Journal of Gastric Cancer

The Korean Gastric Cancer Association (대한위암학회)
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Predictive Value of Insertion/Deletion Rate in Patients With Gastric Cancer Treated With Nivolumab Plus Chemotherapy

  • Hyung-Don Kim (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Hyungeun Lee (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Sun Young Lee (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Yuna Lee (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Jaewon Hyung (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Meesun Moon (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Jinho Shin (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Young Soo Park (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Min-Hee Ryu (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2025.07.10
  • Accepted : 2025.10.13
  • Published : 2026.04.01
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Abstract

Purpose: Immune checkpoint inhibitor plus chemotherapy is the standard first-line treatment for advanced gastric cancer; however, predictive biomarkers for optimal patient selection remain unsatisfactory. This study was aimed at evaluating the predictive value of tumor mutational burden (TMB) and insertion/deletion (Indel) rate in patients with gastric cancer treated with nivolumab plus chemotherapy. Materials and Methods: This retrospective study included 132 patients with gastric cancer treated with first-line nivolumab plus chemotherapy and 185 patients treated with chemotherapy alone, all of whom had next-generation sequencing data available. The TMB and Indel cut-offs were set at 15.63 mutations per megabase and 18.19%, respectively, as determined based on their ability to best distinguish progression-free survival (PFS) among the patients who received nivolumab plus chemotherapy. Results: PFS was favorable for nivolumab and chemotherapy than for chemotherapy alone in both the high and low TMB groups; nevertheless, survival benefits were observed only in the high Indel group. Among the subgroups defined based on both TMB and Indel rates, the high TMB and high Indel rate subgroup showed the greatest benefit from nivolumab plus chemotherapy compared with that from chemotherapy alone. The benefit of this subgroup remained significant in patients with proficient mismatch repair (MMR) tumors, whose survival outcomes were comparable to those of patients with deficient MMR tumors. Among patients treated with nivolumab plus chemotherapy, high TMB and Indel rate were independently associated with favorable survival outcomes. Conclusions: Thus, Indel rate, particularly in combination with TMB, may be a promising predictive biomarker for gastric cancer. However, further validation of their predictive value is warranted.

Keywords

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-249. https://doi.org/10.3322/caac.v71.3
  2. Kim IH, Kang SJ, Choi W, Seo AN, Eom BW, Kang B, et al. Korean practice guidelines for gastric cancer 2024: an evidence-based, multidisciplinary approach (update of 2022 guideline). J Gastric Cancer 2025;25:5-114. https://doi.org/10.5230/jgc.2025.25.e11
  3. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-697. https://doi.org/10.1016/S0140-6736(10)61121-X
  4. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021;398:27-40.
  5. Shitara K, Lordick F, Bang YJ, Enzinger P, Ilson D, Shah MA, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet 2023;401:1655-1668.
  6. Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2023;24:1181-1195. https://doi.org/10.1016/S1470-2045(23)00515-6
  7. Moehler MH, Kato K, Arkenau HT, Oh DY, Tabernero J, Cruz-Correa M, et al. Rationale 305: phase 3 study of tislelizumab plus chemotherapy vs placebo plus chemotherapy as first-line treatment (1L) of advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC). J Clin Oncol 2023;41:286-286. https://doi.org/10.1200/JCO.2023.41.4_suppl.286
  8. Xu J, Jiang H, Pan Y, Gu K, Cang S, Han L, et al. Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer: the ORIENT-16 randomized clinical trial. JAMA 2023;330:2064-2074.  https://doi.org/10.1001/jama.2023.19918
  9. Kim ST, Cristescu R, Bass AJ, Kim KM, Odegaard JI, Kim K, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 2018;24:1449-1458. https://doi.org/10.1038/s41591-018-0101-z
  10. van Velzen MJM, Derks S, van Grieken NCT, Haj Mohammad N, van Laarhoven HWM. MSI as a predictive factor for treatment outcome of gastroesophageal adenocarcinoma. Cancer Treat Rev 2020;86:102024.  https://doi.org/10.1016/j.ctrv.2020.102024
  11. Fashoyin-Aje L, Donoghue M, Chen H, He K, Veeraraghavan J, Goldberg KB, et al. FDA approval summary: pembrolizumab for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma expressing PD-L1. Oncologist 2019;24:103-109. https://doi.org/10.1634/theoncologist.2018-0221
  12. Lee HS. Spatial and temporal tumor heterogeneity in gastric cancer: discordance of predictive biomarkers. J Gastric Cancer 2025;25:192-209. https://doi.org/10.5230/jgc.2025.25.e3
  13. Cho Y, Ahn S, Kim KM. PD-L1 as a biomarker in gastric cancer immunotherapy. J Gastric Cancer 2025;25:177-191. https://doi.org/10.5230/jgc.2025.25.e4
  14. Jardim DL, Goodman A, de Melo Gagliato D, Kurzrock R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell 2021;39:154-173. https://doi.org/10.1016/j.ccell.2020.10.001
  15. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 2017;377:2500-2501. https://doi.org/10.1056/NEJMc1713444
  16. Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 2019;51:202-206. https://doi.org/10.1038/s41588-018-0312-8
  17. Kim HD, Ryu MH, Park YS, Lee SY, Moon M, Kang YK. Insertion-deletion rate is a qualitative aspect of the tumor mutation burden associated with the clinical outcomes of gastric cancer patients treated with nivolumab. Gastric Cancer 2022;25:226-234. https://doi.org/10.1007/s10120-021-01233-1
  18. Lee KW, Van Cutsem E, Bang YJ, Fuchs CS, Kudaba I, Garrido M, et al. Association of tumor mutational burden with efficacy of pembrolizumab±chemotherapy as first-line therapy for gastric cancer in the phase III KEYNOTE-062 study. Clin Cancer Res 2022;28:3489-3498. https://doi.org/10.1158/1078-0432.CCR-22-0121
  19. Turajlic S, Litchfield K, Xu H, Rosenthal R, McGranahan N, Reading JL, et al. Insertion-and-deletionderived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol 2017;18:1009-1021.
  20. Smith CC, Selitsky SR, Chai S, Armistead PM, Vincent BG, Serody JS. Alternative tumour-specific antigens. Nat Rev Cancer 2019;19:465-478. https://doi.org/10.1038/s41568-019-0162-4
  21. Chae YK, Viveiros P, Lopes G, Sukhadia B, Sheikh MM, Saravia D, et al. Clinical and immunological implications of frameshift mutations in lung cancer. J Thorac Oncol 2019;14:1807-1817. https://doi.org/10.1016/j.jtho.2019.06.016
  22. Sui M, Li Y, Wang H, Luo Y, Wan T, Wang X, et al. Two cases of intrahepatic cholangiocellular carcinoma with high insertion-deletion ratios that achieved a complete response following chemotherapy combined with PD-1 blockade. J Immunother Cancer 2019;7:125. https://doi.org/10.1186/s40425-019-0596-y
  23. Lai Z, Markovets A, Ahdesmaki M, Chapman B, Hofmann O, McEwen R, et al. VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res 2016;44:e108.  https://doi.org/10.1093/nar/gkw227
  24. Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandalà M, Ryu Mh, et al. The association of tissue tumor mutational burden (tTMB) using the Foundation Medicine genomic platform with efficacy of pembrolizumab versus paclitaxel in patients (pts) with gastric cancer (GC) from KEYNOTE-061. J Clin Oncol 2020;38:4537. https://doi.org/10.1200/JCO.2020.38.15_suppl.4537
  25. Kim J, Kim B, Kang SY, Heo YJ, Park SH, Kim ST, et al. Tumor mutational burden determined by panel sequencing predicts survival after immunotherapy in patients with advanced gastric cancer. Front Oncol 2020;10:314. https://doi.org/10.3389/fonc.2020.00314
  26. Wang F, Wei XL, Wang FH, Xu N, Shen L, Dai GH, et al. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432. Ann Oncol 2019;30:1479-1486. https://doi.org/10.1093/annonc/mdz197
  27. Park YG, Kim HD, Hyung J, Park YS, Ryu MH. Factors associated with the efficacy of first-line nivolumab plus chemotherapy in advanced gastric cancer patients with deficient mismatch repair. Gastric Cancer 2024;27:840-849.
  28. Lei M, Janjigian YY, Ajani JA, Moehler M, Wang X, Shen L, et al. Abstract CT023: nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 biomarker analyses. Cancer Res 2022;82:CT023-CT023. https://doi.org/10.1158/1538-7445.AM2022-CT023
  29. Hempel L, de Oliveira JV, Gaumann A, Milani V, Schweneker K, Schenck K, et al. Landscape of biomarkers and actionable gene alterations in adenocarcinoma of GEJ and stomach-a real world data analysis. Cancers (Basel) 2021;13:4453. https://doi.org/10.3390/cancers13174453
  30. Kim R, Kim S, Oh BB, Yu WS, Kim CW, Hur H, et al. Clinical application of whole-genome sequencing of solid tumors for precision oncology. Exp Mol Med 2024;56:1856-1868. https://doi.org/10.1038/s12276-024-01288-x
  31. Vokes NI, Liu D, Ricciuti B, Jimenez-Aguilar E, Rizvi H, Dietlein F, et al. Harmonization of tumor mutational burden quantification and association with response to immune checkpoint blockade in nonsmall-cell lung cancer. JCO Precis Oncol 2019;3:PO.19.00171. https://doi.org/10.1200/PO.19.00171