Abstract 6504: Exploratory analysis using serial cell-free DNA in patients treated with amivantamab in non-small cell lung cancer with EGFR exon 20 insertion mutations

Abstract Introduction: Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20 ins) mutation showed limited clinical activity with conventional EGFR tyrosine kinase inhibitors (TKIs). Amivantamab is the first bispecific antibody to be approved for the treatment of metastatic non-small cell lung cancer (NSCLC) with EGFR ex20ins mutation. However, limited data is available in terms of predictive biomarkers and the resistance mechanism. In this study, we conducted an exploratory analysis to elucidate a genomic landscape using circulating tumor DNA (ctDNA) from plasma samples. Patients and Methods: This study include result from 79 blood samples, which has been prospectively collected from 27 EGFR ex20ins mutated NSCLC patients (confirmed by either tissue or plasma-based test) who were treated with amivantamab. ctDNAs were obtained from plasma, which was serially collected at baseline, after 2 cycles of treatment, 2 cycles prior to the treatment discontinuation, and at the time point of disease progression. Guardant OMNI panel (Guardant Health, CA, USA) was used for the genomic profiling. Results: The median follow-up duration was 5. 8 months (range 2. 7-12. 7). The overall response rate was 40. 7% (95% confidence interval CI 24. 5-59. 2, n=11), and median progression-free survival was 5. 8 months (95% CI 3. 9-15. 9) with a median duration of response of 9. 8 months (95% CI, 7. 3-NA). Patients with EGFR ex20ins not detected from ctDNA at baseline (n=10) showed significantly longer PFS compared to patients with EGFR ex20ins identified at baseline plasma sample (n=17) (14. 6 vs 3. 9 months; hazard ratio HR 0. 40, 95% CI 0. 17-0. 95, P0. 05). The most common concurrent somatic variations at baseline were TP53 (62. 9%), TERT (18. 5%), ATM (18. 5%). Longer median PFS was observed in patients without EGFR amplification (n=18) compared to patients with concurrent EGFR amplification (n=9) (11. 1 vs. 2. 5 months; HR 0. 30, 95% CI 0. 11-0. 77, P 0. 05). The presence of plasma EGFR ex20ins at C2D15 predicted poor PFS (17. 8 vs 2. 7 months; HR 0. 17, 95% CI 0. 06-0. 47, P 0. 01), regardless of baseline its presence or absence. Based on the paired analysis using baseline and at the timepoint of disease progression, putative resistance mechanism to amivantamab was identified in 14 patients (60. 8%), which were PDGFRB (28. 5%), followed by PTEN (21. 4%), CHEK2 (21. 4%). Conclusions: This study provides a comprehensive longitudinal ctDNA analysis in patients with EGFR ex20ins mutant NSCLC who were treated with amivantamab. Our results suggested that the presence of ctDNA for EGFR ex20ins mutation and co-alteration with EGFR amplification at baseline might be related to the clinical outcomes of amivantamab. Citation Format: Geun-Ho Park, Sehhoon Park, Hyen-Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Se-Hoon Lee. Exploratory analysis using serial cell-free DNA in patients treated with amivantamab in non-small cell lung cancer with EGFR exon 20 insertion mutations abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6504.