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

• Published in: Nature medicine Vol. 29; no. 10; pp. 2577 - 2585
• Main Authors: Cho, Byoung Chul, Kim, Dong-Wan, Spira, Alexander I., Gomez, Jorge E., Haura, Eric B., Kim, Sang-We, Sanborn, Rachel E., Cho, Eun Kyung, Lee, Ki Hyeong, Minchom, Anna, Lee, Jong-Seok, Han, Ji-Youn, Nagasaka, Misako, Sabari, Joshua K., Ou, Sai-Hong Ignatius, Lorenzini, Patricia, Bauml, Joshua M., Curtin, Joshua C., Roshak, Amy, Gao, Grace, Xie, John, Thayu, Meena, Knoblauch, Roland E., Park, Keunchil
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2023; Nature Publishing Group
• Subjects: 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
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-023-02554-7

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.