Preliminary results of a phase Ib/II combination study of RC48-ADC, a novel humanized anti-HER2 antibody-drug conjugate (ADC) with toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in patients with locally advanced or metastatic urothelial carcinoma.

Abstract

4518 Background: RC48-ADC has shown promising data in HER2-positive and even negative patients with metastatic urothelial carcinoma (mUC) who failed with platinum-based chemotherapy. RC48-ADC combined with anti-PD-1 antibody may have a synergistic antitumor effect. Methods: This is an open-label, multicenter, phase 1b/II trial to evaluate the safety and activity of RC48 combined with toripalimab in mUC. Patients received RC48-ADC at 1.5 or 2 mg/kg, in combination with 3mg/kg toripalimab every two weeks in a dose-escalation and expansion cohort until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The key primary endpoint was safety; secondary endpoints included efficacy and tumor tissue biomarkers. Results: As of 17 Jan 2022 (data cutoff), 41 la/mUC pts (19 males; median age 66 y [42-76]) were enrolled since 20 Aug 2020. 61% patients were systemic treatment naïve, and 54% had visceral metastases (mets), including 24% with liver mets. The primary site was in upper tract UC in 54%. HER2 expression was positive (IHC 2+ or 3+) in 59% patients, and PD-L1 positive (CPS ≥ 10) in 32%. No dose-limiting toxicity was observed. The recommended dose was RC48-ADC 2mg/kg + toripalimab 3mg/kg every 2 weeks. With a median follow-up of 8.0 mos, 36 patients had at least one tumor assessment, the best ORR was 83.3%, and the confirmed ORR was 76.7% (95%CI: 57.7, 90.1), including 10% CR. The cORR was 82.4% for 1L previously untreated mUC patients, 100% for patients with HER2 IHC (2+ or 3+) & PD-L1 (+), 92.3% for HER2 (2+ or 3+) & PD-L1 (-), 50% for HER2 (0 or 1+) & PD-L1 (+), and 50% HER2 (0 or 1+) & PD-L1 (-). DCR was 96.7% (95%CI: 82.8, 99.9). The median PFS was immature and 9.2 mos (95%CI: 5.49, 10.32) by the time and the median OS was not reached. The most common treatment-related AEs were ALT/AST increase (65.9%), peripheral sensory neuropathy (58.5%), appetite decrease (56.1%), asthenia (56.1%), hypertriglyceridemia (48.8%). Grade ≥3 TRAEs included γ-glutamyl transferase increase (12.2%), ALT/AST increase (7.3%), asthenia (7.3%), hypertriglyceridemia (4.9%), and neutropenia (4.9%). 9 pts had irAEs (22.0%, 7.3% ≥ G3), including immune-related pneumonitis, hepatitis, and myositis. Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in patients with mUC and a manageable safety profile. A randomized study of RC48-ADC and toripalimab vs. platinum-based chemotherapy in previously untreated la/mUC patients is ongoing. Clinical trial information: NCT04264936. [Table: see text]

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

“…27 Moreover, the median PFS (6.9 months) was numerically superior to the outcomes of the combined analysis of the RC48-C005 and RC48-C009 studies (5.9 months), the outcomes of the RC48-C011 study (5.5 months), 16 and the data of Chen et al (5.4 months). 27 The study also included 30 patients who received RC48 in combination with a PD-1 inhibitor, showing an ORR of 66.7%, lower than the RC48-C014 study result (76.7%), 19 but higher than that reported by Chen et al (38.8%). 27 The median PFS of 8.2 months was lower than the RC48-C014 study result (9.2 months) but similar to the real-world data from Chen et al (8.5 months).…”

“…Recently conducted Phase II multicenter randomized controlled studies, namely RC48‐C005, RC48‐C009, and RC48‐C011, demonstrated robust ORR and PFS data for UC treated with RC48‐ADC monotherapy, regardless of HER2 expression (IHC 3+, 2+, 1+, or 0), after progression on standard chemotherapy 16–18 . The latest RC48‐C014 study confirmed that the combination of RC48‐ADC with the programmed cell death protein 1 (PD‐1) inhibitor toripalimab outperformed RC48‐ADC monotherapy in terms of ORR and median PFS 19 …”

“…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 . The RC48‐C014 study showed an ORR of 76.7% (95% CI: 57.7%–90.1%), an mPFS of 9.2 months, and an unreached mOS for RC48‐ADC combined with toripalimab in la/mUC patients 19 . This retrospective study sought to evaluate the real‐world efficacy and safety of RC48‐ADC, either alone or in combination with PD‐1 inhibitors, for treating patients with la/mUC.…”

“…[16][17][18] The latest RC48-C014 study confirmed that the combination of RC48-ADC with the programmed cell death protein 1 (PD-1) inhibitor toripalimab outperformed RC48-ADC monotherapy in terms of ORR and median PFS. 19 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).…”

The Evolving Landscape of Antibody–Drug Conjugates: In Depth Analysis of Recent Research Progress

“…The most often used immunotherapeutic agents in combination with ADCs appears to be confined to PD-1 inhibitors with pembrolizumab ,− and nivolumab − dominating and followed by atezolizumab, , durvalumab − and toripalimab − and are currently in various stages of clinical trials. A few representative examples of patents for ADC immunotherapy combination therapy are WO2018160538, US20220133902, WO2022242692, WO2018110515 .…”