1. Cancer Biology
  2. Medicine

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  Is a corresponding author
  15. Yunlong Pan  Is a corresponding author
  16. Jinghua Pan  Is a corresponding author
  1. Department of General Surgery, The First Affiliated Hospital of Jinan University, China
  2. Department of Body Gamma Knife, The First Affiliated Hospital of Jinan University, China
  3. Department of Oncology, The First Affiliated Hospital of Jinan University, China
  4. MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, China
https://doi.org/10.7554/eLife.103559.3
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  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
(2025)
Gamma Knife stereotactic radiotherapy combined with tislelizumab as later-line therapy in pMMR/MSS/MSI-L metastatic colorectal cancer: a phase II trial analysis
eLife 14:RP103559.
https://doi.org/10.7554/eLife.103559.3
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5 figures, 3 tables and 4 additional files

Figures

Figure 1
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Clinical trial flowchart.

(A) Flowchart of therapeutic regimen. (B) Flow diagram of participants in the study.

Figure 2 with 1 supplement
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Clinical trial results.

(A) Swimmer plots of patients. (B) Kaplan-Meier curves of OS for the per-protocol set (N=20). (C) Kaplan-Meier curves of progression-free survival (PFS) for the per-protocol set (N=20). (D) Kaplan-Meier curves of PFS for didn’t receive immunotherapy set (control group) (N=23) and per-protocol set (test group) (N=20). (E) Radiological response from patient. (F) Waterfall plot of best percent change from baseline in patient target lesion (N=20). (G) Waterfall plot of best percent change from baseline in patient off-target lesion (N=12).

Figure 2—figure supplement 1
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Supplementary clinical trial results.

(A) Kaplan-Meier curves of progression-free survival (PFS) for RAS wild-type set (n=9), KRAS set (n=5), and NRAS set (n=6). (B) Kaplan-Meier curves of PFS for simple liver metastasis (n=10) and other metastasis (n=10). (C) Schematic diagram of isodose lines of the planned treatment volume (PTV).

Figure 3 with 1 supplement
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Differentially expressed genes analysis.

(A) Specimens collection flowchart. (B) Transcriptome analysis on differential expression genes between responders (PR) (n=9) and nonresponders (Non-PR) (n=7). DESeq2 was provided to perform differential expression testing. (C) The abundance of predefined 12 immune cell composition before and after treatment between responders (PR) (n=9) and nonresponders (Non-PR) (n=7). The Wilcoxon test was used to determine the statistical significance between subgroups. (D and E) Representative CD8 and PD-L1 immunohistochemistry (IHC) staining of before and after treatment specimens of the patient.

Figure 3—figure supplement 1
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Supplementary differentially expressed genes analysis.

(A) Transcriptome analysis on differential expression genes before and after treatment between nonresponders (Non-PR) (n=7) and responders (PR) (n=9). DESeq2 was provided to perform differential expression testing. (B) Venn diagram of two groups of differentially expressed genes.

Figure 4 with 1 supplement
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Additional immune signatures analysis.

(A) The expression of 12 gene sets previously reported to be associated with response to immunotherapy and prognosis between responders (PR) (n=18) and nonresponders (Non-PR) (n=14). (B–D) 11 gene sets of prognostic value were differentially expressed between responders (PR) (n=18) and nonresponders (Non-PR) (n=14). Box plots are indicated in terms of minima, maxima, center, bounds of box and whiskers (interquartile range value), and percentile in the style of Tukey. The Wilcoxon test was used to determine the statistical significance between subgroups.

Figure 4—figure supplement 1
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Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis of differential expression genes.

(A) GO enrichment analysis was performed to identify the biological process, cellular component, and molecular function of differential expression genes. (B) KEGG enrichment analysis of differential expression genes.

Figure 5 with 1 supplement
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Comparison of responders before and after treatment.

(A) The expression of seven gene sets previously reported to be associated with response to immunosuppressive between before treatment (n=9) and after treatment (n=9) in the responders (PR). (B) The expression of angiogenesis sets between responders (PR) (n=18) and nonresponders (Non-PR) (n=14). (C) The expression of angiogenesis and fibroblasts sets between before treatment (n=9) and after treatment (n=9) in the responders. Box plots are indicated in terms of minima, maxima, center, bounds of box and whiskers (interquartile range value), and percentile in the style of Tukey. The Wilcoxon test was used to determine the statistical significance between subgroups. (D and E) Representative CD31 immunohistochemistry (IHC) staining of before and after treatment specimens of patients.

Figure 5—figure supplement 1
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Comparison of nonresponders before and after treatment.

Tables

Table 1
Baseline demographic and clinical characteristics.
CharacteristicsPatients (n=20)
Age, years, median (IQR), n (%)60 (56–65)
<608 (40%)
≥6012 (60%)
Sex, n (%)
Male15 (75%)
Female5 (25%)
ECOG performance status, n (%)
012 (60%)
18 (40%)
Primary tumor location, n (%)
Left colon and rectum17 (85%)
Right colon3 (15%)
Number of metastatic organs*, n (%)
114 (70%)
≥26 (30%)
Metastatic organ, n (%)
Liver14 (70%)
Lung7 (35%)
Lymph node2 (10%)
Other3 (15%)
Ras mutation type, n (%)
KRAS5 (25%)
NRAS6 (30%)
Other9 (45%)
PD-L1 expression, CPS, n (%)
CPS ≤112 (60%)
CPS＞16 (30%)
Unknown2 (10%)
TMB (mut/Mb), median (IQR), n (%)4.62 (3.08–8.97)
TMB <54 (20%)
TMB ≥5, ≤103 (15%)
TMB >101 (5%)
Unknown12 (60%)

  1. Abbreviations: CPS, combined positive score; ECOG, Eastern Cooperative Oncology Group; IQR, interquartile range; TMB, tumor mutation burden.

  2. *

    Multiple answers allowed.

Table 2
Efficacy outcomes.
All patients (N=20)Liver metastasis (N=14)Other metastasis (N=6)
Best overall response
Complete response (CR), n (%)1 (5%)0 (0%)1 (17%)
Partial response (PR), n (%)12 (60%)8 (57%)4 (66%)
Stable disease (SD), n (%)6 (30%)5 (36%)1 (17%)
Progressive disease (PD), n (%)1 (5%)1 (7%)0 (0%)
ORR, n (%, 95% CI)13 (65%, 40.8–84.6%)8 (57.1%, 28.9–82.3%)5 (83.3%, 35.9–99.6%)
DCR, n (%, 95% CI)19 (95%, 75.1–99.9%)13 (92.9%, 66.1–99.8%)6 (100%, 54.1–100%)

  1. Abbreviations: ORR, objective response rate; DCR, disease control rate.

Table 3
Treatment-emergent adverse events (TEAEs) since the initiation of protocol-specified treatment.
TEAEs, n (%)Patient (N=20)
Grade 1Grade 2Grade 3Grade 4Any grade
Anemia9 (45%)2 (10%)0011 (55%)
Neutropenia1 (5%)0001 (5%)
Nausea10 (50%)3 (15%)0013 (65%)
Poor appetite3 (15%)4 (20%)007 (35%)
Electrolyte disturbance7 (35%)2 (10%)0011 (55%)
Hand-foot syndrome00000
Leukocytopenia2 (10%)0002 (10%)
Aspartate transaminase increased2 (10%)2 (10%)004 (20%)
Lipase increased00000
Proteinuria00000
Thrombocytopenia2 (10%)2 (10%)004 (20%)
Vomiting1 (5%)3 (15%)004 (20%)
Hypothyroidism00000
Triglycerides increased00000
Fatigue6 (30%)3 (15%)009 (45%)
Blood bilirubin increased002 (10%)02 (10%)
Alanine transaminase increased2 (10%)1 (5%)003 (15%)
Peripheral neurotoxicity00000
Hoarseness00000
Rash4 (20%)0004 (20%)
Thyroiditis0 (0%)0000
Diarrhea1 (5%)0001 (5%)
Troponin increased00000
Fever00000
Alkaline phosphatase increased00000
Amylase increased00000
Hypertension00000

Additional files

MDAR checklist
https://cdn.elifesciences.org/articles/103559/elife-103559-mdarchecklist1-v1.docx
Supplementary file 1

COX analysis results.

https://cdn.elifesciences.org/articles/103559/elife-103559-supp1-v1.xlsx
Supplementary file 2

Gene signature list.

https://cdn.elifesciences.org/articles/103559/elife-103559-supp2-v1.xlsx
Source data 1

Nanostring panel RNA sequencing data.

https://cdn.elifesciences.org/articles/103559/elife-103559-data1-v1.xlsx

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  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
(2025)
Gamma Knife stereotactic radiotherapy combined with tislelizumab as later-line therapy in pMMR/MSS/MSI-L metastatic colorectal cancer: a phase II trial analysis
eLife 14:RP103559.
https://doi.org/10.7554/eLife.103559.3