Editor’s Note: The development of modern oncology has provided a variety of groundbreaking treatment options for lung cancer, making it one of the most rapidly evolving solid tumors. To help clinical physicians gain an in-depth and comprehensive understanding of the significant advancements in this field, "Oncology Frontier" has joined forces with Dr. Hua Zhong and Dr. Baohui Han, Director of the Department of Respiratory and Critical Care Medicine at Shanghai Jiao Tong University School of Medicine Affiliated Chest Hospital,  to create a clinical progress series called "Zhong's Insights, Hui's Wisdom." By interpreting high-quality clinical studies in the field of lung cancer, this series aims to promote the improvement of clinical diagnostic and treatment practices. In this 23rd issue of the “Zhong's Insights, Hui's Wisdom” series, Dr. Hua Zhong and Dr. Baohui Han provide their expert analysis on the relationship between PD-L1 expression levels and the efficacy of first-line crizotinib treatment in ROS-1 fusion-positive non-small cell lung cancer (NSCLC) patients. The study was published in Lung Cancer by the Department of Respiratory and Critical Care Medicine at Shanghai Jiao Tong University School of Medicine Affiliated Chest Hospital, with Dr. Runbo Zhong as the corresponding author.

Relationship Between PD-L1 Expression and Crizotinib Efficacy in ROS-1 Fusion-Positive NSCLC Patients

Dr. Baohui Han: Immunotherapy and targeted therapy represent two groundbreaking treatment options in modern oncology for lung cancer. Targeted therapies typically require testing for driver gene mutations, and patients with positive mutations are often prioritized for targeted drug treatments. For patients without driver mutations, PD-L1 expression levels are tested, and based on the expression level, immune checkpoint inhibitors may be used as monotherapy or in combination, according to the overall treatment principles for advanced lung cancer.

Previous studies suggested that driver mutations and PD-L1 expression are mutually exclusive and do not occur in the same patient. However, with the increasing use of NGS (next-generation sequencing) and PD-L1 testing, we have discovered a small subset of patients who exhibit both PD-L1 expression and driver gene mutations. Research on these patients is limited, especially for those with rare mutations combined with high PD-L1 expression. Therefore, this study provides important guidance for clinical treatment decisions.

In fact, previous research on the EGFR pathway revealed that patients with high PD-L1 expression who received targeted therapy had poorer outcomes. As PD-L1 expression increased, the efficacy of targeted therapy decreased, suggesting that high PD-L1 expression combined with driver mutations may define a unique subtype of lung cancer patients. However, since different driver mutations have distinct biological characteristics, it remains unclear whether the phenomenon observed in the EGFR pathway applies to other pathways. In ROS-1 fusion-positive patients, this study found a different conclusion: high PD-L1 expression was not correlated with the efficacy of first-line crizotinib. In addition to crizotinib, next-generation TKIs such as entrectinib and repotrectinib are gradually being introduced into clinical practice. Whether PD-L1 expression affects the efficacy of these drugs remains to be studied further. Additionally, it is still unclear whether patients with or without high PD-L1 expression will develop different resistance mechanisms in the future, which also warrants further investigation.

Currently, more than 10 different fusion partners have been identified in the ROS-1 fusion pathway, with CD74 being the most common. Whether the fusion partner affects treatment efficacy has been debated in previous studies. This study found that patients with different fusion partners all benefited similarly from this treatment, supplementing important data.

Dr. Hua Zhong: As driver gene mutation and PD-L1 testing have become more widespread and clinical experience with these therapies has grown, we have indeed found a small group of patients who exhibit both driver gene mutations and PD-L1 expression. Previous literature reports estimate that this group accounts for 10% to 15% of patients. As Dr. Han mentioned earlier, high PD-L1 expression has been shown to negatively impact the efficacy of targeted drugs in the EGFR pathway.

Another important clinical question is whether targeted therapy and immunotherapy can be used concurrently for patients with both driver mutations and high PD-L1 expression. At least for the EGFR and ALK pathways, this approach seems unlikely to be successful.

Previous studies explored the concurrent use of crizotinib and immune checkpoint inhibitors (e.g., the CheckMate 370 cohort E), but unfortunately, the study was terminated early after enrolling just over 10 patients, as two patients died due to severe liver damage. Subsequent studies, including combinations of crizotinib or alectinib with nivolumab or pembrolizumab, were also explored but similarly terminated due to safety concerns, with toxicity primarily manifesting in the liver. Similar findings have been observed in the EGFR pathway, where combinations of first-generation gefitinib or third-generation osimertinib with immune checkpoint inhibitors also led to increased rates of immune-related liver damage and interstitial lung disease. Therefore, combining immunotherapy with targeted therapy in clinical practice requires extreme caution.

Dr. Baohui Han

• Eminent physician in Shanghai
• Honorary Director of the Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University
• Director of Drug Clinical Trial Institution
• Recipient of State Council special allowance
• Executive Committee Member of the Chinese Society of Clinical Oncology (CSCO)
• Chair of the CSCO Committee on Tumor Angiogenesis Targeting
• Vice President of the Chinese Medical Association for Tumor Immunology and Biology
• Deputy Director of the 8th Shanghai Anti-Cancer Association Board of Directors
• Vice Chair of the Respiratory Committee of the Shanghai Medical Doctor Association

Dr. Hua Zhong

• Director of the Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University
• Chief Physician and Doctoral Supervisor
• Reviewer for the National Natural Science Foundation of China
• Committee member of CSCO’s NSCLC division
• Former visiting scholar at the University of Pittsburgh, specializing in immunotherapy for lung cancer
• Recipient of the Chinese Medical Science Award, second prize, and the Shanghai Cancer Technology Award