Analysis of ctDNA next generation sequencing (NGS) for predicting response to amivantamab and lazertinib among patients with EGFR-mutant NSCLC after progression on osimertinib and platinum-based chemotherapy (CHRYSALIS-2 Cohort A)

Background: Among post-osimertinib (osi), chemotherapy-naïve patients (pts) treated with amivantamab (ami) and lazertinib (laz) in CHRYSALIS Cohort E, NGS of baseline ctDNA and tumor tissue revealed pts with identified EGFR/MET-based resistance (eg, EGFR C797S or MET amplification) were slightly more likely to respond versus those without EGFR/MET-based resistance (ORR=47% vs 29%), but about half of responders had unknown resistance mechanisms (Bauml JCO 2021; 39:15_suppl, 9006). In CHRYSALIS-2 Cohort A (NCT04077463), ami + laz demonstrated an ORR of 33% in the post-osi and platinum-based chemotherapy population (Shu JCO 2022; 40:16_suppl, 9006). This analysis investigated whether EGFR/MET-dependent resistance by ctDNA correlated with response. Methods: Cohort A examined ami + laz in EGFR exon19del or L858R mutated advanced NSCLC whose disease progressed on osi as well as platinum-based chemotherapy. ORR was verified through blinded independent central review. Plasma samples were collected prior to treatment; ctDNA was analyzed by Guardant360. Results: A total of 162 pts were enrolled; of these, 110 (68%) had analyzable ctDNA data, with most common mutations observed in EGFR and TP53. Twenty-eight (25%) pts had resistance categorized as EGFR/MET-dependent and 31 (28%) as EGFR/MET-independent; no genetic resistance mechanism was identified in 51 (46%). The ORR was 29% and 26% in EGFR/MET-dependent and independent pts, respectively. ORR in pts with an unknown resistance mechanism was 39% (Table). Conclusions: Among pts who progressed on osi and platinum-based chemotherapy, genetic profiling of osi resistance by ctDNA did not predict response, with many responders having unknown resistance mechanisms. These results suggest alternative biomarker approaches are needed to identify pts most likely to benefit from ami + laz. Table. ORR by type of resistance mechanism Resistance mechanism n PR ORRa EGFR/MET-dependentb 28 8 29% EGFR/MET-independent 31 8 26% Unknown 51 20 39% All patients 110 36 33% aResponses were assessed by blinded independent central review per RECIST v1.1. bIncludes co-occurring ‘independent’ resistance mechanisms. EGFR, epidermal growth factor receptor; MET, mesenchymal epithelial transition factor; ORR, objective response rate; PR, partial response. Citation Format: Rachel E. Sanborn, Saiama N. Waqar, Byoung Chul Cho, Benjamin Besse, Koichi Goto, Yongsheng Wang, Se-Hoon Lee, Melina E. Marmarelis, Yuichiro Ohe, Dong-Wan Kim, Antonio Calles, Joel Neal, Christina S. Baik, Pasi A. Janne, Joshua C. Curtin, Bharvin Patel, Mike Gormley, S. Martin Shreeve, Joshua M. Bauml, Roland E. Knoblauch, James Chih-Hsin Yang. Analysis of ctDNA next generation sequencing (NGS) for predicting response to amivantamab and lazertinib among patients with EGFR-mutant NSCLC after progression on osimertinib and platinum-based chemotherapy (CHRYSALIS-2 Cohort A) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2166.