Format

Send to

Choose Destination
Lung Cancer. 2020 Mar 19;143:55-59. doi: 10.1016/j.lungcan.2020.03.019. [Epub ahead of print]

A novel ROS1 G2032 K missense mutation mediates lorlatinib resistance in a patient with ROS1-rearranged lung adenocarcinoma but responds to nab-paclitaxel plus pembrolizumab.

Author information

1
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China; Graduate Schools, University of South China, Hengyang, Hunan, 421001, China.
2
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China.
3
Burning Rock Biotech, Guangzhou, 510300, China.
4
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China. Electronic address: zhangyongchang@csu.edu.cn.

Abstract

INTRODUCTION:

ROS1-rearranged non-small cell lung cancer (NSCLC) has demonstrated promising response to lorlatinib; however, no targeted therapy is available after failure of lorlatinib and information on acquired resistance mechanisms mediating lorlatinib resistance among ROS1-rearranged NSCLC patients is limited. We report a ROS1-rearranged NSCLC patient who responded to immunochemotherapy after acquisition of ROS1 G2032K-mediated lorlatinib resistance.

METHODS:

Next-generation sequencing (NGS) was performed on supraclavicular lymph nodes (SLN) and blood samples obtained from the 53-year old male patient with advanced CD74-ROS1-rearranged NSCLC. In vitro experiments with patient-derived SLN tumor cells and in silico homology modeling were performed to investigate mechanisms of G2032K-mediated inhibitor resistance.

RESULTS:

NGS analysis revealed the detection of an acquired ROS1 G2032 K after failure from lorlatinib. Homology modeling revealed the conformational change in the inhibitor binding site induced by the ROS1 G2032 K that disrupted lorlatinib binding. In vitro experiments using patient-derived cells bearing concurrent CD74-ROS1-rearrangement and ROS1 G2032 K demonstrated half-maximal inhibitory concentration IC50 of 730.2 nM for lorlatinib, 812.1 nM for entrectinib, and 1546 nM for crizotinib, indicating resistance to these inhibitors. With PD-L1 expression of TPS 30 %, nab-paclitaxel plus pembrolizumab was administered as fifth-line treatment and achieved partial response, with sustained response ongoing for 7 months as of January 31, 2020.

CONCLUSION:

ROS1 G2032 K is a novel mutation that mediates resistance to lorlatinib. With the lack of targeted therapeutic options after lorlatinib resistance, checkpoint inhibitor plus chemotherapy may be considered as a treatment option in patients with ROS1-rearranged NSCLC.

KEYWORDS:

Lorlatinib; Non-small cell lung cancer; Pembrolizumab; ROS1

Conflict of interest statement

Declaration of Competing Interest Analyn Lizaso and Xinru Mao are employees of Burning Rock Biotech. The other authors declare no conflict of interest.

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center