Combination of bispecific innate cell engager (ICE) AFM24 with atezolizumab in patients with advanced/metastatic non-small cell lung cancer (NSCLC) with EGFR kinase domain mutations (EGFRmut): Initial results from a phase 2a study.

Background: Immune checkpoint inhibitor (ICI) monotherapy has shown limited activity against advanced EGFRmut NSCLC. However, combinatorial approaches may enhance the clinical outcomes and are under evaluation. AFM24 is a tetravalent, bispecific ICE that binds CD16A on NK cells and macrophages and EGFR on solid tumors, redirecting and enhancing immune responses towards EGFR-expressing tumors. Atezolizumab, an anti-PD-L1 antibody, has been approved in patients with various solid tumors. The EGFRmut NSCLC expansion cohort of this Phase 1/2a study explores a possible synergistic effect of AFM24 in combination with atezolizumab in heavily pretreated patients with NSCLC EGFRmut (NCT05109442). Methods: AFM24 is given weekly at 480 mg intravenously (IV) in combination with 840 mg atezolizumab IV fortnightly to patients with advanced or metastatic EGFRmut NSCLC who progressed on ≥1 prior line of therapy, including ≥1 prior TKI. 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, 28 patients received AFM24 and atezolizumab for a mean (range) duration of 21.7 (2–65) weeks. Median (range) age is 65 years (32–83); 67.9% were female. All patients had received prior EGFR-specific TKI, 82% had received platinum-based chemotherapy and 75% 3rd gen TKIs. Patients received a median (range) of 3 (1–8) prior lines of treatment. The combination was well tolerated with no new or unexpected toxicities observed compared to each single agent. The most common treatment-related adverse events (TRAE) were infusion-related reactions in 64% of patients (19 Grade 1–2, 1 Grade 3). 9 patients had ≥G3 TRAEs, the most common being neutropenia/neutrophil count decrease, with no associated infections. No other immune TRAEs were reported. The 22 response-evaluable patients achieved an ORR of 23% (1 CR, 3 PRs, 1 unconfirmed PR), a DCR of 64% and tumor shrinkage in 50% of patients. Responses were deepening over time in 3 patients. With a median follow-up of 9 months, the median PFS was 5.5 months (95% CI 1.9–not-evaluable). 6 (27%) patients have received treatment for over 10 months. Conclusions: AFM24 combined with atezolizumab demonstrated encouraging clinical efficacy in patients with EGFRmut NSCLC who had exhausted prior lines of therapy. Treatment showed a well-managed safety profile. This approach potentially offers a feasible, chemotherapy-free therapeutic option for the EGFRmut NSCLC patients who have progressed to prior TKIs and platinum-based chemotherapy and warrants further evaluation. Clinical trial information: NCT05109442.