Strategies for optimizing immune checkpoint inhibition in advanced non-small cell lung cancer

Abstract

<p dir="ltr">As the incidence of lung cancer surges, transcending traditional risk factors such as smoking, the medical community faces unprecedented challenges. Non-small cell lung cancer (NSCLC) diagnoses have risen across diverse demographics, including non-smokers, reflecting a shift in the disease's epidemiology. This thesis critically assesses the transformative role of immune checkpoint inhibitors (ICIs), a therapeutic class that has revolutionized the treatment of advanced NSCLC. While ICIs have improved survival rates, challenges remain, particularly unpredictable patient responses and maintaining quality of life. This work refines ICI treatment strategies to make them more personalized and effective, thereby shaping the future of cancer therapies and enhancing global patient outcomes.</p><p dir="ltr">Paper I explores the corticosteroid use in 196 advanced NSCLC patients treated with ICIs at Karolinska University Hospital from 2016 to 2019. Patients were categorized based on steroid use for general support, palliative care, or immune- related adverse events (irAEs). Findings show that steroids for irAEs do not compromise survival (p = 0.38) and may serve as predictive markers, while those for palliative care are linked with significantly reduced survival (hazard ratio: 2.7; 95% confidence interval [CI], 1.5-4.9). These results underscore the importance of considering the rationale behind steroid use as a key prognostic and predictive factor. Given that corticosteroid use is a pressing clinical matter, seen daily in oncology practice, understanding its impact on patient outcomes is crucial for guiding treatment decisions in advanced NSCLC.</p><p dir="ltr">Paper Il examines ICIs' intracranial effectiveness in 280 advanced NSCLC patients with brain metastases (BM), a group often excluded from trials. Despite neurological symptoms, ICIs achieved intracranial response rates of 24.2%, highlighting their potential in this underrepresented population. This study addresses a major gap in clinical research and advocates for the inclusion of advanced NSCLC patients with symptomatic BMs in future trials.</p><p dir="ltr">Paper III identifies clinical factors-younger age (p = 0.024), previous radiation treatment (p = 0.027), and BM at diagnosis (p = 0.023)-that significantly improve intracranial disease control. These variables led to the development of predictive groups for disease progression (odds ratio: 27.5; p = 0.004). This research highlights the importance of clinical factors in determining intracranial effectiveness and calls for the development of robust biomarkers to guide ICI treatment decision.</p><p dir="ltr">Paper IV introduces the Brain-Lung Immunotherapy Prognostic (BLIP) score, a novel tool for predicting outcomes in NSCLC patients with BMs undergoing ICI therapy. The BLIP score, validated in 152 patients, stratifies patients into "Good" and "Poor" prognostic groups with median intracranial survival of 15 months (95% CI: 2-4) and 7 months (95% CI: 4-10), respectively. Internal validation showed an AUC of 0.869 with external validation confirming its predictive power (p = 0.0063). This tool offers clinicians a reliable method to optimize ICI therapy and improve patient outcomes in a personalized manner.</p><p dir="ltr">In conclusion, this thesis highlights the nuanced role of corticosteroids, the effectiveness of ICIs against BMs, and the importance of clinical factors guiding treatment. These findings advance our understanding of ICI therapy and advocate for more personalized treatment approaches that consider individual patient profiles. The implications of this research are twofold: it paves the way for more inclusive clinical trials and emphasizes the ongoing need for biomarkers to predict treatment outcomes. Ultimately, this thesis redefines treatment paradigms and sets new standards in oncology, inspiring future trials and potentially influencing global protocols to improve survival and quality of life for millions of NSCLC patients worldwide.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Skribek M,</b> Rounis K, Afshar S, Grundberg O, Friesland S, Tsakonas G, Ekman S, De Petris L. Effect of corticosteroids on the outcome of patients with advanced non-small cell lung cancer treated with immune-checkpoint inhibitors. Eur J Cancer. 2021 Mar;145:245-254. Epub 2021 Jan 5. <a href="https://doi.org/10.1016/j.ejca.2020.12.012">https://doi.org/10.1016/j.ejca.2020.12.012</a></p><p dir="ltr"><br></p><p dir="ltr">II. <b>Skribek M,</b> Rounis K, Makrakis D, Agelaki S, Mavroudis D, De Petris L, Ekman S, Tsakonas G. Outcome of Patients with NSCLC and Brain Metastases Treated with Immune Checkpoint Inhibitors in a 'Real- Life' Setting. Cancers (Basel). 2020 Dec 10;12(12):3707. <a href="https://doi.org/10.3390/cancers12123707">https://doi.org/10.3390/cancers12123707</a></p><p dir="ltr"><br></p><p dir="ltr">III. Rounis K, <b>Skribek M,</b> Makrakis D, De Petris L, Agelaki S, Ekman S, Tsakonas G. Correlation of Clinical Parameters with Intracranial Outcome in Non-Small Cell Lung Cancer Patients with Brain Metastases Treated with Pd-1/Pd-L1 Inhibitors as Monotherapy. Cancers (Basel). 2021 Mar 29;13(7):1562. <a href="https://doi.org/10.3390/cancers13071562">https://doi.org/10.3390/cancers13071562</a></p><p dir="ltr"><br></p><p dir="ltr">IV. <b>Skribek M,</b> Livanou M, Vathiotis I, Strandman V, Thorell A, Koulouris A, Syrigos K, Ekman S, Tsakonas G. The Validated Brain-Lung Immunotherapy Prognostic (BLIP) Score: A Novel Robust Tool for Prognostication in Non-Small Cell Lung Cancer Patients with Brain Metastases. [Manuscript]</p>