Small molecule EGFR inhibitors have proven effective in treatment of Non-Small Cell Lung Cancer (NSCLC) with activating EGFR mutations, however there is minimal to no efficacy in wild-type EGFR NSCLC. Amivantamab, an EGFR/MET bispecific antibody, has demonstrated clinical activity across a diverse range of EGFR activating mutations in an ongoing Phase I trial and differentiates from anti-EGFR antibodies tested previously in NSCLC clinical trials due to dual targeting and enhanced interaction with Fc receptors on immune cells. As candidate biomarkers to predict response in wt EGFR disease, EGFR and MET expression (immunohistochemistry (IHC)) and signaling (proximity ligation assays (PLA)), as well as tumor associated macrophage (TAM) content, were assessed in 39 NSCLC wt EGFR patient-derived xenograft (PDX) models. A strong correlation (EGFR r=0.63; p<0.0001; MET r=0.83; p<0.0001) between the IHC and PLA scores for both EGFR and MET confirmed the expected link between signaling level and receptor expression. Based on these data, 14 models with different levels of EGFR and MET expression and TAM infiltration were selected for amivantamab efficacy assessment. While no correlation was found between MET IHC H-score and efficacy, positive correlations were identified between EGFR H-score and PLA-score to amivantamab efficacy. Exclusion of models with known oncogenic driver mutations downstream of EGFR and MET, such as KRAS and PI3K, led to strong correlations to both EGFR expression and signaling (IHC - r=0.90; p=0.002; PLA - r=0.92; p=0.001). Indeed, models with EGFR H-score ≥170 and no alternative driver mutations achieved prolonged tumor stasis or complete tumor regressions with amivantamab treatment. No correlation between TAM content and amivantamab efficacy was observed. Previous studies have demonstrated superior amivantamab efficacy in models driven by either mutant EGFR or amplification of MET, compared to a version lacking Fc interaction; however, both antibodies demonstrated similar efficacy in 13 out of 14 NSCLC wt EGFR PDX models. This suggests that while amivantamab efficacy requires Fc-interaction in models driven by EGFR mutation or MET amplification (ligand-independent), the Fc-interaction is not required for efficacy in wt EGFR driven NSCLC models. We hypothesize that NSCLC PDX models with higher levels of wt EGFR are more growth dependent on EGFR ligands, and thus inhibited by the ligand blocking activity of amivantamab. The lack of species cross-reactivity with the MET ligand HGF, likely underestimates MET signaling dependencies in these mouse models, although this may play a role in patient tumors. These findings suggest NSCLC patients with elevated wt EGFR expression and lacking driver mutations may achieve therapeutic benefit from amivantamab treatment.

Citation Format: Benjamin Henley, Kristen Chevalier, Matthew Smith, Smruthi Vijayaraghaven, Barbara Bushey, Gerald Chu, Joshua Curtin, Nataša Obermajer, Kathryn Packman, Sylvie Laquerre, Matthew Lorenzi, Eric Haura, Sheri Moores. Efficacy of amivantamab, a bispecific EGFR/MET antibody, correlates with EGFR expression and signaling in NSCLC models with wild-type EGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 953.