Byoung Chul Cho 1 *, Dong-Wan Kim 2, Alexander I. Spira 3, Jorge E. Gomez 4, Eric B. Haura 5, Sang-We Kim 6, Rachel E. Sanborn 7, Eun Kyung Cho 8, Ki Hyeong Lee 9, Anna Minchom 10, Jong-Seok Lee 11, Ji-Youn Han 12, Misako Nagasaka 13, Joshua K. Sabari 14, Sai-Hong Ignatius Ou 13, Patricia Lorenzini 15, Joshua M. Bauml 15, Joshua C. Curtin 15, Amy Roshak 15, Grace Gao 15, John Xie 15, Meena Thayu 15, Roland E. Knoblauch 15 & Keunchil Park 16,17
1Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
2Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea.
3Virginia Cancer Specialists Research Institute, US Oncology Research, Fairfax, VA, USA.
4Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
6Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
7Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA.
8Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea.
9Chungbuk National University Hospital, Cheongju, Republic of Korea.
10Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
11Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
12National Cancer Center, Gyeonggi-do, Republic of Korea.
13University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, USA.
14New York University School of Medicine, New York, NY, USA.
15Janssen R&D, Spring House, PA, USA.
16Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
17Present address: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
*Corresponding author: correspondence to Byoung Chul Cho
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.