Phase I study of MCLA-145, a bispecific antibody targeting CD137 and PD-L1, in solid tumors, as monotherapy or in combination with pembrolizumab.

2520 Background: MCLA-145, a human common light chain bispecific antibody targeting CD137 and the PD-1/PD-L1 axis, is designed to enhance both antigen-mediated T cell activation via CD137 costimulation, and blockade of inhibitory PD-L1. Interim data from the ongoing phase 1 study (NCT03922204) are presented. Methods: Patients (pts) with PD-L1 ≥1% advanced/metastatic solid tumors received MCLA-145 IV as monotherapy Q2W/Q3W in 21/28-d cycles respectively, or in combination with pembrolizumab 200 mg Q3W in 21-d cycles. Pts enrolled in combination had cancers that either relapsed after PD-(L)1 therapies or were immunotherapy naïve. Primary objectives are safety, tolerability and dose-limiting toxicity (DLT) of MCLA-145 alone or combined with pembrolizumab, and determination of the recommended dose for expansion (RDE). Secondary endpoints include efficacy, pharmacokinetics, pharmacodynamics (PD) and immunogenicity. Results: As of a December 4, 2023 data cutoff, 72 pts with 26 cancer types were treated; 25% of pts had non-small cell lung cancer (NSCLC). 3 pts were continuing combination therapy. Monotherapy: 53 pts (median age 60 y, 49% male) were treated across 8 dose levels (47 pts 0.4-75 mg Q2W, 6 pts 40 mg Q3W). Median number of cycles was 2 (range 1-39). 6 pts had DLTs in the 25-75 mg dose range (febrile neutropenia 2 pts, hemolytic anemia, myositis, ALT/AST increase, neutrophil/platelet decrease 1 pt each). Most common adverse events (AEs; all grades/G3-4) were fatigue (51%/4%), decreased appetite (34%/2%), dyspnea (32%/0%), anemia (30%/9%), ALT/AST increase (25%/11%), and pyrexia (25%/0%). The incidence of any G3-4 AE was lower with 40 mg Q3W than across all Q2W dose levels (33% vs 66%). Combination: 19 pts (median age 61 y, 47% male) were treated with MCLA-145 10, 25 or 40 mg plus Q3W. Median number of cycles was 5 (range 1-16). No DLTs occurred. Most common AEs (all grades/G3-4) were fatigue (58%/11%), cough (42%/0%), constipation (32%/0%) and ALT/AST increase (21%/11%). The RDE was established at 40 mg Q3W for both monotherapy and combination. Preliminary antitumor activity was observed with monotherapy (52 evaluable pts): 5 partial responses (PRs) in glioblastoma (lasting >3 y), sarcoma, cervical, anal, and gastric cancer (treated for 2-11 mo); and combination (19 evaluable pts): 1 PR in Merkel cell carcinoma (treated 12+ mo), 1 complete response in PD-L1+ NSCLC (treated 6+ mo), both after prior immunotherapy. Disease control rate was 37% with monotherapy and 68% with combination. Exposure was dose-dependent with a terminal half-life of 69 h at 75 mg. Measure of peripheral blood Ki67+ CD8 T cells supports maximal PD activity at 40 mg. Conclusions: MCLA-145 given alone or in combination with pembrolizumab had a well-tolerated and manageable safety profile with encouraging clinical activity, including in pts who relapsed after PD-(L)1 therapies. Clinical trial information: NCT03922204 .