An open-label, phase I trial of the SIRPα monoclonal antibody, BI 770371, alone and in combination with the PD-1 inhibitor ezabenlimab in patients with advanced solid tumors.

2515 Background: The signal regulatory protein alpha (SIRPα)/CD47 axis is a critical regulator of myeloid cell activation and serves as a myeloid-specific immune checkpoint, making it a potential therapeutic target. The pan-specific SIRPα monoclonal antibody, BI 770371, blocks the SIRPα/CD47 interaction, leading to reactivation of innate antitumor immune responses. This Phase I trial (NCT05327946) aimed to determine the maximum tolerated dose (MTD) and recommended dose for expansion of BI 770371 ± ezabenlimab in patients (pts) with advanced solid tumors. Methods: Pts with ≥1 measurable lesion and ECOG PS of 0/1 were enrolled. Pts received escalating doses ofBI 770371 alone or in combination with ezabenlimab 240 mg once every 3 weeks. Treatment continued until progressive disease, unacceptable toxicity, or pt withdrawal. BI 770731 dose escalation was guided by a Bayesian Logistic Regression Model with overdose control. Primary endpoint was dose-limiting toxicities (DLTs) in the MTD evaluation period (Days 1–21). Secondary endpoints were adverse events (AEs) and DLTs in the on-treatment period. Results: At data cut-off (Nov 22, 2024), 21 pts had received BI 770371 monotherapy across 6 dose levels, and 15 pts had received BI 770371 in combination with ezabenlimab (combination group) across 5 dose levels. In the monotherapy group, median age was 63 years (range: 26–77) and 95% of pts had received ≥3 prior lines of therapy. In the combination group, median age was 61 years (range: 27–78), and 80% had received ≥3 prior therapies. No DLTs were reported during the MTD evaluation period with BI 770371 monotherapy or with the combination; 1 pt in the monotherapy group had a DLT (grade 2 encephalitis, which resolved within 1 week) during the on-treatment period (likely due to prior nivolumab and ipilimumab treatment). In total, 14 (67%) and 10 (67%) pts in the monotherapy and combination groups, respectively, had a treatment-related AE (TRAE). Most common TRAEs with BI 770371 monotherapy were pruritus (24%) and fatigue (19%). Most common TRAEs with the combination were fatigue and decreased appetite (each 20%). Most TRAEs were grade 1/2, one pt in the combination group had two grade 3 TRAEs (diarrhea and fatigue); there were no grade 4/5 TRAEs. Two suspected unexpected serious adverse reactions were seen: grade 2 encephalitis (monotherapy) and grade 3 diarrhea (combination). One pt had an AE leading to discontinuation (grade 2 encephalitis). One pt in the combination group had a partial response; 13 (62%) and 8 (53%) pts in the monotherapy and combination groups, respectively, had stable disease. Conclusions: These preliminary data indicate that BI 770371 is well tolerated alone and in combination with ezabenlimab, with promising antitumor activity seen in heavily pretreated pts with advanced solid tumors. The MTD of BI 770371 was not reached in either group. Clinical trial information: NCT05327946 .