Gamma Knife Stereotactic radiotherapy combined with tislelizumab as later-line therapy in pMMR/MSS/MSI-L metastatic colorectal cancer: A Phase II Trial Analysis

  1. Yiran Zhang
  2. Hanyang Guan
  3. Shijin Liu
  4. Haoquan Li
  5. Zili Bian
  6. Jiashuai He
  7. Zhan Zhao
  8. Shenghui Qiu
  9. Tianmu Mo
  10. Xiangwei Zhang
  11. Zuyang Chen
  12. Hui Ding
  13. Xiaoxu Zhao
  14. Liang Wang
  15. Yunlong Pan
  16. Jinghua Pan
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Abstract

Background

An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.

Methods

In this phase II trial, patients received Gamma Knife SBRT combined with Tislelizumab. Biomarker analysis was performed pre- and post-treatment.

Results

From November 2022 to July 2024, 1of 20 patients achieved CR, 13 of 20 patients achieved PR, 6 achieved SD. mPFS was 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse events included nausea (65%), anemia (55%), and fatigue (45%). RNA sequencing indicated enhanced immune infiltration in PR patients. For patients with pMMR/MSS/MSI-L mCRC who had not responded to first and second-line therapies, the combo of Gamma Knife SBRT and tislelizumab showed high efficacy and reasonable safety. Significant post-radiotherapy improvements in the tumor’s immunosuppressive microenvironment, including lower fibrosis, normalizing of tumor vasculature, and activation of the PD-1/PD-L1 checkpoint pathway were revealed by biomarker analysis.

Conclusions

These results imply that patients with pMMR/MSS/MSI-L mCRC who were unresponsive to the first and second-line chemotherapy, Gamma Knife SBRT with tislelizumab provides a safe and powerful later-line treatment alternative.

Funding

This research was supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University (No. JNU1AF-CFTP-2022-a01223), the National Natural Science Foundation of China (82204436), Natural Science Foundation of Guangdong Province (2024A1515030010, 2022A1515011695), Science and Technology Projects in Guangzhou (2024A03J0825).

Clinical trial number

ChiCTR2200066117.

Statement of significance

This study offers a safe and powerful option for pMMR/MSS/MSI-L mCRC patients fail to first and second-line chemotherapy. And discover Gamma Knife SBRT contributed to potentially converting the suppressive “cold” tumor immune microenvironment into an activated “hot” microenvironment conducive to immunotherapy efficacy in pMMR CRC.

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