PURPOSE: Innate immune cell-based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on NK cells/macrophages and EGFR on tumor cells, redirecting antitumor activity toward tumors. The safety and tolerability of AFM24 were evaluated in this phase I/IIa dose-escalation/dose-expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR. PATIENTS AND METHODS: The main objective in phase I was to determine the MTD and/or recommended phase II dose. The primary endpoint was the incidence of dose-limiting toxicities during the observation period. Secondary endpoints included the incidence of treatment-emergent adverse events and pharmacokinetics. RESULTS: In the dose-escalation phase, 35 patients received AFM24 weekly across seven dose cohorts (14-720 mg). One patient experienced a dose-limiting toxicity of grade 3 infusion-related reaction. Infusion-related reactions were mainly reported after the first infusion; these were manageable with premedication and a gradual increase in infusion rate. Pharmacokinetics was dose-proportional, and CD16A receptor occupancy on NK cells approached saturation between 320 and 480 mg. Paired tumor biopsies demonstrated the activation of innate and adaptive immune responses within the tumor. The best objective response was stable disease in 10/35 patients; four patients had stable disease for 4.3 to 7.1 months. CONCLUSIONS: AFM24 was well tolerated, with 480 mg established as the recommended phase II dose. AFM24 could be a novel therapy for patients with EGFR-expressing solid tumors, with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other immuno-oncology therapeutics.