The study is a prospective randomized interventional study including patients with advanced non-small cell lung cancer, receiving immunotherapy, with the aim of optimizing treatment monitoring. The study aims to investigate the clinical utility of liquid biopsy monitoring in order to reduce the numbers of inefficient treatments and needless toxicity - and to explore the cost-effectiveness and cost-utility of introducing liquid biopsy monitoring in daily clinical practice.

Lung cancer is the leading cause of cancer-related death worldwide with Non-Small Cell Lung Cancer (NSCLC) being the most common subtype. Performance status deterioration due to progressive symptoms and toxicity by treatments are major challenges in managing advanced NSCLC patients. Moreover, standard treatment monitoring by radiologic scans is often imprecise. This technology has limited sensitivity as only a visible increase or decrease in tumor mass can be evaluated, making interpretation challenging and conclusions of whether patients benefit from treatment indefinite. Interpretation of radiologic scans has been further challenged after implementation of immunotherapy, causing immunotherapy-induced recruitment of immune cells resembling increment in tumor size, called "pseudo-progression." More sensitive methods are highly needed to reduce ineffective treatments and needless toxicity. Liquid biopsy has the potential to overcome these challenges by measuring molecular changes with high precision in a dynamic manner. Recent studies have demonstrated its promising potential as a biomarker predictive of treatment efficacy and overall survival. In a recent real-life study, investigators found that ctDNA measurements could reduce 33% of likely inefficient treatments and clarify 79% of non-conclusive CT-scans, highlighting the clinical potential. A randomized interventional multicenter study will be performed, investigating the true clinical potenial of liquid biopsy compared to standard monitoring by radiological scans. A total of 350 patients with advanced NSCLC will be included in the study from three Departments of Clinical Oncology. In the interventional arm, liquid biopsy monitoring will be the basis for treatment discontinuation before the standard two years of immunotherapy in patients reaching a complete molecular response in plasma. Thus clarifying the question if treatment duration can be reduced for the benefit of patients and health cost.

Inclusion Criteria:

• Newly diagnosed, histologically verified, Non-Small Cell Lung Cancer (NSCLC)
• Advanced or locally advanced disease without curative intended treatment options
• Age > 18 years
• Eastern Cooperative Oncology Group (ECOG) score of Performance Status (PS) 0-1
• Measurable disease according to the iRECIST criteria version 1.1.
• Eligible to first line immunotherapy (monotherapy)
• Signed informed consent

Exclusion Criteria:

• Targetable alterations in EGFR, ALK or ROS-1
• Other active cancers