RC48-ADC for metastatic urothelial carcinoma with HER2-positive: Combined analysis of RC48-C005 and RC48-C009 trials.

4520 Background: RC48-ADC (Disitamab Vedotin) is a novel humanized anti-HER2 antibody-drug conjugate (ADC). RC48-ADC demonstrated a promising efficacy with a manageable safety profile in HER2-positive locally advanced or metastatic UC patients who failed to platinum based chemotherapy in RC48-C005 and RC48-C009 trials. Here are the pooled results of the two studies with the supplementary efficacy, safety and updated OS data. Methods: Both of the two trials are single-arm, multi-center, phase II trials. Eligible patients were 18̃80 years old, with central-laboratory confirmed, histologically HER2-postive (IHC2+,3+), unresectable mUC. Patients had at least one line of systemic chemotherapy. The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety were also assessed. Results: RC48-C005 and RC48-C009 enrolled HER2-positive locally advanced or metastatic UC patients from Nov 2017 to Sep 2020. 107 mUC patients (80 males; median age 63 y [40-79]) were enrolled. 64.5% patients had received ≥ 2 lines systemic chemotherapy. 90.7% patients had visceral metastases. As of 04 Sep 2021 (data cutoff), The overall confirmed ORR as assessed by the BIRC was 50.5% (95% CI: 40.6%, 60.3%). Similar responses were observed in prespecified subgroups. cORR was 52.1% (25/48) for patients with liver metastasis and was 55.6% (15/27) in patients with previous PD-1/L1 treatment. The cORR was 62.2% (28/45) for HER2 IHC2+&FISH+ or IHC3+ patients, 55.6% (5/9) for HER2 IHC2+&FISH unknown patients, and 39.6% (21/53) for HER2 IHC2+&FISH- patients respectively. DCR was 82.2% (95% CI:73.7%, 89.0%). The mPFS was 5.9 (95% CI:4.2, 7.2) months. The mOS was 14.2 (95% CI:9.7, 18.8) months. The median OS follow up time was 19.1 months. Most common treatment-related AEs were hypoaesthesia (50.5%), Leukopenia (49.5%), aspartate aminotransferase increased (43.0%), neutropenia (42.1%), alopecia (40.2%), asthenia (39.3%), alanine aminotransferase increase (35.5%), decreased appetite (31.8%). The grade ≥3 TRAEs (≥5%) only included hypoaesthesia (15.0%), neutropenia (12.1%) and r-GT increased (5.6%). Conclusions: RC48-ADC showed continuously a promising efficacy with a manageable safety profile in HER2-postive mUC patients who had failed at least one line systemic chemotherapy. Clinical trial information: NCT03507166, NCT03809013.