HPV-stratified tissue factor expression and multi-omic correlates of overall survival after tisotumab vedotin in cervical cancer.

5537 Background: Cervical cancer (CxC) is heterogeneous, and the impact of HPV status on outcomes with tisotumab vedotin (TV; tissue factor [TF/F3]–targeted ADC) remains incompletely defined. We evaluated HPV-stratified associations between TF expression and real-world overall survival (OS) after TV and explored molecular correlates of long vs short survival. Methods: 274 CxC patients who received TV (HPV+, n=106; HPV-, n=45) underwent DNA and RNA sequencing. HPV16/18/31/33/45 status was determined from whole exome sequencing (WES). Real-world OS was calculated from first TV claim to death/last contact. Hazard ratio (HR) was estimated by Cox proportional hazards, with p-value using log-rank test. TFH was defined as TF (F3) expression (RNA-seq normalized expression) ≥ the cohort-specific median (median split) among TV-treated cases with available data. For transcriptomic comparisons, LS (long survival) and SS (short survival) were defined as above-median vs below-median OS after TV within each HPV stratum, respectively. Results: Among TV-treated patients with available TF/OS data, TFH vs TFL showed no statistically significant OS difference in the overall cohort (n=195; TFH n=98 vs TFL n=97; median OS 11.73 vs 9.79 months; HR 0.765; log-rank p=0.142) or in the HPV+ cohort (n=69; TFH n=35 vs TFL n=34; median OS 10.22 vs 10.35 months; HR 0.602; log-rank p=0.138). In contrast, in the HPV− cohort (n=27; TFH n=14 vs TFL n=13), TFH was associated with improved OS (median OS 21.81 vs 9.79 months; HR 0.251, 95% CI 0.065–0.977; log-rank p=0.032). Transcriptomic profiling suggested HPV-dependent survival: in HPV− patients, LS was enriched for cell-cycle/DDR, and energy metabolism pathways (e.g., p53 pathway NES 1.86; FDR-adjusted p<0.0001), whereas in HPV+ patients, SS was enriched for inflammatory pathways (e.g., interferon-γ response NES −2.25; FDR-adjusted p<0.0001; TNF–NFκB) and LS for tumor-intrinsic metabolic/drug-handling and coagulation-related pathways (e.g., Xenobiotic metabolism, NES 2.13, FDR-adjusted p=0.0021; Coagulation). In the HPV+ cohort, exploratory genomic correlates of survival included enrichment of ARID1A pathogenic mutations (3/18, 16.7% LS vs 0/41, 0% SS; p=0.0073) and AKT2 amplifications (2/17, 11.8% LS vs 0/39, 0% SS; p=0.0292), consistent with tumor-intrinsic pathway alterations in LS. Conclusions: TF expression and HPV status may interact in TV-treated cervical cancer. While TFH was not associated with OS in the overall or HPV+ cohorts, TFH was associated with improved OS in HPV− disease. HPV-stratified transcriptomic analyses further suggest distinct biological contexts of benefit and lack thereof, supporting the need to HPV-stratified biomarker analyses for evaluating TV benefit in CxC, potentially extending to other ADCs, and motivating validation in independent datasets.