Study RC48-C014: Preliminary results of RC48-ADC combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma.

515 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC), which showed promising data in HER2-positive and even negative patients (pts) with metastatic urothelial carcinoma (mUC). Toripalimab is an anti-PD-1 antibody with a durable antitumor effect for mUC. The combination may have a synergistic antitumor effect. Initial RC48-C014 data was previously presented (ASCO 2021); here we reported an update on safety and ORR. Methods: In dose-escalation cohort, pts received 1.5 or 2 mg/kg RC48-ADC + 3mg/kg toripalimab with the traditional 3+3 escalation design. In the expansion cohort, patients received the recommended dose of RC48-ADC + toripalimab every 2 weeks. The primary endpoints were safety/tolerability and recommended RC48-ADC dose; secondary endpoints included pharmacokinetics, ORR per RECIST 1.1, PFS, and OS, stratified by HER2 and PD-L1 expression. Results: As of 23 Sep 2021 (data cutoff), 32 mUC pts (18 males; median age 67 y [52-76]) were enrolled since 20 Aug 2020. Fifty-three percent pts were systemic treatment naïve in the locally advanced or metastatic setting. The primary site was in upper tract UC in 56%; 53% had visceral metastases (mets), including 28% with liver mets; HER2 expression was positive (IHC 3+ or 2+ ISH+) in 19% pts, and PD-L1 CPS≥1 in 56%. No dose-limiting toxicity was reported, and the recommended dose for RC48-ADC was 2mg/kg. At data cutoff, confirmed investigator-assessed ORR was 75% (95%CI: 50.9, 91.3), including 15% CRs; DCR was 95% (95%CI: 75.1, 99.9). The ORR for 1L previously untreated mUC pts was 80% and 75% for pts with liver mets. The ORR was 100% for pts with HER2 (3+), 77.8% for HER2 (2+), 66.7% for HER2 (1+), and 50% for HER2 (0) respectively. The ORR was 97.1% in pts with PD-L1 CPS≥1 and 50% in CPS < 1. Follow-up continues for PFS and OS. Most common treatment-related AEs were anorexia (72%), asthenia (56%, 8%≥G3), aminotransferase level increased (56%, 4%≥G3), peripheral sensory neuropathy (56%), alopecia (52%), nausea (36%), and anemia (32%). The most common immune-related AE was pneumonitis (20%). Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in pts with mUC and a manageable safety profile. Further evaluation of RC48 + toripalimab in mUC is ongoing. Clinical trial information: NCT04264936.