Abstract
The combination of immune-checkpoint blockade with chemotherapy for the first-line treatment of advanced triple-negative breast cancer (TNBC) has generated mixed results. TORCHLIGHT is a randomized, double-blinded phase 3 trial evaluating the efficacy and safety of first-line toripalimab and nab-paclitaxel (nab-P) (n = 353; experimental arm) versus placebo and nab-P (n = 178; control arm) for the treatment of women with metastatic or recurrent TNBC. The primary end point was progression-free survival (PFS) assessed by a blinded independent central review in the PD-L1-positive and intention-to-treat populations. The secondary end points included overall survival and safety. Overall, 200 and 100 patients, in the toripalimab and placebo arm respectively had PD-L1-positive TNBC. At the prespecified interim analysis, a statistically significant improvement in PFS assessed by a blinded independent central review was demonstrated in the experimental arm in the PD-L1-positive population (median PFS 8.4 versus 5.6 months; hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.470–0.906, P = 0.0102). The median overall survival was 32.8 versus 19.5 months (HR = 0.62, 95% CI 0.414–0.914, P = 0.0148). Similar incidences of treatment-emergent adverse events (AEs) (99.2% versus 98.9%), grade ≥3 treatment-emergent AEs (56.4% versus 54.3%) and fatal AEs (0.6% versus 3.4%) occurred in the experimental and control arms. The addition of toripalimab to nab-P provided a significant improvement in PFS for PD-L1-positive patients with metastatic or recurrent TNBC with an acceptable safety profile. ClinicalTrial.gov identifier NCT03777579.
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Data availability
Due to data privacy regulations, access to the raw clinical data is restricted. Requests for access to the patient-level data from this study can be submitted via email to jiangzefei@csco.org.cn with a detailed proposal for approval. In response to the inquiry, please be informed that the timeframe for responding to requests is approximately 2 weeks. A signed data access agreement with the sponsor is required before accessing the data. The trial protocol and statistical analysis plan is in the supplementary documents. Source data are provided with this paper.
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Acknowledgements
This study is sponsored by Shanghai Junshi Biosciences. The authors thank the patients who participated in this study and their families. Professional medical writing and editing support was provided by the Junshi clinical development team. This work was supported by National Major Science & Technology Major Projects (2017ZX09302009) and Shanghai Science and Technology Committee Technology Grant (17431900700). This work was presented at the ASCO Annual Meeting, 3 June 2023.
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Conception and design was the responsibility of Z.J. Provision of study materials or patients was the responsibility of Z.J., Q.O., T.S., Q.Z., Y.T., J.C., Haibo Wang, Y.Y., Xiaojia Wang, X.Z., Y.W., S.G., J.W., L.Z., J.Y., J.Q., M.Y., X.L., T.Y., Ying Cheng, M.L., Aimin Zang, S.W., C.W., Xinhong Wu, J.C., H.L., Y.L., C.G., K.G., C.X., H.X., Xiaohong Wu, J.Y., Qingshan Li, Yiding Chen, Z.C., Anqin Zhang, Y.Z., Y.W., J.N., Qiang Liu, K.W., X.M., L.C., Y.P., P.F., H.Z., D.P., Y.S., Y.H., H.W. and S.C. Data analysis and interpretation was conducted by Z.J., Q.O., T.S., Q.Z., X. Luo, W.Y., R.D. and P.K. Manuscript writing was carried out by all authors. Final approval of manuscript was the responsibility of all authors.
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X. Luo, W.Y., R.D. and C.Y. are employed by Shanghai Junshi Biosciences. P.K. is employed by TopAlliance Biosciences. The other authors declare no competing interests.
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Nature Medicine thanks Hope Rugo, Yisheng Li, and Xichun Hu for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team.
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Extended data
Extended Data Fig. 1 BICR-Assessed PFS Per RECIST v1.1; PFS treatment effects in subgroups (ITT population).
Kaplan–Meier-estimated PFS curves as assessed by the investigator according to RECIST v1.1 are shown to compare the toripalimab plus chemotherapy arm with the placebo plus chemotherapy arm as first-line treatment for patients with initially diagnosed metastatic or recurrent TNBC (Panel A). Censored patients are marked with “|” in the graph. Numbers of patients at risk at indicated time points shown below x-axis. Number of events, median PFS, 1-year and 2-year PFS rates and stratified hazard ratio for PFS are shown to the right of Kaplan–Meier curves. Progression-free survival in key subgroups is shown in Panel B. All hazard ratios were computed using the Cox proportional hazards model. All P values were two-sided with no adjustment of multiplicity. The P values of comparing the Kaplan–Meier curves were computed using the log-rank test stratified by the baseline PD-L1 expression status, history of paclitaxel treatment, and line of therapy at enrollment. The P values of testing the interaction of the subgroup variables with the treatment (Panel B) were computed using the Cox proportional hazards regression model with the treatment arm, the subgroup variable and their interaction as the covariates.
Extended Data Fig. 2 Overall Survival; OS treatment effects in subgroups (ITT Population).
Kaplan–Meier estimates of OS are shown to compare the toripalimab plus chemotherapy arm with the placebo plus chemotherapy arm as first-line treatment for patients with initially diagnosed metastatic or recurrent TNBC (Panel A). 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 OS, 1-year, 2-year and 3-year OS rates, and stratified hazard ratio for death are shown to the right of Kaplan–Meier curves. Overall survival in key subgroups is shown in Panel B. All hazard ratios were computed using the Cox proportional hazards model. All P values were two-sided with no adjustment of multiplicity. The P values of comparing the Kaplan–Meier curves were computed using the log-rank test stratified by the baseline PD-L1 expression status, history of paclitaxel treatment, and line of therapy at enrollment. The P values of testing the interaction of the subgroup variables with the treatment.
Extended Data Fig. 3 Overall Survival (OS) in PD-L1 expression subpopulations.
Kaplan–Meier estimates of OS are shown to compare the toripalimab plus chemotherapy arm with the placebo plus chemotherapy arm as first-line treatment for patients with initially diagnosed metastatic or recurrent TNBC with PD-L1 expression JS311 CPS < 1 (Panel A), 1≤CPS<10 (Panel B) and CPS ≥ 10 (Panel C). Censored patients are marked with “|” in the graph. Numbers of patients at risk at indicated time points are shown below the x-axis. Median OS, and stratified hazard ratio for death are shown at the bottom of Kaplan–Meier curves. All hazard ratios were computed using the Cox proportional hazards model.
Supplementary information
Supplementary Information
Extended data figure legends and study protocol.
Supplementary Tables 1–11
Supplementary Table 1. Summary of reasons for screening failure. Supplementary Table 2. Common reasons (≥5 incidences) for not meeting inclusion criteria or meeting exclusion criteria. Supplementary Table 3. PD-L1 positive TNBC prevalence determined by 22C3 and JS311 IHC assays. Supplementary Table 4. TNM classification for the ITT population. Supplementary Table 5. TNM classification for the PD-L1-positive subgroup. Supplementary Table 6. Subsequent anticancer therapy in intent-to-treat population after the study treatment. Supplementary Table 7. Objective response rate (INV-ORR), disease control rate (INV-DCR) and duration of response (INV-DoR) assessed by the investigator in accordance with RECIST v.1.1 in the PD-L1+ population at the interim PFS analysis. Supplementary Table 8. INV-ORR, INV-DCR and INV-DoR assessed by the investigator in accordance with RECIST v.1.1 in the ITT population at the interim PFS analysis. Supplementary Table 9. Study drug exposure. Supplementary Table 10. Treatment-emergent adverse events reported in at least 10% of the patients in either treatment arm. Supplementary Table 11. Immune-related adverse events (irAEs) reported in more than one patient in either arm as assessed by the investigator.
Source data
Source Data Fig. 2
PFS by BICR source data in the PD-L1+ subgroup.
Source Data Fig. 3
OS source data in the PD-L1+ subgroup.
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Jiang, Z., Ouyang, Q., Sun, T. et al. Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial. Nat Med 30, 249–256 (2024). https://doi.org/10.1038/s41591-023-02677-x
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DOI: https://doi.org/10.1038/s41591-023-02677-x
