Results of a phase 1/2 study of MHB088C: A novel B7H3 antibody-drug conjugate (ADC) incorporating a potent DNA topoisomerase I inhibitor in recurrent or metastatic solid tumors.

3012 Background: MHB088C is an investigational B7H3-directed ADC, created by coupling a humanized anti-B7H3 monoclonal antibody with a highly potent DNA topoisomerase I inhibitor (5~10 times more potent than DXd). Preclinical studies demonstrated robust binding affinity, superior internalization rates, powerful tumor killing activities (3~10 times more potent than the DS-7300a analog in CDX models) and a favorable safety profile with no unique toxicities observed in the GLP study as compared to other B7H3 ADCs and no occurrences of interstitial lung disease (ILD). We here present the safety and efficacy results from a first-in-human phase 1/2 study of MHB088C. Methods: The study enrolled patients (pts) with recurrent or metastatic solid tumor across two segments: dose-escalation (D-esc) and dose-expansion (D-exp). In the D-esc phase, MHB088C was administrated intravenously at doses of 0.8, 1.6, 3.0mg/kg Q2W; 3.0, 4.0 mg/kg Q3W. Results: As of the data cutoff on Dec 31, 2023, 60 pts were enrolled and received at least one dose of MHB088C (D-esc, n=14; D-exp, n=46). 55 pts remain on the treatment and 12 pts had at least one tumor assessment according to RECIST 1.1. Dose-limiting toxicities (DLTs) were platelet count decreased and febrile neutropenia at 4.0 mg/kg Q3W. The MTD was determined to be 3.0 mg/kg Q3W. The most common TRAEs overall in ≥25% of pts were neutrophil count decreased, lymphocyte count decreased, and white blood cell (WBC) count decreased. The most common Grade ≥3 TRAEs (≥5% of pts) were neutrophil count decreased (33.3%), lymphocyte count decreased (30.0%), WBC count decreased (26.7%), platelet count decreased (23.3%), and anemia (15.0%). No ILD was reported. Of12 response-evaluable pts, 5 partial responses (PRs) were observed (ORR: 41.7%). The disease control rate was 91.7% (11/12). In the subset of 3 SCLC pts, all 3 showed PRs (ORR: 100.0%), with one case demonstrating complete response of the target lesion and another with close to 80% tumor volume reduction. The efficacy of 2 SCLC pts was achieved in 1.6 mg/kg Q2W group without major hematologic side effects. All responses among SCLC pts occurred at the first tumor assessment. Conclusions: MHB088C exhibited a manageable safety profile, with striking efficacy in SCLC pts. The dose optimization and expansion study is continuing to establish the RP2D for MHB088C. Clinical trial information: CTR20231298.