Abstract 5198: JNJ-61186372, a novel EGFR/c-Met bispecific antibody, exhibits potent antitumor activity in broad-spectrum of acquired resistance to EGFR-TKIs

Abstract

Abstract Background: 1st generation (erlotinib & gefitinib), 2nd generation (afatinib), and 3rd generation (osimertinib) EGFR TKIs have marked efficacy in patient with EGFR-mutant NSCLC. Unfortunately, patients who show T790M (-) mutation after treated with 1st and 2nd generation EGFR TKI or have C797S (+) mutation or other mechanisms of acquired resistance to 3rd generation EGFR TKI have no therapeutic options for curing cancer in clinic. We introduce a potent therapeutics for overcoming acquired resistance to EGFR-TKIs in several EGFR mutant NSCLC models using JNJ-61186372 (JNJ-372), a bispecific antibody that targets the EGFR and c-Met receptors. Methods: We classified PDC and PDX models into two groups: i) 1st and 2nd generation EGFR TKI acquired resistance models with T790M (-) mutation (YU-1093, YU-1152), ii) 3rd generation EGFR TKI acquired resistance models with C797S (+) mutation (YU-1097), and C797S (-) mutation with unknown resistance mechanisms (YU-1095, YU-1089, YU-1096, YUX-1024_YH1R, YHIM-1035, YHIM-1045, and YHIM-1053). We established 7 patient-derived cells (PDC) and 3 patient-derived xenografts (PDX) model from patients with broad-spectrum acquired resistance to EGFR-TKIs. We performed cell viability test and western blot to investigate antitumor activity of JNJ-372. We evaluated then in vivo antitumor activity of JNJ-372 in PDX and PDC-xenograft models. JNJ-372 was administrated i.p. twice a week at 30 mg/kg. Results: We assessed the ability of JNJ-372 to overcome broad-spectrum of EGFR-TKI acquired resistances. JNJ-372 significantly inhibited cancer cell growth in vitro and in vivo in PDC model harboring T790M (-) mutation. JNJ-372 significantly decreased cell proliferation rate and EGFR downstream signaling in BaF3 cell harboring Del19 (L858R)/T790M/C797S mutant and PDC model harboring Del19/T790M/C797S mutant with amplified KRAS and loss of Rb. C797S (-) cases of four PDCs and three PDX models had i) loss of T790M with c-Met amplification or other acquired resistance mutation and ii) T790M (+) with amplified c-Met. In these models we identified dramatic tumor regression and reduction of EGFR and c-Met expression in vitro and in vivo PDX and PDC-xenograft models. Interestingly, we observed combination treatment of JNJ-372 and c-Met inhibitor showed synergistic immune cell mediated cellular cytotoxicity in EGFR-TKI acquired resistance models harboring c-Met amplification. JNJ-372 exhibited potent inhibition of tumor growth in preclinical models through targeting EGFR and c-Met receptor, decreasing EGFR and c-Met receptor level, inhibiting EGFR downstream signaling cascade and activating ADCC effect in vivo. Conclusion: Our results suggest that JNJ-372 will provide potential and effective therapeutic options for patients with no therapeutic option to overcome broad-spectrum of acquired resistance to EGFR-TKIs. Citation Format: SooHwan Lee, Jiyeon Yun, Seo-Yoon Jeong, Chae Won Park, Seok-Young Kim, Min Hee Hong, Hye Ryun Kim, Byoung Chul Cho. JNJ-61186372, a novel EGFR/c-Met bispecific antibody, exhibits potent antitumor activity in broad-spectrum of acquired resistance to EGFR-TKIs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5198.