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

Abstract

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.

Recent Advances in the Development of Antibody-Drug Conjugates in Urothelial Cancer

“…RC48-C005 (NCT03507166) and RC48-C009 (NCT03809013) are 2 trials that evaluated RC48-ADC in 107 patients with HER-2 positive (immunohistochemistry [IHC] 2+ or 3+) UC. In a combined analysis, confirmed ORR was 50.5%, median PFS was 5.9 months, and median OS was 14.2 months 38 . Grade ≥3 TRAEs were numbness (15.0%) and neutropenia (12.1%), with no dose-limiting toxicity reported 38 .…”

“…38 Grade ≥3 TRAEs were numbness (15.0%) and neutropenia (12.1%), with no dose-limiting toxicity reported. 38 Furthermore, RC48-ADC has shown favorable results in HER-2-negative (IHCor 1+) patients with metastatic UC (NCT04073602). A total of 19 patients were enrolled with ORR of 26.3%.…”

“…In a combined analysis, confirmed ORR was 50.5%, median PFS was 5.9 months, and median OS was 14.2 months 38 . Grade ≥3 TRAEs were numbness (15.0%) and neutropenia (12.1%), with no dose-limiting toxicity reported 38 . Furthermore, RC48-ADC has shown favorable results in HER-2–negative (IHC – or 1+) patients with metastatic UC (NCT04073602).…”

Real‐world effectiveness and safety of RC48‐ADC alone or in combination with PD‐1 inhibitors for patients with locally advanced or metastatic urothelial carcinoma: A multicenter, retrospective clinical study

“…A combined analysis of the RC48‐C005 and RC48‐C009 studies revealed that RC48‐ADC monotherapy achieved an ORR of 50.5% (95% CI: 40.6%–60.3%) in HER2‐positive (IHC2+ and 3+) mUC patients who had progressed on at least one systemic chemotherapy. The disease control rate (DCR) was 82.2% (95% CI: 73.7%, 89.0%), mPFS of 5.9 months (95% CI: 4.2, 7.2) and a median overall survival (mOS) of 14.2 months (95% CI: 9.7, 18.8) 17 . The RC48‐C011 study demonstrated that RC48‐ADC monotherapy achieved an ORR of 26.3% (95% CI: 9.1%, 51.2%) in la/mUC patients with low HER2 expression (IHC1+ and 0), a DCR of 94.7%, an mPFS of 5.5 months (95% CI: 3.9, 6.8), and an mOS of 16.4 months (95% CI: 7.1, 21.7) 16 .…”

Systemic treatment of advanced and metastatic urothelial cancer: The landscape in Australia

“…It has been trialed in a single-arm phase II study in HER2positive locally advanced or mUC patients who failed platinum-based chemotherapy. To date, RC48-ADC has shown promising efficacy with a manageable safety profile (overall response rate was 50.5% (95% CI, 40.6-60.3%) 69. …”