Amivantamab as a salvage therapy post-EGFR-tyrosine kinase inhibitor failure in patients with mutated EGFR non-small cell lung cancer

Background: Amivantamab is an approved dual epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) inhibitor for the treatment of EGFR exon 20 insertion (EGFRex20ins) mutations. Recent data support the use of amivantamab for both common and uncommon EGFR mutations after previous therapies. In this study, we investigated the role of adding amivantamab to the ongoing EGFR-tyrosine kinase inhibitor (TKI) in later lines of therapy upon progression. Methods: Patients treated at Shaare Zedek Medical Center (SZMC) from October 2021 to May 2024 who received amivantamab plus a previous EGFR-TKI. Cohort A included nine patients with common EGFR mutations [four exon 19 deletions (ex19dels), one G719C, four L858R]. Cohort B included six patients with exon 20 insertions. Safety and preliminary efficacy were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Results: In cohort A, the objective response rate (ORR) was 22% (L858R 50%, exon 19 0%), disease control rate (DCR) 44% (L858R 100%, exon 19 0%), median duration of treatment (mDoT) 3 months (L858R 7.5 months, exon 19 2.3 months), and median overall survival (mOS) 6.7 months (L858R 14.4 months, exon 19 4.6 months). In cohort B, ORR was 17%, DCR 83%, mDoT 5.5 months, and mOS 16.2 months. Grade ≥3 toxicities included nausea, diarrhea, rash, infusion reactions, and thromboembolism. Conclusions: This pilot study suggests that adding late-line amivantamab to an ongoing EGFR-TKI may have potential benefits in selected non-small cell lung cancer (NSCLC) patients with EGFR mutations, but resulted in high skin toxicity. Patients with EGFR L858R mutations appeared to show improved responses to amivantamab compared to the lack of response with ex19dels, while acquired resistance was associated with loss of the original EGFR driver mutation and MET alterations. However, these preliminary findings lack robust evidence due to study limitations, and larger, prospective, multi-center trials are needed to validate these results.