Journal Article

Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial

Xie, John, Thayu, Meena, Cho, Byoung Chul, Roshak, Amy, Lee, Jong-Seok, Ou, Sai-Hong Ignatius, Lorenzini, Patricia, Cho, Eun Kyung, Han, Ji-Youn, Curtin, Joshua C., Knoblauch, Roland E., Gomez, Jorge E., Haura, Eric B., Spira, Alexander I., Bauml, Joshua M., Minchom, Anna, Gao, Grace, Lee, Ki Hyeong, Kim, Dong-Wan, Nagasaka, Misako, Sabari, Joshua K., Sanborn, Rachel E., Park, Keunchil, Kim, Sang-We

2023

Overview

Patients with epidermal growth factor receptor ( EGFR )-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR -mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival and overall survival. The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified. In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed overall response rate was 36% (95% confidence interval, 22–51). The median duration of response was 9.6 months, and the median progression-free survival was 4.9 months. Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 . The combination of a bispecific antibody against EGFR and MET with a tyrosine kinase inhibitor (TKI) in patients with TKI-relapsed, chemotherapy-naive, EGFR-mutated advanced NSCLC is safe and shows preliminary efficacy.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/308/2779/109 / 692/308/53/2423 / 692/699/67/1612/2143 / Aniline Compounds - therapeutic use / Antibodies / Anticancer properties / Antitumor agents / Biomarkers / Biomedical and Life Sciences / Biomedicine / Bispecific antibodies / c-Met protein / Cancer Research / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Chemotherapy / Enzyme inhibitors / Epidermal growth factor receptors / ErbB Receptors - genetics / Growth factors / Humans / Immunohistochemistry / Infectious Diseases / Kinases / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Metabolic Diseases / Molecular Medicine / Monoclonal antibodies / Mutants / Mutation - genetics / Neurosciences / Next-generation sequencing / Non-small cell lung carcinoma / Prospective Studies / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Protein-tyrosine kinase / Response rates / Safety / Small cell lung carcinoma / Survival / Targeted cancer therapy / Tyrosine