Chapter 7 242 Integration of the PD-1T signature into prospective trials Biomarkers hold a pivotal role in guiding treatment decisions, but how can we integrate them into clinical trial designs? The treatment landscape for advanced NSCLC has evolved, with ongoing investigations into the synergistic potential of immunotherapy combination therapies. A noteworthy development is the adoption of the combination of chemotherapy and pembrolizumab as the standard of care for newly diagnosed advanced NSCLC patients without targetable oncogenes. This is a result of the improved OS observed within the cohort receiving pembrolizumab plus chemotherapy, in contrast to those receiving chemotherapy alone. Importantly, this effect was observed irrespective of the patients’ tumor PD-L1 status54,55. A debate persists concerning the methodological and essential aspects of PD-L1 IHC testing to determine the ideal candidates for combined chemotherapy and pembrolizumab versus those who should receive pembrolizumab monotherapy. Many physicians tend to favor pembrolizumab monotherapy for patients with a PD-L1 TPS of 50% or higher. This preference is based on the observation that pembrolizumab monotherapy offers improved tolerability and improved health-related quality of life compared to chemotherapy54,57,58. However, it is important to note that no trial has conducted a direct comparison between pembrolizumab plus chemotherapy and pembrolizumab monotherapy59. Consequently, the majority of patients in clinical practice are prescribed the dual therapy. This current approach underscores the need for more accurate and robust biomarkers in the field. How can the PD-1T signature be incorporated in a clinical diagnostic routine where PD‑L1 IHC testing is already widely implemented? As previously mentioned, the predictive utility of PD-L1 remains limited to the subgroup characterized by a TPS ≥50%. The PD-1T signature biomarker may be strategically used to improve patient stratification within this PD-L1 above 50% group (PD-L1high) or in the PD-L1 below 50% group (PD-L1low). To address these considerations, a prospective observational study could be devised to investigate the following clinical questions: 1) Is the omission of chemotherapy in the PD‑1T signature high (PD-1T-high) + PD-L1low group feasible? 2) Should chemotherapy be added in the PD-1T signature low (PD-1T-low) + PD-L1high patients? The concurrent assessment of PD-L1 TPS and PD-1T signature scores can be determined in parallel with minimal tissue sample requirements. A third clinical question of interest could be: Is leaving out pembrolizumab (so patients will only receive chemotherapy) in the PD-1T-low + PD-L1low group non inferior to the combination of chemotherapy plus pembrolizumab? This question is complicated to assess since the effect of chemotherapy on the tumor-reactive capacity of PD1T TILs is currently unknown. There is a possibility that chemotherapy creates an immunogenic environment, potentially priming new tumor-reactive T cells and
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