Association of Programmed Death-Ligand 1 Expression with Fusion Variants and Clinical Outcomes in Patients with Anaplastic Lymphoma Kinase-Positive Lung Adenocarcinoma Receiving Crizotinib.

Abstract

BACKGROUND:

Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib.

MATERIALS AND METHODS:

PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments.

RESULTS:

A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD-L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression-free survival (PFS) was better in tumors with negative PD-L1 expression (ORR/PFS in PD-L1 0% vs. 1%-49% vs. 50%-100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p = .007/.022). The multivariate Cox proportional hazards model revealed that PD-L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160-0.650, p = .002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD-L1 expression.

CONCLUSION:

Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib.

IMPLICATIONS FOR PRACTICE:

Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small-molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD-L1 expression was also associated with worse response rate and shorter progression-free survival of anaplastic lymphoma kinase (ALK)-positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD-L1 compared with long variants (V1, V2, and V6). Testing PD-L1 before initiating crizotinib for ALK-positive lung cancer could be a simple method to provide important prognostic information.

• Authors: Ching-Yao Yang, Wei-Yu Liao, Chao-Chi Ho, Kuan-Yu Chen, Tzu-Hsiu Tsai, Chia-Lin Hsu, Yi-Nan Liu, Kang-Yi Su, Yih-Leong Chang, Chen-Tu Wu, Bin-Chi Liao, Chia-Chi Hsu, Wei-Hsun Hsu, Jih-Hsiang Lee, Chia-Chi Lin, Jin-Yuan Shih, James Chih-Hsin Yang, Chong-Jen Yu
• Journal: The oncologist (Oncologist) Vol. 25 Issue 8 Pg. 702-711 (08 2020) ISSN: 1549-490X [Electronic] England
• PMID: 32386255 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © AlphaMed Press 2020.

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• Protein Kinase Inhibitors
• Crizotinib
• Anaplastic Lymphoma Kinase

Topics

• Adenocarcinoma of Lung (drug therapy, genetics)
• Anaplastic Lymphoma Kinase (genetics)
• B7-H1 Antigen (genetics)
• Crizotinib (pharmacology, therapeutic use)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Mutation
• Protein Kinase Inhibitors (therapeutic use)
• Tumor Microenvironment