A phase 1b study investigating the safety, tolerability and preliminary efficacy of HX009 in post-immune checkpoint inhibitor (CPI) therapy advanced melanoma patients.

e14502 Background: Patients with advanced melanoma have limited treatment options post-immune checkpoint inhibitor (CPI) therapy. HX009 is a first-in-class and rationally designed bispecific antibody (BsAb) fusion protein, targeting PD-1 and CD47 simultaneously, but with weakened CD47 binding, which selectively hones the BsAb for tumor microenvironment through PD-1 interaction, exerting anti-tumor effects with potentially lower toxicity. Preclinical data has demonstrated strong anti-tumor activity in various preclinical models in vivo. Two dose-escalation phase 1 solid tumor studies in Australia and China (NCT05731752; NCT04097769) demonstrated that HX009 is well tolerated and the MTD was not reached up to 15mg/kg dose level. This Phase 1b dose expansion study is to investigate HX009 as a single agent at recommended phase 2 dose of 10mg/kg. Methods: This open-label, multicenter, Phase 1b study enrolled patients with advanced melanoma, and includes Cohort A (treatment-naïve) and Cohort B (post-CPI therapy). Patients received HX009 at 10mg/kg IV every 2 weeks. Primary endpoints are safety and tolerability, objective response rate (ORR) and progress-free survival (PFS) by investigator per RECIST1.1, secondary endpoints include disease control rate (DCR), duration of response (DOR) and Overall survival (OS) by investigator per RECIST1.1 . Here we are reporting preliminary results from Cohort B. Results: As of November 15, 2024, 19 patients were treated ( 18 post-CPI treatment, 1 post BRAF-inhibitor) in Cohort B, comprising 8 females and 11 males with mean age of 55.8(±10.63) years, the median (min, max) prior treatment line was 1.0 (1, 6) . There were 6 cases of acral, 5 cutaneous, 4 mucosal, 4 uncertain subtypes. The most common (≥20%) treatment related AEs (TRAEs) were anemia (26.30%), γ-glutamyl transferase increased (21.10%), and rash (21.10%). The majority of adverse events (AEs) were Grade 1-2 in severity, 3 patients had TRAEs of Grade 3 or higher, including one Grade 3 anemia, one Grade 3 hypokalemia, and one Grade 3 hypophysitis. Among the 17 efficacy-evaluable patients, 3 patients achieved partial response (PR), 2 patients had prolonged stable disease (SD) for more than 8 months with tumor shrinkage. The overall response rate (ORR) was 17.6% (3/17), and the disease control rate (DCR) was 29.4% (5/17). As of the data cutoff date of November 15, 2024, 6 patients were still ongoing in treatment, 2 of the 3 PR patients have received study drug for over 250 days and are still in PR. Conclusions: HX009 has well-tolerated safety profile, and preliminary efficacy data showed promising antitumor activity in post-CPI advanced melanoma patients, warranting further clinical investigation. Clinical trial information: NCT05731752 .