Disitamab vedotin + PD-1 blockade shows comparable short-term OS, favorable DFS/PFS trends vs. gemcitabine/cisplatin in high-risk UTUC.
Background
For patients with high-risk upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy, adjuvant chemotherapy with gemcitabine/cisplatin (GC) is a standard option, but its efficacy is limited, and patients often experience recurrence and significant toxicity. There's a critical need for more effective and tolerable adjuvant strategies. The combination of disitamab vedotin, an antibody-drug conjugate targeting HER2, with PD-1 inhibitors has demonstrated synergistic potential in advanced urothelial carcinoma, offering a promising alternative mechanism to improve outcomes in this high-risk population.
Study Design
This single-center, two-stage observational study enrolled 421 patients with high-risk upper tract urothelial carcinoma. Cohort A evaluated adjuvant GC versus surgery alone using propensity score matching. Cohort B compared adjuvant GC with disitamab vedotin plus PD-1 blockade (ADC+ICI) using overlap weighting, adjusting for ECOG performance status and HER2 IHC category. In Cohort B, 48 patients received gemcitabine/cisplatin and 53 received disitamab vedotin plus PD-1 blockade. Primary endpoints included overall survival (OS), conventional disease-free survival (DFS), non-intravesical progression-free survival (PFS), intravesical recurrence-free survival (IVRFS), and safety.
Results
In Cohort B, after overlap weighting, baseline covariates were well balanced between the ADC+ICI and GC groups. Adjuvant ADC+ICI was not associated with a statistically significant OS improvement versus GC, showing a Hazard Ratio (HR) of 0.47 (95% CI 0.12-1.89; P = 0.287; FDR-adjusted P = 0.403). However, directionally favorable associations were observed for several key endpoints. >Conventional DFS showed a favorable trend with an HR of 0.32 (95% CI 0.11-0.96; nominal P = 0.043; FDR-adjusted P = 0.172). Non-intravesical PFS also trended favorably (HR 0.32, 95% CI 0.09-1.18; P = 0.086), as did IVRFS (HR 0.21, 95% CI 0.04-1.09; P = 0.063). Exploratory analyses suggested that HER2 IHC 2+/3+ tumors might derive particular benefit, showing favorable DFS/PFS signals. Grade ≥3 treatment-related adverse events were similar between both treatment groups.
Key Findings
- Adjuvant disitamab vedotin + PD-1 blockade showed comparable short-term OS vs. GC (HR 0.47, P = 0.287).
- Directionally favorable conventional DFS was observed with ADC+ICI (HR 0.32, nominal P = 0.043).
- Non-intravesical PFS also trended favorably with ADC+ICI (HR 0.32, P = 0.086).
- Intravesical recurrence-free survival showed a favorable trend with ADC+ICI (HR 0.21, P = 0.063).
- Exploratory analysis suggested
HER2 IHC 2+/3+tumors might have favorable DFS/PFS signals with ADC+ICI.
Why It Matters
This study suggests that adjuvant disitamab vedotin plus PD-1 blockade could be a viable alternative to gemcitabine/cisplatin for high-risk UTUC, offering comparable short-term overall survival with potentially improved disease-free and progression-free survival trends, alongside a distinct toxicity profile. For patients intolerant to cisplatin or seeking alternative adjuvant strategies, this combination presents a promising, albeit currently hypothesis-generating, option. While not yet a definitive protocol, these real-world data provide crucial early signals for clinicians and researchers, indicating a need for prospective validation to establish its role in standard care. The exploratory HER2 stratification also hints at a potential biomarker-driven approach for patient selection.
disitamab vedotin
pd-1 inhibitor
urothelial carcinoma
utuc
adjuvant therapy
her2