Emergence of human epidermal growth factor receptor 2 as a key biomarker and therapeutic target in advanced urothelial carcinoma

Table 1 Pivotal clinical trials in the management of human epidermal growth factor receptor 2+ locally advanced or metastatic urothelial carcinoma

Ref.	Study design	Population	Treatment arms	Outcomes	Safety profile
Hussain et al[14], 2007	Phase II, multicenter	109 patients with la/mUC; 57 patients (52%) with confirmed HER2 amplification	Trastuzumab + paclitaxel + carboplatin + gemcitabine	ORR: 70%; PFS: 9.3 months; OS: 14.1 months	Significant hematologic toxicity (neutropenia); peripheral neuropathy; limited cardiac toxicity
Oudard et al[15], 2015	Phase II, randomized, multicenter	75 patients with 1 L la/mUC overexpressing HER2 (IHC 3+ or FISH+)	Experimental arm: Gemcitabine + platinum + trastuzumab; control arm: Gemcitabine + platinum (cisplatin or carboplatin)	ORR: 44% vs 44% (P = NS); PFS: 8.2 months vs 6.1 months (HR = 0.89, P = 0.47); OS: 15.7 months vs 12.2 months (HR = 0.79, P = 0.29); NS benefit from adding trastuzumab to chemotherapy	Similar toxicity profile between arms; no significant increase in cardiac toxicity with trastuzumab
RC48-C005/RC48-C009 (Sheng et al[18], 2025)	Phase II	107 patients with pretreated la/mUC, all with HER2+ expression (IHC 2+ or 3+)	DV monotherapy	ORR: 50.5%; median PFS: 5.6 months; median OS: 14.2 months	Peripheral neuropathy (68.2%); myelosuppression; AST increase (42.1%)
DESTINY-PanTumor02 (Investigation of T-DXd)[20], 2023	Phase II, tumor-agnostic	41 patients with la/mUC, HER2-expressing (IHC 2+ or 3+), progressed after ≥ 1 systemic therapy, median 2 prior lines of therapy	T-DXd	ORR (all patients): 39.0%; ORR (IHC 3+): 56.3%; ORR (IHC 2+): 35.0%; median DOR: 11.8 months (overall)	Grade ≥ 3; AEs: 58.4%; treatment discontinuation due to AEs: 11.6%; adjudicated ILD/pneumonitis: 6.7% (G1-2: 6.4%; G5: 0.4%)
RC48-C016 (Sheng et al[18], 2025)	Phase III	1 L la/mUC patients with HER2 expression (IHC 1+, 2+ or 3+), prior platinum therapy not allowed	Experimental arm: DV + toripalimab; control arm: Platinum-based chemotherapy	PFS: 13.1 months vs 6.5 months (HR = 0.36); OS: 31.5 months vs 16.9 months (HR = 0.54); benefit consistent across all HER2 expression levels	Grade ≥ 3; TRAEs: 55.1% vs 86.9%; DV + toripalimab combination was better tolerated than chemotherapy
MYRETHA trial (RC48 in combo)	Phase II/III	1 L and 2 L settings for la/mUC, exploring combinations with immunotherapy	Multiple arms: DV ± immune checkpoint inhibitors	Primary outcomes pending; aims to establish optimal combination strategy	Safety profile under investigation, expected to be manageable based on prior data

la/mUC: Locally advanced or metastatic urothelial carcinoma; HER2: Human epidermal growth factor receptor 2; IHC: Immunohistochemistry; FISH: Fluorescence in situ hybridization; ORR: Objective response rate; NS: Not significant; PFS: Progression-free survival; OS: Overall survival; ILD: Interstitial lung disease; HR: Hazard ratio; T-DXd: Trastuzumab deruxtecan; TRAEs: Treatment-related adverse events; DV: Disitamab vedotin.