Abstract CT161: Dose-optimization using exposure response analysis in AFM24 (in monotherapy and with atezolizumab) in patients with advanced/metastatic non-small cell lung cancer

Background: AFM24 is a tetravalent, bispecific ICE® that binds CD16A on NK cells and macrophages and EGFR on solid tumors, redirecting and enhancing the innate and possibly the adaptive immune response towards EGFR+ tumors. AFM24 has been administered weekly intravenously (IV) (dose escalation up to 720mg in single agent and 480mg in combination and deemed safe) to patients (pts) in phase 1/2a studies AFM24-101 as monotherapy and in AFM24-102 in combination with 840 mg atezolizumab IV fortnightly. Objective and Methods: A post-hoc exposure response analysis was performed on pts with non-small cell lung cancer treated with AFM24 480mg as a monotherapy or in combination with atezolizumab (N=44). A mean trough value per patient (Tpat) was calculated using all trough values from Day 22 onwards. Pts were split into LOW (Tpat ≤ Median) and HIGH (Tpat > Median) groups and the association between exposure and clinical outcome was assessed. To confirm such correlations a sensitivity analysis using quartiles of exposure was conducted. Results: Overall, 44 pts were included in this analysis with the median trough level (cut point of High (N=22) vs. Low (N=22)) being 97642 ng/mL. Baseline characteristics were generally balanced; pts in the High group had more median lines of prior treatment (3 vs 2) and pts in the LOW group showed higher mean baseline LDH levels (365 U/L vs 202 U/L). Body mass index and actual received mean dose intensity were similar. Preliminary assessment of efficacy demonstrated an apparent better response in pts in the HIGH group throughout all endpoints assessed. Patients in the HIGH group showed a significantly higher Objective Response rate (36.4% vs 4.6% [p = 0.021]), Disease Control Rate (86.4% vs 36.4% [p=0.002]), median Progression Free Survival ([PFS] 7.3 vs 1.9 months [p-value: 0.003)] and Overall Survival (not estimable vs 16 months). An analysis by quartiles confirmed the exposure response correlation with ORR of 0%, 9.1%, 18.2% and 54.6% from the lowest to the highest quartile. PK data showed very early separation between high and low exposure pts starting at the second infusion. In line with the early separation, pts with low exposure had a very high risk of early tumor progression (59% vs 14% PD in the first 2 months). A subgroup analysis in pts treated with AFM24 plus atezolizumab (26 pts) confirmed the findings with 46.2% ORR for high and 7.7% for low exposure. Higher exposure was not associated with increased frequency or severity of AEs. Conclusions: The data show a strong correlation between exposure and clinical outcome with a significantly increased risk for early tumor progression in the low exposure group. PK modeling suggests that a dose of 720mg AFM24 weekly will result in exposure levels exceeding the cutoff for the high exposure group as early as week 2. The 720mg dose, which has already been established as safe in the phase 1 trial, will be used in future AFM24 studies. Citation Format: Anthony El-Khoueiry, Omar Saavedra, Juanita Lopez, Hye Ryun Kim, Daniela Morales-Espinosa, Daniel Schütz, Andre Overesch, Andreas Harstrick, Kerstin Pietzko. Dose-optimization using exposure response analysis in AFM24 (in monotherapy and with atezolizumab) in patients with advanced/metastatic non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr CT161.