Tumor Longevity: a time-dependent biomarker of immune checkpoint inhibitor responsiveness across head and neck, lung, renal and urothelial cancers

BACKGROUND: the duration of tumor persistence within the host-defined as Tumor Longevity (TL) - may capture cumulative biological and immunologic interactions, shaping immunotherapy treatment response. However, the impact of TL on outcomes with immune checkpoint inhibitors (ICI) remains unexplored. We hypothesized that TL may reflect integrated tumor-host dynamics influencing ICI efficacy and investigated this association in patients with head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), renal and urothelial cancer (R/UC). MATERIALS AND METHODS: we conducted a retrospective, observational study including adult patients with advanced HNSCC, NSCLC, R/UC receiving ICI (≥first line) across 2 Italian cancer centers. TL, defined as the time from first histological diagnosis to ICI initiation, was analyzed as a continuous variable using 3-knot restricted cubic spline models. Multivariable logistic and Cox regression analyses assessed associations between TL and disease control rate (DCR), grade (G)≥3 immune-related adverse events (irAEs), and overall survival (OS). RESULTS: 304 patients, diagnosed from 2002 to 2022, started ICI from 2014 to 2022. Median TL was 15.30 months (IQR 5.52-33.05). Overall DCR was 56.25% [95% CI 50.47; 61.91]; CTCAE G ≥ 3 irAEs occurred in 16 (5.2%) patients; 231 (76.0%) patients died. In multivariable analyses, longer TL was associated with higher DCR (OR Q3 vs. Q1 = 3.26; 95%CI 1.24; 8.59, p = 0.004), while no significant associations for G ≥ 3 irAEs (OR = 1.27; 95% CI 0.39-4.12) and OS (HR = 0.79; 95% CI 0.49-1.28; p = 0.407) were observed. CONCLUSIONS: These real-world, hypothesis-raising results suggest that TL may capture clinically relevant information associated with ICI outcomes. TL may represent a pragmatic, time-dependent biomarker integrating tumor behavior and host factors. Prospective and translational studies incorporating TL with molecular and immune profiling are warranted to elucidate whether this association reflects tumor biology, host factors, treatment history, or their combination.