Summary and future perspectives 235 7 Summary and future perspectives The primary objective of this thesis was to identify novel biomarkers that can improve the pretreatment selection for PD-1 blocking agents in advanced non-small cell lung cancer (NSCLC), specifically for patients who are less likely to benefit from this treatment. Chapter 2 of this thesis focused on the assessment of biomarkers that are direct effectors of the anti-tumor immune response. One of the direct effectors, PD-1T tumor infiltrating lymphocytes (TILs), emerged as a key biomarker capable of predicting clinical benefit to PD-1 blockade in NSCLC with a high negative predictive value (NPV). Chapter 3 assessed whether combining PD-1T TILs with other established immune-related biomarkers could improve the predictive accuracy of PD-1T TILs. To facilitate the clinical application of PD-1T TILs as biomarker, chapter 4 of this thesis focused on the development of a gene signature closely associated with PD-1T TILs. This signature was constructed using NanoString technology, a robust clinicalgrade platform known for its proficiency in mRNA profiling, particularly from formalin-fixed paraffin-embedded (FFPE) tissue samples. Chapter 5 and 6 of this thesis highlight alternative bio-sources for biomarker testing, aimed to mitigate the need for invasive tumor biopsy procedures. All chapters will be discussed in more detail in the following sections. Chapter 2; PD-1T TILs as key effectors in the anti-tumor immune response, emerging as a promising biomarker beyond PD-L1 Pharmacological blockade of the inhibitory immune receptor PD-1 and its ligand PD-L1 has transformed the treatment landscape of advanced stage NSCLC. These immune checkpoint blocking (ICB) agents have demonstrated the capacity to induce durable responses, with estimated 5-year overall survival (OS) rates ranging from 16% to 23%1. Nevertheless, a substantial proportion of patients, approximately 60% to 70%, experience disease progression within the first six months after treatment initiation2–4. This raises concerns about the unnecessary exposure of patients to adverse effects, the financial burden, and the potential delay in exploring alternative (experimental) therapeutic options. Hence, the identification of biomarkers capable of selecting patients that will not derive benefit from PD-(L)1 blockade monotherapy has become an urgent necessity. Crucially, false negative test results should be minimized, as the impressive long-term responses observed with PD-(L)1 blockade have made clinicians hesitant to withhold this treatment from their patients. To achieve this goal, a sensitivity and NPV of ≥90% are considered necessary to avoid undertreatment. Concurrently, a specificity of ≥50% is required to effectively reduce overtreatment.
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