Background: AFM24 is a first-in-class, tetravalent, bispecific, fragment crystallizable-silenced antibody that targets epidermal growth factor receptor-expressing (EGFR+) solid tumors. Of its 4 binding sites, 2 are specific for EGFR, and 2 are specific for CD16A, the Fcγ receptor expressed by natural killer (NK) cells and macrophages. The primary mode of action of AFM24 is not to inhibit EGFR signaling, but to redirect NK cells and macrophages to EGFR+ tumor cells to induce antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), respectively. Preclinical studies showed AFM24 induced killing of EGFR+ tumor cell lines, and the activity was independent of EGFR cell surface expression level. A favorable safety profile was also demonstrated in cynomolgus monkeys. Therefore, AFM24 may utilize the patients’ innate immunity to redirect and activate immune cells, overcoming resistance to current therapies and offering a favorable safety profile. An ongoing Phase 1/2a, first-in-human study (NCT04259450) is evaluating AFM24 in patients with locally advanced or metastatic, treatment refractory solid tumors that are known to express EGFR. The Phase 1 dose escalation study was designed to establish the maximum tolerated dose and/or the recommended Phase 2 dose (RP2D) of AFM24 and evaluated the safety, efficacy, immunogenicity, pharmacokinetic (PK) and pharmacodynamic (PD) responses. AFM24 was administered intravenously once weekly until disease progression, intolerable toxicity, patient withdrawal, or termination at the investigator’s discretion. AFM24 had a well-managed safety profile and the RP2D was established. Methods: In parallel to the continuing dose escalation phase, the Phase 2a dose expansion study was initiated, and the first patient was enrolled in January 2022. This study will assess AFM24 at the RP2D of 480 mg in patients with different EGFR-expressing tumors and will follow a Simon’s two-stage design; the trial will progress to the second stage unless the null hypothesis, that the true tumor response rate is below a specified value, is confirmed at the end of stage one. Eligible patients must have positive histological or cytological staining of EGFR in > 1% of tumor cells. The primary endpoint is to establish the overall response rate (assessed by the investigator per RECIST v1.1) in three disease-specific cohorts. These comprise patients with clear cell renal cell carcinoma (ccRCC), KRAS wild-type colorectal cancer (KRASwt CRC), and EGFR-mutant non-small cell lung cancer (EGFRmut NSCLC). Secondary endpoints include treatment-emergent adverse events, serious adverse events, PK, PD, and immunogenicity. Clinical trial information: NCT04259450.