Abstract CT149: A phase 1/2a first-in-human study of AFM24, a CD16A/epidermal growth factor (EGFR) bispecific Innate Cell Engager (ICE®), in patients with locally advanced or metastatic EGFR-expressing solid tumors: Preliminary findings from the dose-escalation phase
Authors: El-Khoueiry Anthony , Lopez Juanita , Saavedra Omar , Awad Mark , Thomas Jacob , Tiu Crescens , Garralda Elena , Rehbein Bettina , Hintzen Gabriele , Pietzko Kerstin , Raab Christa , Rajkovic Erich , Ravenstijn Paulien , Emig Michael 
Published: June 2022

Abstract
AFM24 is a first-in-class, tetravalent, bispecific ICE® that binds to EGFR on tumor cells and CD16A on natural killer (NK) cells and macrophages, inducing antibody-mediated cytotoxicity and antibody-mediated phagocytosis, respectively. Preclinical in vitro and in vivo studies have demonstrated AFM24 can induce killing of EGFR+ solid tumor cell lines, independently of EGFR mutational status; toxicology testing in cynomolgus monkeys revealed a favorable safety profile. An ongoing phase 1/2a study (NCT04259450) is evaluating the safety, efficacy, immunogenicity, pharmacokinetic (PK) and pharmacodynamic responses of AFM24 in patients with locally advanced or metastatic, treatment refractory solid tumors that are known to express EGFR. AFM24 is administered intravenously Q1W until disease progression, intolerable toxicity, investigator’s discretion or patient withdrawal. As of 29 Oct 2021, 29 patients (median [range] age 58 [29-81] years; number of prior therapies 4 [2-8]), predominantly with colorectal- (CRC, 16/29; 10 KRAS mutant) and non-small cell lung cancer (NSCLC, 7/29; 6 EGFR mutant), were treated with AFM24 across six dose levels (14-480 mg flat). The median number of AFM24 doses administered was 8, range 1-29. The most frequently reported (≥20% of patients) AFM24-related treatment-emergent adverse events (TEAEs) were infusion-related reactions (IRR, 20/29), nausea (7/29) and headache (6/29). There were no on-study deaths; two patients had serious TEAEs (one Grade 3 IRR and one Grade 2 hypoxia) and five patients had transient and reversible Grade 3-4 TEAEs (two Grade 3 IRRs, one Grade 3 hypertension, three ≥Grade 3 lymphocytopenia) attributed to AFM24, respectively. There was one dose-limiting toxicity at 40 mg (Grade 3 IRR). Best objective response was stable disease in 8/24 response-evaluable patients; three patients had stable disease for ≥4 months (two CRC, one NSCLC). Dose-proportional PK between 320 and 480 mg indicated saturation of target-mediated elimination. CD16A receptor occupancy (CD16ARO) on circulating blood cells was correlated with exposure and seemed to level off at 480 mg. Estimated intra-tumoral AFM24 concentrations and CD16ARO were in the range associated with maximum tumor cell killing in vitro. TNF-α, IFN-γ and IL-10 increased over time; other cytokines including IL-6 showed only transient increases. AFM24 has a well-managed safety profile and shows pharmacodynamic activity at doses of 320-480 mg. In parallel to continued dose escalation, expansion in disease specific cohorts has been launched at 480 mg. Other studies are evaluating AFM24 in combination with atezolizumab, and in combination with autologous NK cells holding the potential to activate the innate immune response to fight EGFR+ cancer.
Citation Format: Anthony El-Khoueiry, Juanita Lopez, Omar Saavedra, Mark Awad, Jacob Thomas, Crescens Tiu, Elena Garralda, Bettina Rehbein, Gabriele Hintzen, Kerstin Pietzko, Christa Raab, Erich Rajkovic, Paulien Ravenstijn, Michael Emig. A phase 1/2a first-in-human study of AFM24, a CD16A/epidermal growth factor (EGFR) bispecific Innate Cell Engager (ICE®), in patients with locally advanced or metastatic EGFR-expressing solid tumors: Preliminary findings from the dose-escalation phase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT149.