Enfortumab vedotin (EV) represents a novel treatment for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) refractory to platinum-based chemotherapy and PD(L)-1 containing therapies. Real-world data are crucial for informing health policy decisions and validating clinical trial findings. We conducted a multicentre, retrospective real-world analysis comprising 128 patients with la/mUC from 16 Austrian centres treated with EV from April 2022 to April 2024, presenting the second largest real-world cohort to date. Data were analysed for efficacy and safety parameters. The median age was 69 years, the objective response rate 31% and the disease control rate 47%, with 9% of patients exhibiting a complete remission, 23% a partial remission and 16% a stable disease. After a median follow-up of 6.2 months, the median progression-free survival (mPFS) and the median overall survival (mOS) reached 4.8 and 10.75 months, respectively. Patients with good ECOG PS 0-1, metachronous metastatic disease and absence of liver metastases had significantly better OS. No difference in efficacy was observed in patients who received a reduced dose EV after experiencing adverse events. The safety profile was acceptable, showing grade ≥3 TRAEs in 25.8% of patients. In our real-world population, the administration of EV was feasible and effective, with no new safety signals. Lower efficacy data compared to previous trials might be explained by the use in later therapy lines and in patients with poorer ECOG PS. Our data corroborate the efficacy and safety of EV monotherapy in later lines.

Introduction: Combinations of immune-checkpoint inhibitors (ICIs) are the standard of care (SOC) for treatment-naive metastatic renal cell carcinoma (mRCC) patients. In this multicenter study, we evaluated the RW safety and efficacy of cabozantinib plus nivolumab in mRCC patients. Methods: Data were retrospectively collected from twelve cancer centers in Germany, Switzerland, and Austria. Patients with advanced or mRCC were eligible. The investigator-based objective response rate (ORR) and progression free survival (PFS) were calculated from the start of the treatment to progression or death. Descriptive statistics and Kaplan–Meier (KM) plots were utilized where appropriate. Results: In total, 96 eligible patients (66.6% male) with a median age of 66.0 years were included. The most common histology was clear-cell RCC (ccRCC) in 63.4% (n = 61). A prior nephrectomy was performed in 60.4% (n = 58). ECOG 0-1 was 68.8% (n = 66). A partial response was documented in 43.8% of patients (n = 42), a stable disease in 32.3% (n = 31), and a progressive disease in 8.3% (n = 8) as the best overall response. Response data were not evaluable in 13.5% (n = 13). The median follow-up time was 12.7 months (95% CI, 10.0–15.3). The PFS rate at 6 months was 89.8% in the overall population (86.8% for ccRCC; 90.0% for non-ccRCC). Adverse events (AEs) were reported in 82.3% (n = 79) for all grades and 41.7% (n = 40) for grades 3–5. Elevated liver enzymes (34.4%), diarrhea (31.3%), and hand–foot syndrome (29.2%) were the three most frequent AEs of any grade and causality. Discussion/Conclusions: In this real-world cohort of mRCC patients, the application of cabozantinib plus nivolumab was shown to be safe and feasible. Our data support the use of cabozantinib plus nivolumab as a first-line standard therapy in mRCC patients. Major limitations were the retrospective data capture and short follow-up time of our study.

Antibody‐drug conjugates (ADCs) and immunotherapy have changed the treatment landscape for locally advanced and metastatic urothelial carcinoma (la/mUC). Clinical trials have demonstrated the superiority of enfortumab vedotin (EV) combined with pembrolizumab (P) over chemotherapy. This retrospective, multicentre Austrian registry analysis evaluated the effectiveness and safety of EV + P in treatment‐naïve la/mUC patients in a real‐world setting. This study included 203 first‐line EV + P treated patients from 20 Austrian centres. The majority were male (77.3%), with a median age of 70 years (range, 26–92), while 33.5% were ≥75 years. Comorbidities were common, with 25.1% having a Charlson Comorbidity Index (CCI) ≥ 5, and 46.3% moderate to severe renal impairment. Among 195 evaluable patients, the objective response rate (ORR) was 63.6% (95% CI, 56.6–70.0), including 21.5% complete responses and 42.1% partial responses. Disease control was achieved in 75.4% (95% CI, 68.9–80.9). Median progression‐free survival (PFS) and overall survival (OS) were not reached after a median follow‐up of 5.8 months. Poor outcomes were associated with ECOG PS >2 (PFS, p = .003; OS, p < .001) and CCI ≥5 (PFS, p = .011; OS, p = .08). EV + P was generally well tolerated; grade ≥3 treatment‐related adverse events occurred in 38.4% of patients and immune‐related adverse events in 19.2%. Limitations of this study include its retrospective design and short follow‐up. These findings support the clinical use of EV + P as first‐line treatment for la/mUC, demonstrating substantial effectiveness and manageable toxicity in a large real‐world population, including elderly and comorbid patients. Extended follow‐up is warranted to determine long‐term survival and predictive markers of response.

We aimed to investigate the effectiveness of oncological treatments in metastatic CRC related to comorbidities and age. This retrospective study included 1105 patients from three oncological centers. aaCCI and CCI was available from 577 patients. An aaCCI > 3 was of the highest predictive value compared to other aaCCI-levels, CCI or age (p < 0.001 for all). Treatment (best supportive care (BSC), systemic treatment only (STO) and resection of metastases (ROM)) significantly prolonged survival in patients with aaCCI > 3 (STO: HR 0.39, CI 0.29–0.51; ROM: HR 0.16, CI 0.10–0.24) and patients older than 70 years (STO: HR 0.56, CI 0.47–0.66; ROM: HR 0.23, 0.18–0.30). Median overall survival was shorter in patients with aaCCI or age > 70 years and interaction for treatment type not significant for aaCCI, but significant for age older or younger than 70 years (STO: p = 0.01; ROM p = 0.02). BSC is more often considered as optimal care for patients with an aaCCI > 3 (37.6% vs. 12.4%; p < 0.001) or age > 70 years (35.7% vs. 11.2%; p < 0.001). Older patients or patients with comorbidities benefit from cancer-specific therapy independently of their age and comorbidities.

Purpose: Enfortumab vedotin (EV) is standard therapy for metastatic urothelial carcinoma (mUC), yet the predictive relevance of Nectin cell adhesion molecule 4 (NECTIN4) expression—especially membranous versus cytoplasmic—remains unclear. In this study, we sought to extend previous findings on NECTIN4 gene amplification in parallel with a systematic subcellular evaluation of Nectin-4 expression. Experimental Design: We retrospectively analyzed 179 EV-treated patients with mUC. NECTIN4 amplification was assessed by fluorescence in situ hybridization (FISH) and Nectin-4 protein levels by immunohistochemistry (IHC). A four-tier membranous scoring algorithm (0, 1+, 2+, and 3+) adapted from the College of American Pathologists (CAP) HER2 gastric guidelines was benchmarked against H-score. We integrated amplification status with membranous staining to refine predictive stratification and compared associations with objective response rate (ORR) with those observed in EV-301 data. Results: Combining membranous and cytoplasmic compartments resulted in a median composite H-score of 260 (78.2% ≥ 150), closely matching Nectin-4 expression prevalence reported in EV-301 (median, 250; 82.6% ≥ 150). A ≥150 cutoff enriched for EV responders in both cohorts, with an ORR of 45.8% versus 20% (P = 0.001) in EV-301. High membranous expression based on the scoring (2+/3+) predicted response (ORR, 55.1% vs. 25.5%; P < 0.001), with longer progression-free survival [PFS; 7.1 vs. 2.9 months; hazard ratio (HR) = 0.45] and overall survival (OS; 12.3 vs. 6.9 months; HR = 0.57), whereas cytoplasmic expression lacked predictive value. NECTIN4-amplified tumors showed particularly favorable outcomes (PFS, 12.2 months; OS, 30.1 months). An integrated three-tier model—amplified, nonamplified/high-membranous, and nonamplified/low-membranous—yielded ORRs of 77.2%, 42.9%, and 26.1% and separated survival outcomes. Conclusions: Our Nectin-4 scoring system integrating NECTIN4 amplification with membranous Nectin-4 expression accurately predicts outcomes, supporting combined genomic and membranous assessment as complementary biomarkers for optimizing EV selection. See related article by YYY, p. XX .