and safety of omitting concurrent cisplatin from toripalimab-based combination therapy in locoregionally advanced NPC.
Methods
Trial Design and Patients
The trial was performed and reported according to the Good Clinical Practice guidelines, the Declaration of Helsinki, and the CONSORT 2025 guideline. The ethics committee approved the trial protocol and all amendments. All patients provided written informed consent before enrollment (eAppendix 1 in Supplement 2). We recruited patients from 13 academic hospitals in China (eTables 1-2 in Supplement 2). Eligible patients had newly diagnosed T4N1M0 or T1-4N2-3M0 NPC (according to the 8th edition of the American Joint Committee on Cancer staging system), nonkeratinizing carcinoma, were aged 18 to 65 years, and had an Eastern Cooperative Oncology Group Performance Status score of 0 or 1. The main criteria for exclusion comprised systemic use of glucocorticoids or any type of immunosuppressant, active autoimmune disease, HIV or active infection requiring systemic treatment, being administered a live vaccine within 30 days prior to screening, or severe coexisting illness (Supplement 1).
Randomization and Masking
Patients were centrally registered by an online instant response system and randomized (1:1) via a computer program using permuted block randomization (block sizes of 4), stratified by treatment center and clinical stage (III vs IVA), by a study coordinator of the Clinical Trials Center of the leading center. The block structure was disclosed solely to the statistician, who was not involved in the clinical aspects of the trial. Group assignment was unmasked, while the central imaging review committee that evaluated treatment response had no access to treatment information.
Interventions
Patients were randomly assigned (1:1) to receive toripalimab combined with gemcitabine-cisplatin induction chemotherapy and concurrent cisplatin–radiotherapy (standard therapy group) or toripalimab combined with gemcitabine-cisplatin induction chemotherapy and radiotherapy (concurrent cisplatin–sparing group) (eFigure 1 in Supplement 2). Toripalimab was administered at a fixed dose of 240 mg triweekly for 17 cycles, comprising 3, 3, and 11 cycles in the induction, radiotherapy, and adjuvant phases, respectively. All patients received 3 cycles of intravenous induction gemcitabine (1 g/m2 on days 1 and 8 of each 3-week cycle) and cisplatin (80 mg/m2 on day 1) once every 3 weeks. During the radiotherapy phase, intensity-modulated radiotherapy was adopted with the proposed prescribed dose of 69.96 Gy at 2.12 Gy per fraction for the planning target volume of the gross tumor. Patients in the standard therapy group received an additional 2 cycles of intravenous cisplatin (100 mg/m2 on day 1 of each 3-week cycle), concurrently with radiotherapy. Toripalimab dose modification was not permitted12 and rechallenging required expert consensus per guidelines.13 Dose delay and treatment discontinuation are detailed in eAppendices 2 and 3 in Supplement 2. Radiotherapy plans were developed according to guidelines and evaluated by a radiotherapy planning and quality assurance committee.14 All patients were overseen according to the antiemesis guideline.15
End Points and Assessments
This study preset 2 coprimary end points of failure-free survival, defined as the period between randomization and the date of treatment failure (distant metastasis or locoregional recurrence) or all-cause death, and the incidence of all-grade vomiting. Vomiting was documented by attending physicians based on the patient’s concerns and symptoms during each treatment cycle, and was evaluated and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Secondary end points included overall survival, locoregional recurrence-free survival, distant metastasis-free survival, safety, tumor response (according to the Response Evaluation Criteria in Solid Tumors, version 1.1), QoL, and tolerability.
All patients underwent follow-up assessment every 3 months for the first 3 years following completion of radiotherapy, every 6 months in the next 2 years, and annually thereafter (eAppendix 4 in Supplement 2). Acute toxicities were assessed by CTCAE version 5.0. Late radiation toxicities were assessed 3 months after radiotherapy by the Late Radiation Morbidity Scoring Scheme.16 Immune-related adverse events were managed according to guidelines and assessed up to 100 days after discontinuing toripalimab.12 Patients were required to assess tolerability over the last 3 weeks using the Patient-Reported Outcomes questionnaire of the CTCAE (PRO-CTCAE) version 1.0.17 The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 module, version 3; the Head and Neck–specific 35 module, version 1; and Functional Assessment of Cancer Therapy (FACT)-General scale and additional scale of Head and Neck cancer, version 4.0, were utilized to assess QoL. The QoL assessments were conducted at baseline; at week 7 (after the induction phase); at weeks 10, 13, and 16 (after each cycle of toripalimab during radiotherapy); and at weeks 36, 51, and 75 (after half and full course of adjuvant toripalimab and 6 months thereafter) (eAppendices 5-6 in Supplement 2).
Biomarker Assessments
Tumor programmed cell death ligand 1 (PD-L1) membrane expression in formalin-fixed, paraffin-embedded tumor samples was assessed at a central laboratory using immunohistochemistry via the Dako 22C3 pharmDx assay (Agilent Technologies). Epstein-Barr virus (EBV) DNA load was assessed using quantitative real-time polymerase chain reaction from baseline and serial on-treatment blood samples (eAppendix 7 in Supplement 2).
Statistical Analysis
We assumed an 88% rate of 3-year failure-free survival based on relevant trial data and expert consensus.3 The noninferiority margin was set at 8%, according to previously published review and literature in NPC.18,19 Noninferiority was achieved as the lower limit of the 1-sided 95% CI for the difference in failure-free survival greater than −8%. Assuming a 5% 1-sided type 1 error rate and a 12% loss to follow-up rate, at least 532 patients were needed to achieve 80% power under the assumption of no difference in failure-free survival. The superiority test indicated that 86 patients were estimated to be necessary to provide the trial with 80% power under a 5% 1-sided type 1 error rate to detect a reduction in the incidence of all-grade vomiting favoring the concurrent cisplatin–sparing group (Supplement 1). The final sample size of 532 was based on the larger of the 2 hypotheses. The trial was considered positive only if both coprimary end points achieved statistical significance, allowing the α to remain unsplit.
Efficacy analyses were performed in the intention-to-treat (ITT) population who had undergone randomization. Safety and tolerability were analyzed in patients who began the assigned treatment (safety analysis population) and who completed at least 1 PRO-CTCAE questionnaire, respectively. Patients who completed the baseline and at least 1 on-treatment assessment were analyzed for QoL. Coprimary end points were also assessed in the per-protocol population who completed all required treatment until at least 6 cycles of adjuvant toripalimab or an event of treatment failure or death occurred. The Kaplan-Meier method was used to estimate survival, which was compared using a log-rank test. A stratified Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% CIs, with treatment as a single covariate and trial center and clinical stage as stratification factors. The assumption of proportional hazards was confirmed using Schoenfeld residuals (eFigure 2 in Supplement 2).20 The incidence of all-grade vomiting was compared using the χ2 test, and presented as relative risks (RRs) and 95% CIs. The treatment by covariate interaction was tested based on unstratified Cox proportional hazards model. Patients who remained alive without event or lost to follow-up were censored. Patients who were first diagnosed with locoregional recurrence were censored for distant metastasis and vice versa.
A clinically meaningful change to the European Organisation for Research and Treatment of Cancer score was identified as 10 points or more,21 while the minimum clinically important difference in the FACT score varied according to specific items.22 In the analysis of covariance, QoL differences between groups are presented as adjusted least-squares mean changes from baseline. All patients completed electronic questionnaires on mobile phones, with submission requiring the completion of all items without missing data. Thus, statistical imputation was not used. Except for primary end points, other P values were 2-sided, with a significance threshold of .05 without multiplicity adjustment.
An independent statistician initiated a planned interim analysis on October 20, 2023. Type 1 errors were controlled using the Lan-DeMets α spending function implementation of an O’Brien-Fleming boundary, with an α of .003 for the interim and .049 for the final analysis. The independent data monitoring committee reviewed the interim data and recommended continuing the study. All analyses were conducted after database lock on March 31, 2025, using R version 4.2.1 (R Foundation) and SPSS version 24.0 (IBM). This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov (NCT04907370).
Results
Patients and Treatment
From August 2021 to July 2022, we enrolled 532 eligible patients who were assigned randomly to the concurrent cisplatin–sparing group (n = 266) or the standard therapy group (n = 266) (Figure 1). The 2 groups showed balanced baseline characteristics (Table 1). Among the 532 patients, the median (IQR) age was 47 (39-54) years, with 398 (74.8%) male individuals and 134 (25.2%) female individuals; 369 (69.4%) had stage IVA disease. In the concurrent cisplatin–sparing and standard therapy groups, 260 (97.7%) vs 261 (98.1%) patients started induction-phase treatment, 245 (92.1%) vs 242 (91.0%) began radiotherapy-phase treatment, 229 (86.1%) vs 225 (84.6%) initiated adjuvant toripalimab, and 206 (77.4%) vs 194 (72.9%) entered the per-protocol population, respectively (Figure 1).
Figure 1. Flow of Patients in a Trial of Toripalimab Combination Therapy With or Without Concurrent Cisplatin.
aRandomization was stratified by trial center and clinical stage.
bThree of the 15 patients who discontinued from the concurrent cisplatin–sparing group and 1 of the 19 patients who discontinued from the standard therapy group did not receive radiotherapy.
cThree of the 19 patients who dropped out from the standard therapy group after the induction phase did not receive toripalimab during the radiotherapy phase, but resumed it in the adjuvant phase and were consequently excluded from the per-protocol population.
GP indicates gemcitabine-cisplatin; PD-1, programmed cell death protein 1.
Table 1. Baseline Characteristics of Patients in a Trial of Toripalimab Combination Therapy With or Without Concurrent Cisplatin.
| Characteristic | No. (%)a | |
|---|---|---|
| Concurrent cisplatin–sparing group (n = 266) | Standard therapy group (n = 266) | |
| Age, median (IQR), y | 47 (39-54) | 47 (38-54) |
| Sex | ||
| Male | 198 (74.4) | 200 (75.2) |
| Female | 68 (25.6) | 66 (24.8) |
| ECOG performance status scoreb | ||
| 0 | 260 (97.7) | 260 (97.7) |
| 1 | 6 (2.3) | 6 (2.3) |
| Current or former smokingc | 100 (37.6) | 111 (41.7) |
| Alcohol consumption | 46 (17.3) | 50 (18.8) |
| Concomitant chronic diseasesd | ||
| Hepatitis B virus | 19 (7.1) | 10 (3.8) |
| Hypertension | 10 (3.8) | 12 (4.5) |
| Type 2 diabetes | 7 (2.6) | 15 (5.6) |
| Obsolete pulmonary tuberculosis | 3 (1.1) | 3 (1.1) |
| Kidney stones | 3 (1.1) | 2 (0.8) |
| Coronary heart disease | 2 (0.8) | 1 (0.4) |
| Depression | 1 (0.4) | 0 |
| Pathology | ||
| Undifferentiated nonkeratinizing | 236 (88.7) | 237 (89.1) |
| Differentiated nonkeratinizing | 30 (11.3) | 29 (10.9) |
| Tumor categorye | ||
| T1 | 7 (2.6) | 7 (2.6) |
| T2 | 33 (12.4) | 32 (12.0) |
| T3 | 111 (41.7) | 112 (42.1) |
| T4 | 115 (43.2) | 115 (43.2) |
| Node categorye | ||
| N1 | 47 (17.7) | 49 (18.4) |
| N2 | 122 (45.9) | 120 (45.1) |
| N3 | 97 (36.5) | 97 (36.5) |
| Clinical stagee | ||
| III | 84 (31.6) | 79 (29.7) |
| IVA | 182 (68.4) | 187 (70.3) |
| Pretreatment cell-free EBV DNA | ||
| Positive | 215 (80.8) | 224 (84.2) |
| Negative | 43 (16.2) | 36 (13.5) |
| Not available | 8 (3.0) | 6 (2.3) |
| PD-L1 combined positive scoref | ||
| <1 | 31 (11.7) | 38 (14.3) |
| 1-19 | 57 (21.4) | 56 (21.1) |
| ≥20 | 34 (12.8) | 40 (15.0) |
| Not available | 144 (54.1) | 132 (49.6) |
Abbreviations: EBV, Epstein-Barr virus; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed cell death ligand 1.
Unless otherwise indicated.
The ECOG performance status score is evaluated by clinicians prior to the initiation of treatment to assess a patient’s level of functioning in terms of ability to care for oneself, daily activity, and physical ability. Scores range from 0 to 5, with 0 indicating full activity and 5 indicating death; higher scores reflect greater functional decline.
Smoking did not include other methods, such as vaping, smoking of cigars or pipes, or chewing tobacco.
Assessed via medical record review.
Tumor category, node category, and clinical stage were assessed according to the 8th edition of the TNM Staging System by the American Joint Committee on Cancer.
PD-L1 combined positive score was calculated by dividing the number of PD-L1–expressing tumor cells, lymphocytes, and macrophages by the total number of viable tumor cells, then multiplying by 100 for the percentage. Tumor PD-L1 membrane expression was assessed at a central laboratory in the leading center.
Among patients receiving toripalimab during the entire treatment, 106 (40.8%) of 260 in the concurrent cisplatin–sparing group and 129 (49.4%) of 261 in the standard therapy group had at least 1 dose delay of toripalimab; 75 (28.8%) vs 88 (33.7%) discontinued toripalimab permanently; and 173 (66.5%) vs 166 (62.5%) completed all 17 cycles of toripalimab, respectively (eTable 3 in Supplement 2). During the radiotherapy phase, at least 1 dose delay and permanent discontinuation of toripalimab were observed in 49 (20.0%) and 16 (6.5%) of 245 patients in the concurrent cisplatin–sparing group, and 72 (29.8%) and 20 (8.3%) of 242 patients in the standard therapy group, respectively (eTable 4 in Supplement 2). Chemoradiotherapy adherence and dosimetric parameters are detailed in eTables 5 and 6 in Supplement 2.14
Efficacy
At final follow-up (March 21, 2025), the median follow-up was 37.0 (range, 4.0-50.0) months, and 355 (69.2%) of 513 surviving patients had at least 36 months of follow-up. The ITT analysis showed that complete response was observed in 39 patients (14.7%) in the concurrent cisplatin–sparing group and 38 (14.3%) in the standard therapy group after the induction phase, and in 234 (88.0%) vs 237 (89.1%) after the radiotherapy phase. The percentage of undetectable cell-free EBV DNA in the concurrent cisplatin–sparing group was 73.0% (165/226) post induction and 87.8% (144/164) post radiotherapy, compared with 71.7% (165/230) and 84.7% (133/157), respectively, in the standard therapy group (eTable 7 in Supplement 2). Sixty-three events of treatment failure or death were recorded, with 30 in the concurrent cisplatin–sparing group and 33 in the standard therapy group (Table 2). eTables 8 and 9 in Supplement 2 detail treatment failures and salvage therapies.
Table 2. Three-Year Survival Outcomes and the Incidence of Vomiting by Randomization Group.
| Variable | Concurrent cisplatin–sparing group (n = 266) | Standard therapy group (n = 266) | Difference in 3-y event rates, % (95% CI)a | HR or relative risk (95% CI)b,c | P valued | ||
|---|---|---|---|---|---|---|---|
| Patients with events, No. (%) | Rate at 3 y, % (95% CI) | Patients with events, No. (%) | Rate at 3 y, % (95% CI) | ||||
| Primary end points | |||||||
| ITT or safety populatione | |||||||
| Failure-free survival | 30 (11.3) | 88.3 (84.4 to 92.2) | 33 (12.4) | 87.6 (83.5 to 91.7) | 0.7 (−3.9 to ∞) | 0.92 (0.66 to 1.79) | .73 |
| Incidence of all-grade vomiting | 68 (26.2) | NA | 156 (59.8) | NA | 33.6 (26.9 to ∞) | 0.44 (0.35 to 0.55) | <.001 |
| Per-protocol populationf | |||||||
| Failure-free survival | 25 (12.1) | 87.5 (83.0 to 92.0) | 24 (12.4) | 87.8 (83.1 to 92.5) | −0.3 (−5.7 to ∞) | 0.99 (0.56 to 1.73) | .96 |
| Incidence of all-grade vomiting | 59 (28.6) | NA | 124 (63.9) | NA | 35.3 (27.6 to ∞) | 0.45 (0.35 to 0.57) | <.001 |
| Secondary end points | |||||||
| ITT populatione | |||||||
| Overall survival | 10 (3.8) | 96.1 (93.7 to 98.5) | 9 (3.4) | 96.5 (94.1 to 98.9) | −0.4 (−3.6 to 2.8) | 1.12 (0.36 to 2.20) | .81 |
| Locoregional recurrence-free survival | 18 (6.8) | 92.9 (89.8 to 96.0) | 16 (6.0) | 93.6 (90.7 to 96.5) | −0.7 (−5.0 to 3.6) | 1.14 (0.45 to 1.72) | .70 |
| Distant metastasis-free survival | 17 (6.4) | 93.2 (90.1 to 96.3) | 22 (8.3) | 91.6 (88.1 to 95.1) | 1.6 (−2.9 to 6.1) | 0.76 (0.70 to 2.47) | .40 |
| Per-protocol populationf | |||||||
| Overall survival | 7 (3.4) | 96.6 (94.1 to 99.1) | 4 (2.1) | 97.9 (97.7 to 98.1) | −1.3 (−4.5 to 1.9) | 1.66 (0.49 to 5.69) | .41 |
| Locoregional recurrence-free survival | 14 (6.8) | 92.9 (89.4 to 96.4) | 10 (5.2) | 94.6 (91.3 to 97.9) | −1.7 (−6.4 to 3.0) | 1.33 (0.59 to 3.00) | .49 |
| Distant metastasis-free survival | 15 (7.3) | 92.3 (88.6 to 96.0) | 16 (8.2) | 91.8 (87.9 to 95.7) | 0.5 (−4.8 to 5.8) | 0.89 (0.44 to 1.79) | .74 |
Abbreviations: HR, hazard ratio; ITT, intention to treat; NA, not applicable.
Differences in primary and secondary end points between groups were tested using a 1- and 2-sided α level of 5%, respectively. The between-group difference in vomiting incidence, where higher values indicated poorer safety, was converted into additive inverse to align with the direction of superiority.
HR and relative risk were applied to survival outcomes and vomiting incidence, respectively, using the standard therapy group as the reference. HRs with corresponding 95% CIs were estimated using stratified and unstratified Cox proportional hazards models based on the ITT and per-protocol populations, respectively; trial center and clinical stage were used as stratification factors.
HRs for survival outcomes refer to patients with 3-year event rates. Relative risks for the incidence of vomiting refer to patients with vomiting events.
Comparisons of survival outcomes and the incidence of all-grade vomiting were conducted using the log-rank test and χ2 test, respectively.
Survival outcomes were analyzed in the ITT population (concurrent cisplatin–sparing group [n = 266] vs standard therapy group [n = 266]), while the incidence of all-grade vomiting was analyzed in the safety population (concurrent cisplatin–sparing group [n = 260] vs standard therapy group [n = 261]).
All analyses were performed in the per-protocol population (concurrent cisplatin–sparing group [n = 206] vs standard therapy group [n = 194]).
The ITT-based primary end point of 3-year failure-free survival was 88.3% in the concurrent cisplatin–sparing group and 87.6% in the standard therapy group, with a difference of 0.7% (1-sided 95% CI lower limit, −3.9%), which met the noninferiority criterion (P = .002 for noninferiority). The stratified HR was 0.92 (95% CI, 0.66-1.79; P = .73) (Figure 2A). Per-protocol analysis showed that the 3-year failure-free survival rate was 87.5% vs 87.8% in the concurrent cisplatin–sparing and standard therapy groups (difference, −0.3% [1-sided 95% CI lower limit, −5.7%]; P = .02 for noninferiority) (eFigure 3 in Supplement 2). Post hoc sensitivity analysis showed the 1-sided 97.5% CI lower limit corresponding to the between-group difference in 3-year failure-free survival was −4.8% (P = .002 for noninferiority) and −5.9% (P = .007 for noninferiority) in the ITT and per-protocol analyses, respectively.
Figure 2. Kaplan-Meier Analysis of Survival in the Intention-to-Treat Population.
Censored observations in the Kaplan-Meier curves are indicated by vertical lines. The log-rank test was performed using a stratified Cox proportional hazards model; trial center and clinical stage were used as stratification factors. Kaplan-Meier analysis of survival in the per-protocol population is shown in eFigure 3 in Supplement 2.
No secondary survival end points differed significantly between the concurrent cisplatin–sparing and standard therapy groups: 96.1% vs 96.5% for overall survival (HR, 1.12 [95% CI, 0.36-2.20]; P = .81) (Figure 2B), 92.9% vs 93.6% for locoregional recurrence-free survival (HR, 1.14 [95% CI, 0.45-1.72]; P = .70) (Figure 2C), and 93.2% vs 91.6% for distant metastasis-free survival (HR, 0.76 [95% CI, 0.70-2.47]; P = .40) (Figure 2D). Similar results were observed in the per-protocol population (eFigures 3-4 in Supplement 2). No significant difference in failure-free survival between the 2 groups was observed across different subgroups, including those defined by postinduction EBV DNA status, while undetectable EBV DNA levels were associated with better survival (eFigures 5-8 in Supplement 2). Discontinuation, rather than delay, of toripalimab was associated with poorer failure-free survival (eFigure 9 in Supplement 2).
Safety
The incidence of all-grade vomiting was reduced significantly in the concurrent cisplatin–sparing group relative to that in the standard therapy group based on the safety analysis population (26.2% [68/260] vs 59.8% [156/261]; difference, 33.6% [1-sided 95% CI, 26.9%-∞]; RR, 0.44 [95% CI, 0.35-0.55]; P < .001) and the per-protocol population (28.6% [59/206] vs 63.9% [124/194]; difference, 35.3% [1-sided 95% CI, 27.6%-∞]; RR, 0.45 [95% CI, 0.35-0.57]; P < .001) (Table 2). Post hoc, the 2-sided 95% CIs for the above between-group safety difference were 25.6% to 41.6% in the safety analysis and 26.1% to 44.4% in the per-protocol analysis. Acute grade 3 to 4 adverse events were observed in 136 (52.3%) and 166 (63.6%) patients in the concurrent cisplatin–sparing and standard therapy groups, respectively, with the greatest reductions in leukopenia (39 [15.0%] vs 80 [30.7%]), anemia (8 [3.1%] vs 30 [11.5%]), fatigue (2 [0.8%] vs 21 [8.0%]), and vomiting (10 [3.8%] vs 27 [10.3%]) (Table 3) (eTable 10 in Supplement 2). No treatment-related deaths were observed.
Table 3. Adverse Events in the Safety Analysis Population.
| Adverse event | No. (%) | |||
|---|---|---|---|---|
| Concurrent cisplatin–sparing group (n = 260)a,b | Standard therapy group (n = 261)a | |||
| All gradesc | Grades 3-4c | All gradesc | Grades 3-4c | |
| Any acute adverse eventd | 260 (100.0) | 136 (52.3) | 261 (100.0) | 166 (63.6) |
| Dry mouth | 223 (85.8) | 2 (0.8) | 228 (87.4) | 2 (0.8) |
| Oropharyngeal pain | 182 (70.0) | 26 (10.0) | 191 (73.2) | 30 (11.5) |
| Dermatitis | 180 (69.2) | 7 (2.7) | 191 (73.2) | 9 (3.4) |
| Leukopenia | 166 (63.8) | 39 (15.0) | 236 (90.4) | 80 (30.7) |
| Anemia | 152 (58.5) | 8 (3.1) | 198 (75.9) | 30 (11.5) |
| Mucositis | 150 (57.7) | 34 (13.1) | 215 (82.4) | 61 (23.4) |
| Neutropenia | 143 (55.0) | 38 (14.6) | 181 (69.3) | 61 (23.4) |
| Anorexia | 115 (44.2) | 11 (4.2) | 195 (74.7) | 27 (10.3) |
| Fatigue | 114 (43.8) | 2 (0.8) | 196 (75.1) | 21 (8.0) |
| Constipation | 105 (40.4) | 0 | 157 (60.2) | 2 (0.8) |
| Weight loss | 97 (37.3) | 2 (0.8) | 153 (58.6) | 4 (1.5) |
| Nausea | 89 (34.2) | 12 (4.6) | 160 (61.3) | 29 (11.1) |
| Dysphagia | 80 (30.8) | 2 (0.8) | 104 (39.8) | 9 (3.4) |
| Increased alanine aminotransferase | 71 (27.3) | 3 (1.2) | 71 (27.2) | 6 (2.3) |
| Rash | 70 (26.9) | 6 (2.3) | 60 (23.0) | 7 (2.7) |
| Vomiting | 68 (26.2) | 10 (3.8) | 156 (59.8) | 27 (10.3) |
| Thrombocytopenia | 61 (23.5) | 10 (3.8) | 129 (49.4) | 26 (10.0) |
| Hypothyroidism | 58 (22.3) | 1 (0.4) | 58 (22.2) | 0 |
| Pruritus | 48 (18.5) | 0 | 46 (17.6) | 1 (0.4) |
| Increased aspartate aminotransferase | 47 (18.1) | 1 (0.4) | 60 (23.0) | 3 (1.1) |
| Insomnia | 34 (13.1) | 6 (2.3) | 70 (26.8) | 4 (1.5) |
| Increased creatinine | 32 (12.3) | 0 | 41 (15.7) | 3 (1.1) |
| Any immune-related adverse evente | 139 (53.5) | 13 (5.0) | 148 (56.7) | 22 (8.4) |
| Any late adverse eventf | 206 (79.2) | 9 (3.5) | 207 (79.3) | 11 (4.2) |
| Dry mouth | 145 (55.8) | 1 (0.4) | 148 (56.7) | 3 (1.1) |
| Impaired hearing | 103 (39.6) | 5 (1.9) | 118 (45.2) | 4 (1.5) |
| Middle ear inflammation | 91 (35.0) | 0 | 97 (37.2) | 0 |
| Dental caries | 59 (22.7) | 3 (1.2) | 62 (23.8) | 3 (1.1) |
| Dysgeusia | 51 (19.6) | 0 | 52 (19.9) | 0 |
| Neck superficial soft tissue fibrosis | 37 (14.2) | 0 | 37 (14.2) | 0 |
| Dysphagia | 35 (13.5) | 1 (0.4) | 50 (19.2) | 0 |
| Blurred vision | 27 (10.4) | 0 | 24 (9.2) | 0 |
| Peripheral sensory neuropathy | 22 (8.5) | 0 | 30 (11.5) | 1 (0.4) |
| Trismus | 15 (5.8) | 0 | 14 (5.4) | 0 |
A patient may have had more than 1 adverse event, but only the highest severity grade for each adverse event during the entire treatment course was recorded. No adverse event of grade 5 (led to death) occurred in this study.
Treatment-related adverse events are listed in descending order of frequency in the concurrent cisplatin–sparing group according to different categories.
The National Cancer Institute Common Toxicity Criteria version 5.0 scale was used to grade acute adverse events. The Late Radiation Morbidity Scoring Scheme of the Radiation Therapy Oncology Group was used to grade late radiation toxicities. The adverse event grading system rates adverse events from mild (1) to death (5), with 3 or 4 representing severe or potentially life-threatening events.
Acute adverse events of all grades occurring in at least 10% of patients in both groups are reported. Detailed data on acute adverse events are presented in eTable 10 in Supplement 2.
Defined as adverse events occurring within 100 days after toripalimab discontinuation, determined through consultation with a multidisciplinary board to be possibly related to toripalimab, lacking a clear etiology but considered to involve potential immune-mediated mechanisms, or requiring immunomodulatory or systemic steroid treatment. Detailed data on immune-related adverse events are presented in eTable 11 in Supplement 2.
Late adverse events of all grades occurring in at least 1% of patients in both groups are reported.
Immune-related acute adverse events of all grades were observed in 139 (53.5%) and 148 (56.7%) patients in the concurrent cisplatin–sparing and standard therapy groups, respectively, whereas that of grades 3 to 4 occurred in 13 (5.0%) and 22 (8.4%), respectively (Table 3) (eTable 11 in Supplement 2). Individually, 4 (1.5%) and 5 (1.9%) patients in the concurrent cisplatin–sparing and standard therapy groups required systemic steroid treatment; none of them received immunosuppressants (eTable 12 in Supplement 2). Late adverse events of all grades occurred in 206 (79.2%) and 207 (79.3%) patients in the concurrent cisplatin–sparing and standard therapy groups, respectively, whereas that of grades 3 to 4 occurred in 9 (3.5%) and 11 (4.2%), respectively (Table 3).
Health-Related QoL and Tolerability
The overall participation rates for the QoL and tolerability questionnaires were 87.5% and 94.7%, respectively. The concurrent cisplatin–sparing group showed significant advantages in global health status/QoL, physical functioning, role functioning, nausea and vomiting, constipation, swallowing, sexuality, and head and neck total score, in which the standard therapy group had both clinically meaningful deterioration from baseline and significantly worse QoL at weeks 10 and 13 (eFigure 10, eTables 13-15 in Supplement 2). During the radiotherapy phase, the concurrent cisplatin–sparing group had a better tolerability on all attributes of nausea, vomiting, constipation, and fatigue than the standard therapy group (eFigure 11 in Supplement 2). Similar results were observed throughout the entire treatment (eTables 16-18 in Supplement 2).
Discussion
To the study investigators’ knowledge, this is the first phase 3 randomized clinical trial to establish a PD-1 blockade–based, concurrent cisplatin–sparing regimen for locoregionally advanced NPC, demonstrating noninferior failure-free survival and reduced all-grade vomiting compared with standard therapy. Omitting concurrent cisplatin significantly improved gastrointestinal tolerability, with QoL benefits extending to both functional and global health domains.
Compared with the CONTINUUM regimen,3 where concurrent cisplatin was retained with PD-1 blockade during the radiotherapy phase, the concurrent cisplatin–sparing group in this study demonstrated improved safety. This was evident in both the overall incidence (52.3% vs 74.0%) and the acute grades 3 to 4 adverse effects that had the most impact on patients’ self-perception, such as nausea (4.6% vs 14.0%), vomiting (3.8% vs 11.0%), and mucositis (13.1% vs 33.0%). In clinical practice, omitting concurrent cisplatin can reduce hospitalizations and treatment costs; eliminate the need for chemotherapy-related supportive measures, such as high-volume hydration; and avoid the intrinsic toxicity risks of chemotherapy that may exacerbate radiotherapy-related adverse events.23 As patient-centered treatment experiences gain increasing attention, these advantages may substantially improve patient care and contribute to redefining the standard of care in NPC.
Considering the clinical need to reduce toxicity related to concurrent cisplatin, this trial was designed with a forward-looking approach. Although standard therapy was not included in clinical guidelines when this study began in August 2021, the CONTINUUM trial—completed in March 2020 and involving tumor-node stage compositions comparable to that of the present study—supported the combination of PD-1 blockade with induction-concurrent chemoradiotherapy in locoregionally advanced NPC. This treatment approach was subsequently recommended by the 2024 Chinese Society of Clinical Oncology guidelines for high-risk patients with locoregionally advanced NPC (T4N1M0 or T1-4N2-3M0).24 Unlike in head and neck cancer, where trials adding PD-(L)1 blockade to chemoradiotherapy yielded both negative (KEYNOTE-412, JAVELIN Head and Neck 100)25,26 and positive results,27,28 this study, together with 2 other trials,3,4 demonstrated clear survival benefits in locoregionally advanced NPC. This is primarily attributed to NPC being a unique EBV-related tumor with high immunogenicity and abundant lymphocyte infiltration. From a biological perspective, this study combined PD-1 blockade with gemcitabine-cisplatin, a strategy known to enhance cytotoxic T cell activity and improve antitumor efficacy.29 Irradiation can also activate tumor-associated dendritic cells, which in turn support effector CD8+ T cells and mobilize tumor-specific immunity.30
As the next step, extended follow-up will be prioritized, given that the study is still maturing. Furthermore, the finding that toripalimab discontinuation is associated with poorer survival underscores the need to define an optimal treatment duration for long-term immunotherapy to ensure efficacy and improve real-world applicability. Although capecitabine is an effective adjuvant treatment for locoregionally advanced NPC,31 it was prohibited to focus purely on the objective of omitting concurrent cisplatin. Two phase 3 trials are being conducted: one evaluating the value of adjuvant PD-1 blockade in the context of chemoradiotherapy plus capecitabine (NCT05342792), and the other assessing the value of adjuvant capecitabine in the setting of chemoradiotherapy plus PD-1 blockade (NCT06900218). These efforts will provide further insight into their roles in NPC.
Limitations
This study has limitations. First, in North America, NPC in White patients predominantly presents as the keratinizing type with limited association to EBV infection and is therefore typically treated with concurrent chemoradiotherapy followed by adjuvant chemotherapy.32 As only 4.3% (23/532) of patients in this study were from nonendemic provinces, further investigation is needed to evaluate the generalizability of results to nonendemic populations. Second, 51.9% of patients (276/532) lacked PD-L1 expression data. Previous studies showed no significant correlation between PD-L1 expression and prognosis in NPC3,4; therefore, PD-L1 testing was not mandated in this study. Third, the study lacks objective long-term toxicity assessments, such as hearing tests and neurological examinations. Fourth, the open-label design may introduce reporting bias in both physician-assessed safety and patient-reported subjective scores, potentially influencing result interpretation. Fifth, a cost-effectiveness analysis was not conducted to evaluate the increased costs associated with the 17-cycle toripalimab, and the potential cost savings from the omission of concurrent cisplatin.
Conclusions
Toripalimab combination therapy without concurrent cisplatin resulted in noninferior 3-year failure-free survival and improved safety in vomiting, along with a favorable QoL-tolerability profile in patients with locoregionally advanced NPC.
Trial Protocol
eAppendix 1. Trial oversight
eAppendix 2. Dose modification and treatment discontinuation
eAppendix 3. Procedures and plans of radiotherapy
eAppendix 4. Assessments and follow-up
eAppendix 5. Description of the analysis of tolerability
eAppendix 6. Description of the analysis of health-related quality-of-life
eAppendix 7. Biomarker assessments
eFigure 1. Trial design
eFigure 2. The proportional-hazards assumption test based on Schoenfeld residuals in the intention-to-treat population
eFigure 3. Kaplan–Meier analysis of survival in the per-protocol population
eFigure 4. Difference in the rate of failure-free survival at 3 year between the concurrent cisplatin-sparing and standard-therapy groups with noninferiority margin and 95% CI
eFigure 5. Forest plots of the effects of treatment on failure-free survival within prespecified subgroups
eFigure 6. Forest plots of the effects of treatment on failure-free survival within prespecified subgroups defined by different PD-L1 CPS cutoffs
eFigure 7. Kaplan–Meier analysis of failure-free survival in the subgroup based on the EBV DNA after the induction phase
eFigure 8. Kaplan–Meier analysis of failure-free survival by post-induction EBV DNA levels
eFigure 9. Kaplan–Meier analysis of failure-free survival by the delay and discontinuation of toripalimab
eFigure 10. Patient-reported outcomes for health-related QoL in the radiotherapy phase
eFigure 11. Patient-reported outcomes for tolerability in the radiotherapy phase
eTable 1. Recruitment sites
eTable 2. Patient sources
eTable 3. Compliance with toripalimab during the entire treatment period
eTable 4. Compliance with toripalimab during the radiotherapy phase
eTable 5. Compliance with chemotherapy and radiotherapy
eTable 6. Dosimetric parameters for patients receiving radiotherapy
eTable 7. Tumor response and detection of EBV DNA
eTable 8. Details of events
eTable 9. Salvage therapies after treatment failure
eTable 10. Details of acute toxicity during the entire treatment period regardless of incidence
eTable 11. Acute adverse events with potential immunological causes
eTable 12. Systemic steroids treatment for acute adverse events with potential immunological causes
eTable 13. Completion rates of QoL questionnaires by the EORTC and FACT systems
eTable 14. Baseline mean and LS mean change from baseline of EORTC scores among patients with pretreatment and ≥ 1 on-treatment assessment
eTable 15. Baseline mean and LS mean change from baseline of FACT scores among patients with pretreatment and ≥ 1 on-treatment assessment
eTable 16. Completion rates of PRO-CTCAE questionnaires
eTable 17. Tolerability according to PRO-CTCAE questionnaires during the radiotherapy phase
eTable 18. Tolerability according to PRO-CTCAE questionnaires during the entire treatment period
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eAppendix 1. Trial oversight
eAppendix 2. Dose modification and treatment discontinuation
eAppendix 3. Procedures and plans of radiotherapy
eAppendix 4. Assessments and follow-up
eAppendix 5. Description of the analysis of tolerability
eAppendix 6. Description of the analysis of health-related quality-of-life
eAppendix 7. Biomarker assessments
eFigure 1. Trial design
eFigure 2. The proportional-hazards assumption test based on Schoenfeld residuals in the intention-to-treat population
eFigure 3. Kaplan–Meier analysis of survival in the per-protocol population
eFigure 4. Difference in the rate of failure-free survival at 3 year between the concurrent cisplatin-sparing and standard-therapy groups with noninferiority margin and 95% CI
eFigure 5. Forest plots of the effects of treatment on failure-free survival within prespecified subgroups
eFigure 6. Forest plots of the effects of treatment on failure-free survival within prespecified subgroups defined by different PD-L1 CPS cutoffs
eFigure 7. Kaplan–Meier analysis of failure-free survival in the subgroup based on the EBV DNA after the induction phase
eFigure 8. Kaplan–Meier analysis of failure-free survival by post-induction EBV DNA levels
eFigure 9. Kaplan–Meier analysis of failure-free survival by the delay and discontinuation of toripalimab
eFigure 10. Patient-reported outcomes for health-related QoL in the radiotherapy phase
eFigure 11. Patient-reported outcomes for tolerability in the radiotherapy phase
eTable 1. Recruitment sites
eTable 2. Patient sources
eTable 3. Compliance with toripalimab during the entire treatment period
eTable 4. Compliance with toripalimab during the radiotherapy phase
eTable 5. Compliance with chemotherapy and radiotherapy
eTable 6. Dosimetric parameters for patients receiving radiotherapy
eTable 7. Tumor response and detection of EBV DNA
eTable 8. Details of events
eTable 9. Salvage therapies after treatment failure
eTable 10. Details of acute toxicity during the entire treatment period regardless of incidence
eTable 11. Acute adverse events with potential immunological causes
eTable 12. Systemic steroids treatment for acute adverse events with potential immunological causes
eTable 13. Completion rates of QoL questionnaires by the EORTC and FACT systems
eTable 14. Baseline mean and LS mean change from baseline of EORTC scores among patients with pretreatment and ≥ 1 on-treatment assessment
eTable 15. Baseline mean and LS mean change from baseline of FACT scores among patients with pretreatment and ≥ 1 on-treatment assessment
eTable 16. Completion rates of PRO-CTCAE questionnaires
eTable 17. Tolerability according to PRO-CTCAE questionnaires during the radiotherapy phase
eTable 18. Tolerability according to PRO-CTCAE questionnaires during the entire treatment period
Data Sharing Statement
