153P - Efficacy and toxicity of HER2-targeted antibody-drug conjugates (ADCs) in the treatment of metastatic urothelial cancer (mUC): A systematic review

Background

mUC is an aggressive disease with limited overall survival. HER2 overexpression is associated with poor prognosis and occurs in a significant number of patients (pts) with mUC. HER2-targeted ADCs represent a promising strategy in mUC, with multiple ongoing clinical trials. We aimed to realize a systematic review of efficacy and toxicity of anti-HER2 ADCs in mUC.

Methods

A systematic review of the literature was performed in June 2022 according to PRISMA statement. The search method included the terms bladder carcinoma or urothelial carcinoma; disitamab vedotin; HER2-targeted therapy; antibody-drug conjugate. Only prospective clinical trials were included.

Results

Ultimately, 6 phase 1 or 2 clinical trials with 236 pts were selected and 3 drugs were identified: Disatamab vedotin (DV), Trastuzumab Deruxtecan (TDXd), and MRG002. Efficacy outcomes are presented in the table. DV was tested as monotherapy in two phase 2 trials with HER2+ pts (IHC 2 or 3+); the overall response rate (ORR) ranged from 46.9 to 51.2%. Another phase 2 trial tested DV in HER2- pts, ORR was 26 % and disease control rate (DCR) was 94.7%. Preliminary results of DV combined with toripalimab as 1L in cis-ineligible pts or 2L treatment showed a RR of 76.7% and DCR of 96.7%. An ongoing trial is testing MRG002 in HER2+ pts; first results demonstrated ORR of 55% and DCR of 59%. A phase 1b is testing TDXd combined with nivolumab, the ORR was 36.7%, with a median duration of response of 13.1 months. There is a remarkable heterogeneity of HER2 positivity definition among the studies. However, subgroup analysis in all trials suggest some association between the level of HER2 expression and efficacy. TRAE occurred in 100% of included pts, incidence of G3 ranged from 15.8% to 73.5%. Most commons AE were hypoesthesia, alopecia, AST/ ALT increase and hematologic toxicity. Notably, pneumonitis occurred in 23.5% of patients treated with TDXd + nivolumab Table: 153P

Conclusions

HER2-targeted ADCs are associated with high response rates in the treatment of mUC, including responses in HER2- pts. DV received FDA breakthrough therapy designation in 2020 for 2L treatment of HER2+ mUC. Confirmatory trials and better biomarker-based patient selection are needed.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.