Incidence and clinical outcomes of HER2-altered bladder cancer (BC) patients (pts).

Abstract

556 Background: Bladder cancer has one of the highest rates of human epidermal growth factor receptor 2 (HER2) alteration. Novel HER2-directed agents are being investigated in metastatic BC. We sought to define the incidence and clinical characteristics of HER2-altered BC across disease states. Methods: We retrospectively analyzed our single-institution, clinically annotated cohort of urothelial BC pts with available genomic profiling data (MSK-IMPACT). We quantified the prevalence of HER2 alterations, defined as driver mutation (based on OncoKB), and/or amplification, across BC disease states. We examined the association between HER2 alteration and disease progression and survival. The Kaplan-Meier method was used for time-to-event analyses. Results: A total of 1073 BC pts underwent MSK IMPACT profiling of tumor tissue derived from the following disease states: 36% (n = 380) non-muscle invasive (NMI)BC, 41% (n = 443) muscle invasive (MI)BC, and 23% (n = 250) (met)BC. At initial diagnosis, the median age was 67 years, 77% (n = 822) were male, 86% (n = 928) were white, and 66% (n = 710) were smokers. Overall, 16% (n = 177) of pts had any oncogenic HER2 alteration (Table), including 11% with a HER2 driver mutation and 7% with HER2 amplification The most frequent mutations were S310F (40%, n = 53) and S310Y (14%, n = 19). The rate of HER2 amplification was different among the three groups (p = 0.002), 9% in MIBC and metBC compared to 3% in NMIBC. Among 514 pts with NMIBC, the median time to progression (TTP) to MIBC or metBC was 111.6 months (95% Cl: 85.7-NR). Among NMIBC pts, TTP was significantly shorter for HER2-amplified (n = 17) vs. non-amplified (n = 497) (HR = 1.99, 95%CI: 1.05-3.76, p = 0.034, median 26 vs. 114 months). Among pts with metBC receiving frontline platinum-based chemotherapy (n = 143), the median overall survival (OS) was 25.3 months (95%CI: 18.5-33.9). OS was numerically higher in pts with any oncogenic HER2 alteration (n = 26) compared to wild-type (n = 117) (HR = 0.59, 95% Cl: 0.33-1.07, p = 0.082), though this difference was not statistically significant. The median OS for platinum-refractory metBC pts receiving 2nd line immunotherapy (n = 63) was 10.3 months (95%CI: 7.2-31.6), and the association between OS and HER2 alteration was not significant (HR = 0.57, 95%CI: 0.24-1.37, p = 0.2). Conclusions: HER2 amplification is more frequent in MIBC and metBC than in NMIBC. In NMIBC, HER2 amplification is associated with shorter TTP to MIBC or metBC. HER2 alteration in metBC is associated with a non-significant trend towards improved OS in frontline platinum-treated pts, though this analysis is limited by small sample size.[Table: see text]

Current State of Cell Therapies for Genitourinary Malignancies

“…One trial (NCT03740256) combines the use of a human epidermal growth factor receptor 2 (HER2)–specific CAR T with an immunostimulatory oncolytic virus to enhance immune reactivity. HER2 has been found to be altered in bladder cancer and in a study was found to be altered in 16% of bladder tumors 62,63 . Overall, CAR T cells for the treatment of bladder cancer are in the early stages of clinical development and target antigens that are overexpressed in bladder tumors.…”

“…HER2 has been found to be altered in bladder cancer and in a study was found to be altered in 16% of bladder tumors. 62,63 Overall, CAR T cells for the treatment of bladder cancer are in the early stages of clinical development and target antigens that are overexpressed in bladder tumors.…”

Efficacy of Antibody Drug Conjugates Alone and in Combination with other Agents in Metastatic Urothelial Carcinoma: A Scoping Review

“…HER2 is overexpressed in 12.4% of UC [65,70]. Moreover, potentially targetable HER2 mutations in UC may be underrecognized with a prevalence of 11% and are enriched in tumors with micropapillary histology [71][72][73]. Despite considerable interest in HER2 as a target in UC, trials involving kinase inhibitors, monoclonal antibodies, and even the ADC trastuzumab emtansine (T-DM1) have generated underwhelming efficacy results or concerning toxicity profiles [74,75].…”

HER2 Expression Associated with Clinical Characteristics and Prognosis of Urothelial Carcinoma in a Chinese Population

“… 9 In addition, HER2 amplification is enriched in muscle invasive bladder cancer (MIBC) and metastatic disease compared with non-muscle invasive bladder cancer (NMIBC). 10 Therefore, HER2 alteration might be correlated with aggressive disease in bladder cancer.…”