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.

Xinan Sheng Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Beijing Cancer Hospital, Beijing, China info_outline Xinan Sheng, Li Zhou, Zhisong He, Hongqian Guo, Xieqiao Yan, Siming Li, Huayan Xu, Juan Li, Zhihong Chi, Lu Si, Chuanliang Cui, Lili Mao, BIN LIAN, Bixia Tang, Xuan Wang, Xue Bai, Jun Guo

Authors Xinan Sheng Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Beijing Cancer Hospital, Beijing, China info_outline Xinan Sheng, Li Zhou, Zhisong He, Hongqian Guo, Xieqiao Yan, Siming Li, Huayan Xu, Juan Li, Zhihong Chi, Lu Si, Chuanliang Cui, Lili Mao, BIN LIAN, Bixia Tang, Xuan Wang, Xue Bai, Jun Guo Organizations Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Beijing Cancer Hospital, Beijing, China, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, China, Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, Beijing, China, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Genitourinary Oncology，Peking University Cancer Hospital & Institute, Beijing, China, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology,Peking University Cancer Hospital & Institute, Beijing, China, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital & Institute, Beijing, China, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Melanoma and Sarcoma Oncology, Beijing Cancer Hospital, Beijing, China, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital & Institute, Beijing, China, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute, Beijing, China, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Melanoma & Sarcoma,Peking University Cancer Hospital & Institute, Beijing, China Abstract Disclosures Research Funding Pharmaceutical/Biotech Company 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. Stratification cORR HER2 IHC (2+/3+) PD-L1 (+) 100% (5/5) HER2 IHC (2+/3+) PD-L1 (-) 92.3% (12/13) HER2 IHC (1+) PD-L1 (+) 50% (2/4) HER2 IHC (1+) PD-L1 (-) 50% (3/6) HER2 IHC (0) PD-L1 (+) - HER2 IHC (0) PD-L1 (-) 50% (1/2) Total 76.7% (23/30)