Abstract B153: Resistance mechanisms to mobocertinib in treating NSCLC with EGFR exon 20 insertion mutations

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Abstract Background: Mobocertinib is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that received FDA accelerated approval for non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations, based on data from a pivotal phase 1/2 study of mobocertinib (NCT02716116). In platinum-pretreated patients (pts) with EGFR ex20ins NSCLC (N=114), the overall response rate (ORR) was 28%, median duration of response was 17.5 months, and median progression-free survival was 7.3 months. Despite this encouraging clinical activity, de novo and acquired resistant mechanisms to mobocertinib remain largely unknown. Methods: Tumor samples and circulating tumor DNA (ctDNA) samples were obtained from platinum-pretreated pts with EGFR ex20ins+ NSCLC treated with mobocertinib (NCT02716116) and subjected to next-generation sequencing (NGS) analyses. CtDNA was collected at baseline, cycle 3 day 1 (C3D1) and progression per protocol. Tumor growth assay was performed in BaF3 cells and patient-derived xenograft models to evaluate efficacy of combination therapies to overcome resistance. Results: At baseline, in tumor (n=56), the combined presence of BRAF and PIK3CA mutations alone (n=9) or together with copy number gains (CNV) in EGFR, MYC, CDK4, or CCND1 (n=19) was significantly associated with inferior ORR to mobocertinib with odd ratios of ‘infinity’ (p=0.045) and 13.21 (p=0.0047), respectively. Individual co-occurring gene mutations and CNV were not significantly associated with differential clinical outcomes. Longitudinal analysis of paired tumor-blood samples at baseline and C3D1 showed that 22 out of 55 pts (40%) achieved clearance at C3D1, including 81.2% (13/16) of PR pts, 50% of SD pts, and 20% of PD pts. CtDNA was also used to assess emerging mutations after mobocertinib progression after at least 5 months of treatment (n=18). TP53 (n=11) and acquired secondary EGFR (n=5) were the most common genes with emerging variants, including EGFR T790M (n=4) and D379E (n=1). With this observation, T790M was engineered in Ba/F3 cells in the context of EGFR ex20ins mutations (H773_V774insNPH and 769_D770insASV). T790M did confer resistance to mobocertinib in vitro, and to all EGFR TKIs tested including osimertinib. In patient-derived xenograft models (H773_V774insNPH and 769_D770insASV), the combination of mobocertinib plus the bispecific monoclonal antibody amivantamab demonstrated greater antitumor activity than either agent alone. Conclusions: Our results indicate that bypass pathway alterations are associated with de novo resistance whereas T790M emergence mediates acquired resistance to mobocertinib. Future research is warranted to determine the potential clinical benefits of combination strategies in patients with EGFR ex20ins+ NSCLC. Citation Format: Xiuning Le, Monique Nilsson, Sampurna Chatterjee, Zhenqiang Su, Junqin He, Hibiki Udagawa, Xiaoxing Yu, Alissa Poteete, Qian Huang, John V Heymach, Sylvie Vincent. Resistance mechanisms to mobocertinib in treating NSCLC with EGFR exon 20 insertion mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B153.