A phase 1 study of SHR-A1912, a CD79b targeted antibody-drug conjugate (ADC), in patients (pts) with B-cell non-Hodgkin lymphoma (B-NHL).

7064 Background: CD79b is an attractive therapeutic target for B-NHL. SHR-A1912 is a novel ADC containing an anti-CD79b monoclonal antibody conjugated to the DNA topoisomerase I inhibitor. Here, we present results of the dose-escalation (D-ESC) and dose-expansion (D-EXP) parts of a first-in-human phase 1 study of SHR-A1912 in B-NHL. Methods: Pts with histologically confirmed B-NHL that had failed to respond to or had progressed after ≥1 prior anti-cancer therapy were enrolled. The D-ESC part commenced with accelerated titration at 0.1 and 0.3 mg/kg and then switched to an i3+3 scheme at escalated doses starting from 0.6 mg/kg (Q3W, IV). In the D-EXP part, additional pts were enrolled to selected doses (approximately 10–12 pts in total per dose level). Primary objectives were to assess the safety and tolerability of SHR-A1912 and determine the RP2D. Results: As of Nov 7, 2023, 49 pts were enrolled (n=1, 1, 7, 3, 13, 13, and 11 in the 0.1, 0.3, 0.6, 1.2, 1.8, 2.7, and 3.6 mg/kg dose cohorts), including 33 pts with diffuse large B-cell lymphoma (DLBCL), 12 with follicular lymphoma (FL), and 4 with marginal zone lymphoma (MZL). Pts had received a median of 2 lines of prior treatment (range, 1–9). DLTs occurred in 3 pts during D-ESC (grade 4 decreased neutrophil count lasting ≥3 days in 0.6 and 3.6 mg/kg cohorts, 1 pt for each; grade 3 pneumonia in 2.7 mg/kg cohort, 1 pt). The 1.8, 2.7, and 3.6 mg/kg cohorts were expanded. Overall, grade ≥3 treatment-related adverse events occurred in 20 (40.8%) pts, with the most common (≥20%) being decreased neutrophil count. 41 pts with baseline target lesions had at least one post-baseline assessment; ORR was 56.1% (95% CI, 39.8–71.5), and 6-mo DoR rate was 62.7% (95% CI, 26.7–84.8). As for subtypes, ORR was 51.9% in pts with DLBCL (57.1% and 77.8% in the 2.7 and 3.6 mg/kg cohorts, respectively), 63.6% in pts with FL, and 66.7% in pts with MZL (Table). The mean half-life of conjugated antibody ranged from 4.7 to 5.3 days for pts in the 1.8–3.6 mg/kg cohorts, with volume of distribution close to human plasma volume. The plasma exposure of free toxin was low, with the molar ratio of toxin/conjugated-antibody <1%, and no accumulation was observed. Conclusions: SHR-A1912 was tolerable up to 3.6 mg/kg and had promising anti-tumor activity in pts with previously treated B-NHL, supporting further investigations of SHR-A1912. Clinical trial information: NCT05113069 . Table: see text