Lorigerlimab, a Bispecific PD-1×CTLA-4 DART Molecule in Patients (pts) with Metastatic Castration-Resistant Prostate Cancer (mcrpc): A Phase 1 Expansion (exp) Cohort.

155 Background: Lorigerlimab (MGD019) is an investigational, bispecific Fc-bearing (IgG4) DART molecule designed to enhance CTLA-4 blockade on dual expressing, tumor infiltrating lymphocytes, while maintaining maximal PD-1 blockade on PD-1 expressing cells. Lorigerlimab has approximate dose proportional PK across 1–10 mg/kg IV dosing Q3W, with sustained PD-1 receptor occupancy evident at doses ≥1 mg/kg Q3W. MGD019-01 is a global first-in-human dose finding and activity estimating study of lorigerlimab in advanced solid tumors (AST). Methods: The exp phase of MGD019-01 evaluates single agent safety, PK, and antitumor effects of lorigerlimab at the recommended dose for exp of 6 mg/kg IV Q3W in 4 tumor specific cohorts. Confirmed responses were noted in each cohort. Preliminary results of the mCRPC cohort are reported here. Response evaluable pts received ≥1 dose and had ≥1 postbaseline imaging evaluation. Measurable lesions were evaluated per RECIST v1.1 and skeletal metastases assessed by bone scan. Prostate specific antigen (PSA) response was defined as a ≥50% (PSA50) or ≥90% (PSA90) PSA decline from baseline with confirmation ≥3 weeks later. Expression of proliferation marker, Ki67, and inducible costimulator (ICOS) by peripheral T cells was assessed by flow cytometry. Results: At data cutoff (9/10/22), 127 pts with AST received ≥1 dose of lorigerlimab 6 mg/kg. Median exposure was 10 weeks (range, 0.1, 94.4) with median of 4 infusions. 6 pts remain on therapy; 36 discontinued for PD (n=13), AEs (n=17), or patient/physician decision (n=6). Treatment related adverse events (TRAE) occurred in 109/127 (85.8%) pts. TRAEs occurring in ≥15% of pts were fatigue, pruritus, hypothyroidism, pyrexia. Rates of grade ≥3 TRAEs and immune-related AEs were 32.3% and 7.9%, respectively. AEs leading to drug discontinuation occurred in 22.8% of pts. There were no fatal AEs related to lorigerlimab. In the mCRPC exp cohort (n=42), pts had a median of 2 prior lines of therapy for CRPC, >80% received prior ART or taxanes; 88% had visceral (liver, 26%; lung, 26%) or nodal disease and 95% had bone metastases. 42 pts were PSA response evaluable; 35 were RECIST evaluable. ORR was 25.7% (9/35; 9 confirmed PRs). Median duration of response was 16.1 weeks (range 6–25+ weeks). 5 responders remain on study, 4 discontinued for unrelated fatal AEs: COVID-19 (2) cardiac arrest (1) C. difficile infection (1). Confirmed PSA50 and PSA90 response rates were 28.6% (12/42) and 21.4% (9/42), respectively. Increased frequencies of Ki67+ and ICOS+ T cells were observed on day 8 posttreatment compared to pretherapy per the flow cytometry analyses from 35 pts. Conclusions: Lorigerlimab demonstrates a manageable safety profile with evidence of encouraging and durable antitumor activity in a chemotherapy refractory mCRPC population. Randomized evaluation of lorigerlimab in mCRPC is warranted. Clinical trial information: NCT03761017 .