Background: Innate Cell Engagers (ICE) are bispecific molecules that bind both a tumor cell-surface antigen and to CD16A expressed on natural killer (NK) cells and macrophages, inducing antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), respectively. As epidermal growth factor receptor (EGFR) is often overexpressed in several types of solid tumors, this provides an ideal tumor-cell surface antigen which may be targeted using ICE molecules. AFM24 is a first in class, tetravalent, bispecific, novel ICE targeting EGFR. By binding to EGFR on tumor cells and CD16A on innate immune cells, AFM24 may utilize a patient’s innate immunity to induce ADCC/ADCP towards tumor cells. Anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors, which enhance the anti-tumor activity of a patient’s adaptive immunity, have also demonstrated efficacy as monotherapy and are playing an increasingly prominent role in treatments. The combination of AFM24 and the PD-L1 inhibitor, atezolizumab, may therefore represent a rational new treatment modality, enhancing both the innate and adaptive immune responses to target EGFR+ tumor cells. Methods: An ongoing Phase 1/2a open-label, non-randomized, multicenter, dose escalation (Phase 1) and dose expansion (Phase 2a) study was initiated in November 2021 (NCT05109442) to evaluate the safety, tolerability and efficacy of AFM24 in combination with atezolizumab. The primary aim of the Phase 1 study is to determine the maximum tolerated dose and the recommended Phase 2 dose (RP2D) of AFM24. Eligible patients must have advanced histologically confirmed EGFR+ disease and confirmed disease progression after treatment with ≥1 prior therapy. Patients undergo a safety lead-in phase with AFM24 as a single agent 7 days before receiving the combination therapy. A standard 3+3 design will be used to determine the RP2D. Escalating doses of AFM24 will be given to each cohort as weekly intravenous (IV) infusions; the starting dose and at least two planned dose escalations are based on results from the ongoing AFM24 monotherapy trial (NCT04259450). Atezolizumab will be given at a fixed dose of 840 mg as a biweekly IV infusion. Patients will receive AFM24 and atezolizumab treatment until disease progression, intolerable toxicity, patient withdrawal, or termination at the investigator’s discretion. The Phase 2a study will then establish the overall response rate (as per RECIST v1.1) and safety of combination therapy in patients with advanced/ metastatic, or treatment refractory gastric, esophagogastric, hepatocellular, hepatobiliary, pancreatic, or non-small cell lung cancer. For both phases, secondary endpoints include treatment-emergent adverse events, serious adverse events, pharmacokinetics, pharmacodynamics, and immunogenicity. Clinical trial information: NCT05109442.