Phd in TRANSATIONAL MEDICINE AND ONCOLOGY

Thesis title: Gender-related disparities in tolerability to novel anti-cancer treatment in Non-Small Cell Lung Cancer (NSCLC): moving toward personalized care pathway

Importance: Patients (pts) suffering from cancer often experience a range of supportive care needs partially determined from side effects of anticancer therapies. Research suggest that gender may affect the tolerability to systemic anticancer treatment in advanced/metastatic non-small cell lung cancer (a/mNSCLC). However, this aspect is poorly explored in regard of biomarker-driven therapies, namely tyrosine kinase inhibitors (TKIs) and antibody drug conjugates (ADCs). Objective: this study was to assess gender-related differences in tolerability to biomarker-driven therapies, including approved TKIs and investigational ADCs among a/mNSCLC patients. Design: A nationwide health data system for approved TKIs (2018-2023) and a mono-institutional patients’ cohort for investigational ADCs (2017-2024) were retrospectively and independently analyzed. Setting: We investigated the impact of gender on the incidence of symptomatic and chronic (>3 months) adverse events (AEs) among a/m NSCLC treated with approved TKIs and the pattern of treatment related adverse events (TRAEs) with investigational ADCs monotherapy in phase 1-2 clinical trials. Participants: Adults (≥18 years) diagnosed with a/m NSCLC were included in our study. Control groups were patients treated with immunotherapy-based regimens (ICI-cohort) and patients from a geographically and demographically matched general population (control cohort). Main outcomes: to evaluate the incidence of AEs by gender among NSCLC pts treated with TKIs, from initiation to up to 3 months post-TKI. To evaluate treatment-related adverse events (TRAEs) graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 among NSCLC pts treated with ADCs. Data on clinically significant (Grade ≥2) TRAEs were collected from electronic Case Report Form, along with clinical and survival data. Statistical analysis was conducted to test the correlation between toxicity outcomes and gender. Results: In the TKIs cohort men were less prone to chronic/severe psychiatric AEs and more prone to chronic/severe pneumonia. In the ADCs cohort, women experienced more frequent and severe TRAEs, potentially resulting in longer hospitalizations. In the same cohort, females were at higher risk of developing metabolic AEs. Conclusions and relevance: Our findings highlight the distinct tolerability profile across a/mNSCLC males and females treated with biomarker-driven therapies. Future efforts should focus on more inclusive toxicity reporting in clinical trials and the implementation of gender-informed supportive care strategies to improve cancer care equity.