Gemcitabine-cisplatin (GP) chemotherapy is the standard first-line systemic treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In this international, double-blind, phase 3 trial (ClinicalTrials.gov identifier: NCT03581786), 289 patients with RM-NPC and no previous chemotherapy for recurrent or metastatic disease were randomized (1/1) to receive either toripalimab, a monoclonal antibody against human programmed death-1 (PD-1), or placebo in combination with GP every 3 weeks for up to six cycles, followed by monotherapy with toripalimab or placebo. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee according to RECIST v.1.1. At the prespecified interim PFS analysis, a significant improvement in PFS was detected in the toripalimab arm compared to the placebo arm: median PFS of 11.7 versus 8.0 months, hazard ratio (HR) = 0.52 (95% confidence interval (CI): 0.36–0.74), P = 0.0003. An improvement in PFS was observed across key subgroups, including PD-L1 expression. As of 18 February 2021, a 40% reduction in risk of death was observed in the toripalimab arm compared to the placebo arm (HR = 0.603 (95% CI: 0.364–0.997)). The incidence of grade ≥3 adverse events (AEs) (89.0 versus 89.5%), AEs leading to discontinuation of toripalimab/placebo (7.5 versus 4.9%) and fatal AEs (2.7 versus 2.8%) was similar between the two arms; however, immune-related AEs (39.7 versus 18.9%) and grade ≥3 infusion reactions (7.5 versus 0.7%) were more frequent in the toripalimab arm. In conclusion, the addition of toripalimab to GP chemotherapy as a first-line treatment for patients with RM-NPC provided superior PFS compared to GP alone, and with a manageable safety profile.
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All requests for data will be reviewed by the leading clinical site, Sun Yat-Sen University Cancer Center, and the study sponsor, Shanghai Junshi Biosciences, to verify whether the request is subject to any intellectual property or confidentiality obligations. Requests for access to the patient-level data from this study can be submitted via email to email@example.com with detailed proposals for approval. A signed data access agreement with the sponsor is required before accessing shared data. Source data are provided with this paper.
No custom code was used for statistical analysis in this study.
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This study is sponsored by Shanghai Junshi Biosciences. The authors thank the patients who participated in this study and their families. This work was supported by National Major Science & Technology Major Projects (no. 2017ZX09302009) awarded to H.F., and a Shanghai Science and Technology Committee Technology Grant awarded to H.F. (no. 17431900700).
H.F. and S.Y. are employed by Shanghai Junshi Bioscience and TopAlliance Biosciences. P.K. is employed by TopAlliance Biosciences. R.-H.X. has served in consulting or advisory roles for Bristol-Myers Squibb, Merck Serono, Roche, Astellas and AstraZeneca. The remaining authors have no competing interests.
Peer review information Nature Medicine thanks J. Jack Lee, Anthony Chan and Douglas Adkins for their contribution to the peer review of this work. Javier Carmona was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Between Nov 10, 2018, and Oct 20, 2019, 408 NPC patients were screened for eligibility at 35 sites from mainland China, Taiwan and Singapore. A total of 289 eligible patients were randomized 1:1 to the toripalimab combination arm (n = 146) or the placebo combination arm (n = 143). After completion of chemotherapy, 231 patients continued to receive maintenance treatment (115 in the toripalimab arm and 118 in the placebo arm).
Kaplan-Meier estimates of PFS as assessed by a blinded independent review committee according to RECIST v1.1 are shown to compare the toripalimab plus chemotherapy arm with the placebo plus chemotherapy arm in PD-L1 + and PD-L1- subgroups. PD-L1 positive status was defined as the presence of membrane staining of any intensity in ≥1% of tumor cells or immune cells by JS311 IHC staining. Censored patients are marked with “┃” in the graph. Numbers of patients at risk at indicated time points are shown below the x-axis. Number of events and median PFS rates are shown to the right of Kaplan-Meier curves.
Kaplan-Meier estimates of PFS as assessed by a blinded independent review committee according to RECIST v1.1 are shown to compare the toripalimab plus chemotherapy arm with the placebo plus chemotherapy arm in PD-L1 + patients. PD-L1 positive status was defined as the presence of membrane staining of any intensity in ≥1% of tumor cells or immune cells by JS311 IHC staining. Censored patients are marked with “┃” in the graph. Numbers of patients at risk at indicated time points are shown below the x-axis. Number of events, median PFS and stratified hazard ratio for disease progression or death are shown to the right of Kaplan-Meier curves. The hazard ratio was computed using the Cox proportional hazards model. The p-value was two-sided with no adjustment of multiplicity and computed using the unstratified log-rank test.
Kaplan-Meier estimates of PFS as assessed by a blinded independent review committee according to RECIST v1.1 are shown to compare the toripalimab plus chemotherapy arm with the placebo plus chemotherapy arm in PD-L1- patients. PD-L1 negative status was defined as the presence of membrane staining of any intensity in <1% of tumor cells and <1% immune cells by JS311 IHC staining. Censored patients are marked with “┃” in the graph. Numbers of patients at risk at indicated time points are shown below the x-axis. Number of events, median PFS and stratified hazard ratio for disease progression or death are shown to the right of Kaplan-Meier curves. The hazard ratio was computed using the Cox proportional hazards model. The p-value was two-sided with no adjustment of multiplicity and computed using the unstratified log-rank test.
PFS by BICR and investigator source data.
OS source data.
Source data for exposure and clinical events in the ITT population and DoR in patients with confirmed objective responses.
PFS by BICR in PD-L1 expression subgroups source data.
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Mai, HQ., Chen, QY., Chen, D. et al. Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial. Nat Med 27, 1536–1543 (2021). https://doi.org/10.1038/s41591-021-01444-0