381O First-in-human/phase I trial of HS-20089, a B7-H4 ADC, in patients with advanced solid tumors

B7-H4, a transmembrane glycoprotein in the B7 superfamily, has limited expression in normal tissues but is highly expressed in various cancers. HS-20089 is a novel B7-H4 directed antibody-drug conjugate (ADC) with a drug to antibody ratio of 6. We conducted a first-in-human phase I trial to evaluate the dose-limiting toxicity (DLT), safety, tolerability, pharmacokinetics, and efficacy of HS-20089 in patients (pts) with advanced solid tumors refractory to standard therapy. Eligible pts were enrolled in sequentially escalating dose cohorts (0.7 to 7.2 mg/kg) of HS-20089 administered intravenously every 3 weeks. The accelerated titration combined with Bayesian optimal interval (BOIN) was used as the dose escalation schedule in this phase I dose escalation trial. As of Apr. 11th, 2023, 44 pts with advanced solid tumors (41 breast cancers, 2 ovarian cancers, and 1 endometrial cancer) received HS-20089 treatment. Three DLTs were observed in 2 pts (both in 7.2 mg/kg). The most common treatment-emergent adverse events (≥20%) were leukopenia, neutropenia, nausea, anemia, thrombocytopenia, vomiting, fatigue, increased alanine aminotransferase, anorexia, increased aspartate aminotransferase and hyponatremia. No interstitial lung disease and infusion reaction were reported. Of 33 response-evaluable pts, 8 partial responses (PRs) were observed in pts treated with HS-20089 (response rate: 24.2%), including 3 confirmed PRs and 5 PRs awaiting confirmation. The disease control rate was 63.6%. In the subset of 16 triple-negative breast cancer (TNBC) pts, 6 PRs were observed (response rate: 37.5%), including 2 confirmed PRs and 4 PRs awaiting confirmation. At potential target therapeutic dose (4.8 and 5.8 mg/kg), 5 PRs of 12 pts were observed (response rate: 41.7%) in TNBC. The patient achieving PR with the longest treatment duration of 403 days remains on treatment in 0.7 mg/kg cohort. Based on data from the ongoing study, HS-20089 was well tolerated and showed antitumor activities in advanced solid tumors, with encouraging clinical efficacy in TNBC.