Patient Reported Outcome Measurements (PROMs) Impact on Clinical Outcome in firsT Line settIng Non- Small-Cell Lung Cancer (NSCLC) According to Chemo- Immunotherapy reGimen

Patient-reported outcomes measures (PROMs) are tools to assess patients' views on aspects of their health and condition, including health-related quality of life, symptom status, physical function and mental health. In medical oncology, PROMs are emerging as useful indicators not only of patient well-being, but also of treatment efficacy. Measurement of quality of life (QoL) has an intrinsic role in the definition of treatment value and, in the absence of head-to-head comparisons showing differences in overall survival or other traditional endpoints, comparison in terms of QoL can usefully inform the choice among alternative treatment options. The recent availability of alternative strategies in advanced NSCLC, in particular different combination therapies in first line setting, requires models to support clinical decision in tailoring individual treatments. In this model, the integration of PROMs could be essential in promoting a patient-centered approach to cancer care.

EORTC QLQ-C-30, exploring general functioning, and EORTC LC-13, specific for lung cancer are the most used PROMs tools in thoracic oncology.

QoL is a complex and composite outcome, which includes different aspects of patients' well-being, such as anxiety, depression and emotional stress. The latter has been measured in patients with lung cancer using PHQ-9 and Generalized Anxiety Disorder 7-item scales. Of note, a significant association with reduced response and worse survival upon immunotherapy was reported, suggesting an impact of emotional stress on patients' immune system and consequently on treatment outcomes.

Considering the broad effect of immunotherapy on the endocrine system and hormones' functions, it is likely that sexual health and sleep, other nuances of the QoL field, could be also affected by immunotherapy. So far, both sexual and sleep dysfunctions have been poorly explored in clinical trials. Furthermore, "time toxicity" defined as number of days with physical contact with healthcare system, could significantly affect patients' emotional distress sphere and has never been explored in NSCLC upon chemo-immunotherapy combinations.

Based on these assumptions, we believe that chemo-ICI (4 cycles of platinum-based doublet chemotherapy + anti- PD-1 followed by single agent chemo and immunotherapy maintenance) or double-ICI chemo (2 cycles of platinum-based doublet chemotherapy + anti-PD-1 and anti-CTLA-4, followed by maintenance with combo immunotherapy) regimens may have distinct effects on several QoL domains. This could be due to the intrinsic differences in the drugs used (i.e. addition of anti-CTLA-4 agents), treatment related toxicities and different tumor shrinkage activity.

The present study aims to compare QoL by validated questionnaires (EORTC QLQ-C-30, EORTC LC13) in the two above mentioned cohorts of patients with metastatic lung adenocarcinoma, having an additional focus in sexual (EORTC QLQ-SH-22), emotional stress (PHQ-9, Generalized Anxiety Disorder 7-item scale) and sleep disorders (PSQI) as previously reported. Time toxicity will be measured by analyzing the time patients spend in contact with healthcare system, such as visits and treatment. A defined cut off considers time toxicity severe when it exceeds 20% of the total care time.

• To assess the impact on overall survival of all the PROMs items under investigation [Time frame: After 4 cycles, after 8 cycles, and at disease progression]