Work

456 External validation of the SITC consensus definitions of primary and secondary resistance to immune checkpoint inhibitors in patients with solid tumors

Year: 2026

Type: conference-paper

Abstract: Background The Society for Immunotherapy of Cancer (SITC) proposed consensus definitions of primary and secondary resistance to immune checkpoint inhibitors (ICIs) in 2020 and 2023 to standardize resistance classification across clinical trials and practice. 1 2 However, real-world validation of these consensus criteria remains limited. We evaluated the prognostic performance of the SITC resistance framework and assessed whether alternative resistance cutoffs improved prognostic discrimination.Methods We conducted a retrospective cohort study of adult patients with solid tumors treated with ICIs at the American University of Beirut Medical Center, a tertiary care center in the MENA region. Patients were classified according to the 2020 SITC ICI Monotherapy consensus definitions as non-resistant, primary resistant, or secondary resistant. The primary endpoint was overall survival (OS), and secondary endpoints included duration of response (DOR) and the evaluation of alternative resistance cutoffs, with landmark OS analyses performed descriptively. Survival outcomes were evaluated using Kaplan-Meier analysis and Cox proportional hazards modeling, with model discrimination assessed via the concordance statistic (C-statistic).Results Of 676 patients treated with ICIs, 608 met initial eligibility criteria, and 595 were classified according to the SITC resistance framework (176 non-resistant, 125 secondary resistant, and 294 primary resistant). OS differed significantly across resistance categories (log-rank p < 0.0001; figure 1), with median OS of 31.4, 31.4, and 12.2 months for the non-resistant, secondary resistant, and primary resistant groups, respectively. In multivariable analysis, secondary resistance (adjusted hazard ratio [aHR] 2.15, 95% CI 1.06-4.35; p = 0.034) and primary resistance (aHR 6.99, 95% CI 3.58-13.60; p < 0.001) independently predicted worse OS. The SITC resistance classification remained an independent predictor of OS, with consistent findings across sensitivity analyses. Landmark OS analysis demonstrated sustained separation across resistance categories through 24 months, and a cutoff refinement analyses at 3, 6, 9, 12, 18, and 24 months showed that a 3-month cut point yielded a marginally higher C-statistic (0.774) compared with the SITC original 6-month definition (0.768), a difference that was statistically detectable but clinically negligible (table 1). The median DOR progressively decreased from non-resistant to secondary and primary resistance (36.6, 13.7, and 3.2 months).Conclusions SITC consensus definitions of primary and secondary ICI resistance demonstrated strong prognostic validity in an independent real-world cohort. Although earlier cutoffs produced marginally higher statistical discrimination, the improvement was unlikely to be clinically meaningful, supporting continued use of the current SITC consensus definitions in both clinical research and practice. Future integration of translational and biomarker data may further improve resistance stratification and prognostication.References Kluger HM, Tawbi HA, Ascierto ML, Bowden M, Callahan MK, Cha E, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer. 2020 Mar;8(1):e000398.Rizvi N, Ademuyiwa FO, Cao ZA, Chen HX, Ferris RL, Goldberg SB, et al. Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy. J Immunother Cancer. 2023 Mar;11(3):e005920.Ethics Approval The study was approved by the Institutional Review Board of the American University of Beirut (IRB ID: BIO-2024-0295). The requirement for informed consent was waived given the retrospective nature of the study.Abstract 456 Figure 1 Kaplan-Meier overall survival curves according to SITC resistance categoryAbstract 456 Table 1Cut point refinement analysis

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0456