Resistance to immune checkpoint inhibitors in advanced lung cancer: Clinical characteristics, potential prognostic factors and next strategy

Jiebai Zhou; Xinyuan Lu; Haixing Zhu; Ning Ding; Yong Zhang; Xiaobo Xu; Lei Gao; Jian Zhou; Yuanlin Song; Jie Hu

doi:10.3389/fimmu.2023.1089026

Resistance to immune checkpoint inhibitors in advanced lung cancer: Clinical characteristics, potential prognostic factors and next strategy

Front Immunol. 2023 Jan 26:14:1089026. doi: 10.3389/fimmu.2023.1089026. eCollection 2023.

Authors

Jiebai Zhou¹, Xinyuan Lu², Haixing Zhu³, Ning Ding¹, Yong Zhang¹, Xiaobo Xu¹, Lei Gao¹, Jian Zhou¹, Yuanlin Song^{1

4}, Jie Hu^{1

5}

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
² Key Laboratory of Public Health Safety, School of Public Health, Ministry of Education, Fudan University, Shanghai, China.
³ Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai, China.
⁵ Department of Pulmonary and Critical Care Medicine, Shanghai Geriatrics Center, Shanghai, China.

Abstract

Background: Immune checkpoint inhibitors (ICIs) have shown unprecedented clinical benefit in cancer immunotherapy and are rapidly transforming the practice of advanced lung cancer. However, resistance routinely develops in patients treated with ICIs. We conducted this retrospective study to provide an overview on clinical characteristics of ICI resistance, optimal treatment beyond disease progression after prior exposure to immunotherapy, as well as potential prognostic factors of such resistance.

Methods: 190 patients diagnosed with unresectable lung cancer who received at least one administration of an anti-programmed cell death 1 (PD-1)/anti-programmed cell death-ligand 1(PD-L1) at any treatment line at Zhongshan Hospital Fudan University between Sep 2017 and December 2019 were enrolled in our study. Overall survival (OS) and progression-free survival (PFS) were analyzed. Levels of plasma cytokines were evaluated for the prognostic value of ICI resistance.

Results: We found that EGFR/ALK/ROS1 mutation and receiving ICI treatment as second-line therapy were risk factors associated with ICI resistance. Patients with bone metastasis at baseline had a significantly shorter PFS1 time when receiving initial ICI treatment. Whether or not patients with oligo-progression received local treatment seemed to have no significant effect on PFS2 time. Systemic therapies including chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. TNF, IL-6 and IL-8 were significantly elevated when ICI resistance. Lower plasma TNF level and higher plasma IL-8 level seemed to be significantly associated with ICI resistance. A nomogram was established to prognosis the clinical outcome of patients treated with ICIs.

Conclusion: Patients with EGFR/ALK/ROS1 mutation, or those receiving ICI treatment as second-line therapy had higher risk of ICI resistance. Patients with bone metastasis had poor prognosis during immunotherapy. For those patients with oligo-progression after ICI resistance, combination with local treatment did not lead to a significantly longer PFS2 time. Chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. Levels of plasma cytokines including TNF, IL-6 and IL-8 were associated with ICI resistance.

Keywords: advanced lung cancer; immune checkpoint inhibitor; plasma cytokines; prognostic factor; resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Immunological* / pharmacology
Carcinoma, Non-Small-Cell Lung* / drug therapy
ErbB Receptors
Humans
Immune Checkpoint Inhibitors / therapeutic use
Interleukin-6
Interleukin-8
Lung Neoplasms* / pathology
Prognosis
Protein-Tyrosine Kinases
Proto-Oncogene Proteins
Receptor Protein-Tyrosine Kinases
Retrospective Studies

Substances

Immune Checkpoint Inhibitors
Interleukin-6
Interleukin-8
Protein-Tyrosine Kinases
Antineoplastic Agents, Immunological
Proto-Oncogene Proteins
Receptor Protein-Tyrosine Kinases
ErbB Receptors

Grants and funding

This work was supported by Shanghai Respiratory Research Institute (YJS-100-3), Shanghai Municipal Key Clinical Specialty (shslczdzk02201), Science and Technology Commission of Shanghai Municipality (20DZ2254400) and Beijing CSCO Clinical Oncology Research Foundation (YBMS2019-077).