End-of-life management and causes of death in ALK-positive non-small cell lung cancer in France: a multicentric analysis.

Background: Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) represents a distinct molecular subtype characterized by younger age at diagnosis, prolonged survival with sequential ALK tyrosine kinase inhibitors (TKIs) therapy, and a high incidence of central nervous system (CNS) metastases. Despite major therapeutic advances, metastatic ALK-positive NSCLC remains incurable, yet end-of-life (EOL) outcomes in this population are poorly described. We aimed to characterize causes of death, EOL management, and factors associated with palliative care referral and place of death in patients who died from metastatic ALK-positive NSCLC. Methods: We conducted a retrospective multicentric cohort study including all deceased patients with histologically confirmed metastatic ALK-positive NSCLC treated in seven centers in France between 2009 and 2023. Clinical characteristics, molecular data, treatment sequences, CNS progression, causes of death, and EOL care indicators were collected from medical records. Causes of death were classified as cancer-related or non-cancer-related. Multivariable logistic regression analyses were performed to identify factors associated with palliative care referral and in-hospital death. Results: Among 232 screened patients, 89 deceased patients were included. Median age at diagnosis was 59.9 years, 58.4% were female, and 62.9% were never-smokers. Median overall survival (OS) was 26 months. CNS progression occurred in 59.6% of patients, with a median interval of 11 months between first CNS progression and death. Overall, 79.8% of deaths were cancer-related, mainly due to neurological failure (36.6%), respiratory failure (29.6%), or cachexia (29.6%). In the last 2 weeks of life, 71.9% of patients were still receiving active anti-cancer treatment. Most deaths occurred in hospital settings (73.1%). Only 51.1% of patients were referred to a palliative care specialist. Palliative care referral was associated with lower rates of in-hospital death, earlier treatment discontinuation, more frequent multidisciplinary decisions focused on comfort care, and better documentation of treatment limitation orders. In multivariable analysis, active anti-cancer treatment within the last 2 weeks of life was the strongest independent predictor of in-hospital death. Conclusions: Despite prolonged survival with ALK-targeted therapies, most patients with metastatic ALK-positive NSCLC die from cancer-related causes, frequently after intensive hospital-based care. Palliative care referral remains suboptimal but is associated with improved EOL outcomes. Early and systematic integration of palliative care should be considered an essential component of the management of metastatic ALK-positive NSCLC.