# Targeted Therapy in Metastatic Bladder Cancer: Present Status and Future Directions
## 4 Targetting ErbB Receptor Family Signaling  
The ErbB family consists of four RTKs: epidermal growth factor receptor (EGFR, also called HER-1 or ErbB-1), HER2 (also called ErbB-2 or HER-2/Neu), HER3 (ErbB3), and HER4 (ErbB4) [26]. Of these, EGFR and HER-2 have been implicated in BC. EGFR gene amplifications have been described in 9-14% of MIBC cases [9; 27]. EGFR expression is enriched in the basal/squamous subtype [7; 27]. Likewise, the activity of the EGFR regulon is also increased in basal/squamous tumors [7; 28]. The basal/squamous expression subtype is a major MIBC subtype, found in approximately 35% of MIBC patients and is associated with poor outcome after radical cystectomy [7]. Despite upregulated EGFR mRNA expression and increased activity of the EGFR regulon in basal/squamous MIBC, the EGFR targeting antibody cetuximab did not show any additional benefit over gem/cis in patients with mUC, irrespective of the EGFR status [29]. HER2 is amplified or mutated in 9% of MIBC cases [8; 9; 10; 30]. A study of 90 MIBC patients treated with cystectomy showed that HER2 overexpression detected using immunohistochemistry (IHC) was associated with a lower recurrence-free and cancer-specific survival [31]. In contrast, a larger study that compared two primary tumor samples with two matched lymph node metastasis from 137 patients using fluorescence in situ hybridization (FISH) and IHC could not confirm these findings; while HER2 amplifications in primary tumors were associated with lower overall survival, there was poor concordance between the HER2 gene amplifications (using FISH) and protein expression (using IHC) [30]. Interestingly, a higher frequency of HER2 amplifications was described in lymph node metastases compared to primary MIBC tumor samples (15.3% vs. 8.7%) [30]. Thus, while HER2 amplifications seem to be associated with a poor prognosis and more frequent tumor progression, the prognostic implications of HER2 overexpression are currently unclear. Both HER2 amplification and overexpression are well-validated biomarkers for anti-HER2 targeted therapy in breast and gastric cancers but clinical trials investigating HER2 inhibition in MIBC patients with HER2 or EGFR alterations have not been promising. Treatment with lapatinib, an EGFR/HER2 specific small-molecule inhibitor, showed no efficacy over that of a placebo in a phase III trial in mUC patients with positive EGFR and HER2 expression [32]. Furthermore, HER2 inhibition with the monoclonal antibody trastuzumab in conjunction with gem/cis or gemcitabine and carboplatin (gem/carbo) did not yield additional clinical benefit in mUC patients with HER2 overexpression, compared to chemotherapy alone [33]. \begin{table}
\begin{tabular}{c c c} \hline
**Drug** & **Target** & **Clinical Trials** \\ \hline
**erdafitinib** & FGFR1-4 & NCT03473743, NCT02465060 (MATCH) \\ \hline infrigratinib (BGJ-398) & FGFR1-3 & NCT04197986 (PROOF 302), \\ \hline
**AZD4547** & ** FGFR1-4, Kit, CSF1R** & NCT02546661 (BSCAY), NCT02465060 \\ \hline
**(MATCH)** \\ \hline
**rogaratinib (BAY 116.3877)** & FGFR1-4 & NCT03410693 (PORT-1) \\
**derazantinib (ARQ 087)** & ** FGFR2** & NCT04045613 (FIDES-02) \\ \hline
**afatinib (BIBW2992)** & ErbB1-4 & NCT02780687 (LUX Bladder-1) \\ \hline
**trastuzumab denxtacean (DS-8201a)** & ErbB2 & NCT03823572 \\ \hline
**cabozantinib (XL184)** & VEGFR, c-MET, AXI, RET & NCT01688999, NCT0386632, NCT03824691 \\
**copanlish (XL184)** & **VEGF, c-MET, AXI, RET & NCT01688999, NCT0386632, NCT03824691 \\
**copanlish (XL184)** & **mTOR** & **NCT012465060 (MATCH)** \\
**cogk** **cogkBiological differences between MIBC and breast cancer might provide an explanation why HER2-targeted therapy has not been as successful in MIBC as in breast cancer. Differences in response to HER2-targeted therapy observed between breast cancer and mUC patients might be explained by dissimilar HER-2 mutations driving tumor growth.