Abstract
Radiotherapy displays unique antitumor synergism with immune checkpoint inhibitors, which is indicated by high pathological complete response (pCR) rates from single-arm trials of locally advanced rectal cancer (LARC). Here we test the efficacy and safety of the radiation–immune checkpoint inhibitor combination in patients with LARC in a phase 2, randomized trial conducted in eight major colorectal cancer centers in Beijing. In total, 186 eligible all-comer (proficient mismatch repair and deficient mismatch repair) participants were enrolled. The patients were randomly assigned to receive neoadjuvant chemoradiation + concurrent/sequential PD-1 blockade (experiment groups A/B) or neoadjuvant chemoradiation alone (control group). Radical surgeries were scheduled after neoadjuvant treatments. The primary endpoint was the pCR rate. The pCR rates were 27.1%, 32.7% and 14.0% for experiment groups A and B and the control group, respectively. The difference in pCR rates between experiment group B and the control group reached statistical significance (risk ratio 2.332, 95% confidence interval 1.106–4.916; P = 0.019). No substantial differences between either one of the experiment groups and the control group were observed regarding adverse reaction, surgical complication and disease progression. Our results show that adding PD-1 blockade after neoadjuvant chemoradiation increases the pCR rate for patients with LARC and raises no substantial safety concerns. Phase 3 trials with larger sample sizes are warranted (ClinicalTrials.gov identifier NCT05245474).
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Data availability
Deidentified individual-level patient data are shared as files in Supplementary Information, which contain the entirety of data for all-purpose validation of the results. The study protocol and the statistical analysis plan are also available as files in Supplementary Information. Source data are provided with this paper.
Code availability
Custom R codes used for the generation of forest plots are available at GitHub via https://github.com/pk2spl/Codes-of-the-POLARSTAR-trial/.
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Acknowledgements
This trial is financially supported by Beijing Li Huanying Medical Foundation (to Z.Z.), Beijing Postdoctoral Research Foundation (grant 2023-ZZ-038, to K.P.), BeiGene (to Z.Z.) and National Key Technologies R&D Program (grant 2015BAI13B09, to Z.Z.). The experimental drugs (tislelizumab) are supplied by BeiGene. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Contributions
Conceptualization: K.P. Data curation: J.G., J.Z., L.X., Z.G., Y.W., A.L., J.H., G.W., X.W., F.L., Y.Y., J.Z. and G.C. Formal analysis: K.P. and Y.K. Funding acquisition: K.P. and Z.Z. Investigation: Y.Y., K.P., G.L. and X.L. Methodology: Y.K., H.W., K.P., G.C. and J.Z. Project administration: Y.Y. Resources: A.L., J.H., G.W., X.W., Y.Y., A.W., Y.X. and Z.Z. Software: K.P. Supervision: Z.Z. Validation: H.Y. Visualization: K.P. Writing (original draft): K.P. Writing (review and editing): K.P., Y.Y., G.L., X.L., Y.K., A.W., Y.X., H.Y. and Z.Z.
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Extended data
Extended Data Fig. 1 Radiological tumor regression of the three groups.
MRI-recorded tumor regression of the primary lesion from baseline (i.e. pre-radiotherapy) to post-treatment (i.e. pre-surgery) re-evaluation.
Extended Data Fig. 2 Detailed distribution of the NAR scores in the three groups.
Concurrent plan: n = 57, sequential plan: n = 51, control: n = 46. (A) The distribution of the NAR scores along with the best fit normal distribution curve in the three groups. Red arrow points to the column of patients with low NAR score. (B) Comparison of NAR scores with boxplot. Data are presented as median values (centres) and interquartile range (left and right boundaries of boxes), with whiskers indicating 5-95 percentiles and dots indicating outlier values.
Extended Data Fig. 3 Subgroup analysis of pCR rate.
Data are presented with forest plot, with centres indicating values of risk ratios (RR) and error bars indicating 95% confidence intervals of RRs. (A) between Experiment group A and Control group. (B) between Experiment group B and Control group.
Supplementary information
Supplementary Information
Trial protocol and statistical analysis plan.
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Yang, Y., Pang, K., Lin, G. et al. Neoadjuvant chemoradiation with or without PD-1 blockade in locally advanced rectal cancer: a randomized phase 2 trial. Nat Med 31, 449–456 (2025). https://doi.org/10.1038/s41591-024-03360-5
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DOI: https://doi.org/10.1038/s41591-024-03360-5
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