Abstract: FR-OR003
Differential Nephrotoxicity of Antibody-Drug Conjugate Payloads: A Propensity Score-Matched Analysis of Monomethyl Auristatin E vs. Topoisomerase I Inhibitors
Session Information
- Advancing Onconephrology Precision: Biomarkers, Therapeutic Targets, and Patient Outcomes
October 23, 2026 | Location: Room 401, Convention Center
Abstract Time: 04:50 PM - 05:00 PM
Category: Onconephrology
- 1600 Onconephrology
Authors
- Capriles, Guido M., TriHealth Inc, Cincinnati, Ohio, United States
- Sabbagh, Bana, TriHealth Inc, Cincinnati, Ohio, United States
- Khan, Fayaz Aijaz Ahmed, TriHealth Inc, Cincinnati, Ohio, United States
- Rajput, Amit K., TriHealth Inc, Cincinnati, Ohio, United States
Background
Antibody-drug conjugates (ADCs) cause renal adverse events like acute kidney injury (AKI), but determining causality is confounded by indication bias. Monomethyl Auristatin E (MMAE) payloads are heavily used in urothelial carcinoma, a population with high baseline rates of obstructive uropathy and platinum exposure. Topoisomerase-I (Topo-I) payloads are used in populations with preserved baseline renal function (e.g., breast cancer). We aimed to determine if MMAE-associated AKI is driven by patient comorbidities or intrinsic payload toxicity.
Methods
We conducted a retrospective study using the FDA Adverse Event Reporting System (Q1 2019-Q1 2025). Reports for five major ADCs were grouped by payload: MMAE (enfortumab, polatuzumab, brentuximab) vs. Topo-I controls (sacituzumab, trastuzumab deruxtecan). The primary outcome was AKI. To isolate payload toxicity from indication bias, we used 1:1 propensity score matching (PSM) adjusting for age, sex, reporting year, urothelial carcinoma indication, and concomitant nephrotoxins (platinum, immunotherapy, PPIs, NSAIDs). The adjusted reporting odds ratio (aROR) was calculated via logistic regression on the matched cohort, alongside an E-value for sensitivity analysis.
Results
Pre-match (N=4,237), the MMAE cohort (n=2,455) had a significantly higher prevalence of urothelial carcinoma (47.6% vs. 7.0%) and platinum use (14.2% vs. 4.4%) than Topo-I controls (n=1,782). PSM successfully balanced the cohorts, yielding 3,564 matched patients (1,782 pairs; SMD <0.1 for all covariates). In the matched analysis, the MMAE payload was associated with a 3.93-fold higher odds of AKI compared to Topo-I (aROR 3.93; 95% CI 2.75–5.76; p<0.001). This signal persisted despite strict adjustments for bladder cancer and prior nephrotoxins. The association was highly robust against unmeasured confounding (E-value=7.32). High AKI rates were consistent across the MMAE class, including non-urothelial agents like polatuzumab (8.5%).
Conclusion
This propensity-matched analysis demonstrates that ADC-associated nephrotoxicity is an independent class effect of the MMAE payload, not merely an artifact of the urothelial cancer population. Payload class serves as a critical risk stratification tool, warranting intensive renal monitoring for patients receiving MMAE therapies.