Programmed death-ligand 1 copy number alterations may provide an additional predictive measure for response to immunotherapy in non-small cell lung cancer

1. Programmed death-ligand 1 copy number loss was identified as an independent risk factor for the progression of the disease

2. Copy number alteration provides additional therapy prediction on top of immunohistochemistry

Evidence Rating Level: 1 (Excellent)

Study Rundown: First-line treatment for non-small cell lung cancer (NSCLC) includes immune checkpoint inhibitor (ICI) therapy. To determine which patients are most likely to benefit from this treatment, the expression of programmed death ligand 1 (PD-L1) is determined by immunohistochemistry (IHC) which uses a tumour proportion score based on PD-L1 staining. This study examined whether PD-L1 copy number (CN) alterations are useful additional biomarkers compared to standard IHC when anticipating a patient’s tumour response to ICI therapy as they are a stable intra-tumour parameter, characterized by loss, gain or neutral. The primary outcomes of this study were progression-free survival (PFS) and overall survival (OS). This study found an overall median PFS of 3.2 months and a median OS of 14.6 months. Both standard IHC and CN had good predictive values for PFS and OS. While TPS > 50% via IHC predicted the group most likely to respond to ICI therapy, CN loss independently predicted the group with the worst response; however, only in PD-L1 low positive group. The authors built a risk prediction model combining both IHC and CN which grouped patients based on the presence of poor responders (e.g., TPS < 50 or CN loss). The 3 categories included high risk (both risk factors), intermediate risk (one risk factor), and low risk (neither risk factor) and were superior to conventional IHC staining. Limitations of this study include its limited generalizability due to a single-centre focus in South Korea. Overall, the results from this study suggest that utilizing PD-L1 CN may aid efforts to predict response to ICI therapy in NSCLC.

Click to read the study in the Journal of Thoracic Oncology

Relevant Reading: Programmed Death-Ligand 1 Heterogeneity and Its Impact on Benefit From Immune Checkpoint Inhibitors in NSCLC

In-Depth [retrospective cohort]: This retrospective comparative study based in Korea had a final cohort of 291 patients, each of whom was diagnosed with advanced NSCLC. The median overall PFS was 3.2 months (95% confidence interval (CI), 2.4-4.3) and an overall OS of 14.6 months (95% CI, 12.3-17.6). IHC-stained PD-L1 discriminated the highest response group with an HR of 0.63 (95% CI, 0.48 – 0.85) for PFS and HR of 0.70 (95% CI, 0.52-0.94) for OS. A CN loss had numerically the worse PFS HR 1.32 (95% CI, 1.00 – 1.73), and OS of HR 1.39 (95% CI, 1.05 – 1.85). CN loss had a significant impact only in the PD-L1 low positive group for PFS (p = 0.039) but not on OS (p = 0.097). The proposed risk model by the authors was able to fine-tune risk prediction between intermediate-risk and high-risk groups (OS, p = 0.016) which traditional IHC did not. Altogether, this study demonstrates a signal of clinical benefit in using CN as an adjunct to IHC-based prediction.

Image: PD

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