Novel Therapies in Urothelial Carcinoma

A Biomarker-Driven Approach

G. Iyer; J. E. Rosenberg


Ann Oncol. 2018;29(12):2302-2312. 

In This Article

Re-conceptualizing Targeted Therapy

Platinum Chemotherapy as Targeted Therapy

As discussed above, cisplatin-based combinations remain the standard-of-care for NAC. Cisplatin-based NAC is associated with improved survival, with a 14%–25% relative risk reduction for death from muscle-invasive UC.[64,66] The benefits of this approach are most apparent in patients with pathologic down-staging at the time of surgical resection, but the molecular determinants of response to cisplatin are unproven. Identifying extreme responders to platinum chemotherapy would therefore allow targeting of this treatment to those who would benefit most, and spare those who would not from the side-effects of treatment.

Of note, somatic genomic alterations in DNA damage repair (DDR)-associated genes have been associated with benefit from both NAC and PD1/PD-L1 blockade. An initial extreme responder analysis of patients with complete responses or residual carcinoma in situ within the bladder following neoadjuvant cisplatin-based chemotherapy and RC for muscle-invasive disease versus patients with residual muscle-invasive or higher stage disease identified point mutations within the DNA helicase ERCC2 as strongly associated with response (9 of the 25 responders harbored ERCC2 mutations versus 0 of 25 nonresponders). These results have since been validated in a separate cohort of patients receiving NAC for muscle-invasive bladder cancer as part of a clinical trial in which ERCC2 mutations were also associated with improved survival.[67] A subsequent retrospective analysis of 100 patients with locally advanced or metastatic UC who underwent exon capture sequencing revealed an association between the presence of DDR gene alterations and improved progression-free and overall survival.[68] In this analysis, a higher mutation load was observed in DDR gene altered tumors. Defects in other DDR genes, including RB1, ATM, and FANCC, were detected in patients who responded to NAC.[69] Emerging evidence also suggests an association between overall response to PD1/PD-L1 blockade and the presence of somatic DDR alterations.[70]

A high frequency of patients with germline DDR mutations has also been reported. In a recent study, 12/25 pathogenic or likely pathogenic mutations in 22 patients with urothelial cancer originating from all sites within the urinary tract had heritable DDR gene alterations in CHEK2, BRCA1, BRCA2, ATM, BRIP1, and NBN.[71] The role of these germline alterations will require validation.

Recent research suggests that RNA expression of noncoding microRNAs may contribute to the control of gene expression patterns and can identify basal and luminal muscle-invasive bladder cancer subtypes. These could act as biomarkers for tumors with higher infiltration rates and provide candidate therapeutic targets.[72] Molecular subtyping to predict response to NAC in muscle-invasive bladder cancers is also an area which may allow prediction of outcomes with cisplatin-based combination chemotherapy. The benefit of NAC varies between molecular subtypes (as identified by transcriptome-wide microarray analysis), with patients with basal tumors exhibiting a substantial improvement in outcomes with NAC as compared to other subtypes.[73]

Immune-delivery of Cytotoxic Chemotherapy

Antibodies can be used for the targeted delivery of chemotherapeutic molecules to tumor cells in the form of antibody–drug conjugates (ADCs); the monoclonal antibody targets a tumor antigen and cleavage of the linker leads to internalization and liberation of the cytotoxic component. Promising results from early phase studies have been observed with some ADCs in advanced UC. Enfortumab vedotin (ASG-22ME) is an ADC comprising a fully human antibody targeting nectin-4 and the potent microtubule-disrupting agent monomethyl auristatin E (MMAE). Moderate-to-strong staining for nectin-4 has been observed in 60% of bladder tumor specimens, with positive pre-clinical results in vitro and in vivo in several cancer models.[74] Initial interim clinical results show encouraging antitumor activity in patients with metastatic UC treated with enfortumab vedotin.[75] ASG-15ME is an ADC comprising an antibody targeting the bladder tumor antigen SLITRK6 and MMAE. It is in phase I investigation as monotherapy in patients with metastatic UC, with positive results from an exploratory analysis reported.[76] In addition, sacituzumab govitecan (IMMU-132), is an ADC comprising an anti-TROP-2 antibody and the active metabolite of irinotecan (SN-38). TROP2 is a cell-surface receptor over-expressed by many human tumors, including those of the urinary bladder,[77] and in six patients with metastatic, platinum-resistant UC, three had a clinically significant response to sacituzumab govitecan.[37]