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Background ICIs, with or without tyrosine kinase inhibitors (TKIs), represent the backbone first-line treatment for patients (pts) with mccRCC. While multiple ICI-based regimens are approved in the metastatic setting, limited data exist on the efficacy of ICI rechallenge after progression on prior ICI-based therapy.Methods Using the TriNetX research database, we conducted a large-scale, retrospective outcome analysis of pts with mccRCC treated with at least two lines of ICI-based therapy across major international healthcare institutions. Descriptive statistics were used to characterize the cohort. Kaplan-Meier analysis estimated progression-free survival (PFS) and overall survival (OS) following ICI rechallenge. Propensity score matching (PSM) was applied to adjust for age, sex, stage at diagnosis, metastatic sites, and type of prior ICI.Results Among 6,737 pts with mccRCC, 288 (201 M, 87 F) received ≥2 lines of ICI between 2016 and 2024. The baseline mean age was 63.8 years. The most common first-line regimens were nivolumab (N) + cabozantinib (44.1%), N + ipilimumab (26.5%), pembrolizumab (P) + axitinib (20%), and P + lenvatinib (8.4%). The most frequent ICI rechallenge sequences were: N > N (47.6%), P > P (22.2%), N > P (17%), and P > N (13.2%). At diagnosis, 37% had stage IV disease. Median duration of prior ICI therapy was 19.5 months, and the median interval between ICI therapies was 8.91 months ( table 1). After a median follow-up of 19.3 months, median OS following ICI rechallenge was 33.2 months, and median PFS was 8.54 months. PFS was comparable across treatment sequences: N>N (8.05 months), P>P (7.44 months), N>P (9.21 months), and P>N (7.0 months). Median PFS following N + ipilimumab was 7.9 months (range 0.1–55), compared to 8.55 months (range 0.3–69.9) after ICI+TKI. Pts rechallenged ≥6 months after prior ICI had longer median PFS (8.8 vs. 5.2 mos) and OS (34.9 vs. 19.4 mos; p = 0.014); trends were similar for the ≥12-month subgroup (OS: 34.9 vs. 25.9 mos; p = 0.312). After PSM adjustment, the efficacy of ICI rechallenge appeared to be independent of all matched covariates when comparing the <6-month and ≥6-month subgroups (p = 0.05) (figure 1).Conclusions Our results outline opportunities for ICI rechallenge, regardless of the prior immunotherapy administered. Improved outcomes with longer intervals (≥6 months) between treatments suggest timing is a key driver of efficacy and should be investigated in prospective trials.Abstract 450 Table 1Characteristics of the selected patients before starting rechallenge ICI Abbreviations: ICI: immune-checkpoint inhibitor; PD-L1: programmed death-ligand-1*ICIs were admitted as single agents or in combinationsAbstract 450 Figure 1Kaplan-Meier curves for OS by time to ICI rechallenge. Median OS was 34.9 months for rechallenge ≥ 6 months vs. 19.4 months for rechallenge at <6 months (log-rank p = 0.014). HR = 1.693; 95% CI: 1.108–2.585