Bispecific innate cell engager (ICE) AFM24 in combination with atezolizumab in patients with advanced/metastatic <i>EGFR</i> -expressing non-small cell lung cancer (NSCLC) without driver mutations: Initial results from a phase 2a study.

2609 Background: Novel treatments are needed for patients with advanced/metastatic NSCLC without actionable driver mutations who progress after prior therapies including checkpoint inhibitors (CPI) and platinum-based chemotherapy. 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. The EGFR -wildtype ( EGFR -WT) NSCLC expansion cohort of the Phase 1/2a study (NCT05109442) is evaluating the combination of AFM24 and atezolizumab. Methods: AFM24 is given weekly at 480 mg intravenously (IV) in combination with 840 mg atezolizumab IV fortnightly to patients with advanced or metastatic EGFR -WT NSCLC who progressed on ≥1 prior line of therapy, including at least a platinum doublet and a CPI. The primary endpoint is overall response rate (ORR) by RECIST v1.1 by Investigator assessment. Secondary endpoints include safety, pharmacokinetics, and immunogenicity. Treatment is given in 28-day cycles until disease progression, intolerable toxicity, investigator discretion, or patient withdrawal of consent. Results: As of 15 January 2025, 43 patients received AFM24 and atezolizumab for a mean (range) duration of 19.6 (1–78) weeks. Median (range) age is 67 (40–79) years; 72% male; all patients had an ECOG performance status of 0 (14%) or 1 (86%). Median (range) number of prior lines is 2 (1–7). All patients had discontinued their previous CPI treatment due to progressive disease. The combination was well tolerated with no unexpected toxicities; infusion-related reactions, the most common adverse events (AE), were reported in 54% of patients (28 Grade 1–2, 4 Grade 3). Most common ≥G3 treatment-related AEs were ALT/AST elevations in 2 patients, all fully resolved. The 35 response-evaluable patients showed an ORR of 23% (8 responses: 1 complete response, 7 partial responses), tumor shrinkage in 46% (16/35) and a disease control rate (DCR) of 77%. Of the 8 responders, 6 had never achieved an objective response on prior CPIs. Preliminary median progression-free survival (PFS) is 5.5 months (95% CI 2.9–7.4), with 29% of patients still on treatment. Conclusions: AFM24 in combination with atezolizumab shows promising clinical efficacy in patients who failed prior treatment including platinum-based chemotherapy and CPI. Patients showed a tolerable and well-managed safety profile. A considerable DCR of 77%, with some long, sustained responses was observed. Confirmed responses were achieved in patients who had not responded to prior CPI. This combination treatment approach could offer a promising chemotherapy-free alternative to patients who have exhausted the available therapeutic options and could provide a strategy to overcome resistance to prior CPI. Clinical trial information: NCT05109442 .