New generation ALK-inhibitors burden in lung cancer patients cardiovascular health: analysis from real world data

Introduction Second (alectinib, brigatinib) and third (lorlatinib) generation ALK-inhibitors (ALK-i) are the cornerstone in the treatment of patients with ALK translocated non-small cell lung cancer (NSCLC). Although ALK-i have shown unprecedented survival results, cardiovascular (CV) risk factor worsening and cardiotoxicity may hinder these benefits. Purpose The aim of this study is to describe the CV toxicities reported in patients treated with second or third ALK-i in our institution. Methods We retrospectively collected data from electronic clinical records of 45 patients treated with a new generation ALK-i, irrespective of its use in front or subsequent line. However, as some patients received more than one ALK-i, the total treatment records was 69. We used the SCORE-2 and the SCORE-OP systems to assess the CV risk before the start of the treatment. Results Baseline characteristics of the population are described in Table-1. Overall, the whole cohort baseline CV risk was low (26 patients, 57,8%), although 17 patients (37,8%) and 2 patients (4,4%) were of high or very high risk. The median follow up from the start of the first ALK-i for each patient was 21 months (range: 1-93). At the data cut-off, 26 patients (57,8%) were alive and remained on treatment with, 7 patients (15,6%) receiving a new generation ALK-i for over 5 years. During the follow up period, we identified 30 (43,5%) cases of worsening CV risk factors or CV adverse events related to ALK-i therapy. The most frequently reported toxicities were dyslipidemia (19 patients, 27,5%) and hypertension (13 patients, 18,8%). Other cardiovascular complications included new onset arrythmias (4 patients), thromboembolic events (2 patients) or new onset diabetes (1 patient). Notably only two patients developed a major cardiovascular adverse event (MACE): one case of heart failure in a patient receiving brigatinib and one sudden cardiovascular death within weeks of initiating alectinib. Overall, 9 patients (13%) required referral to the Cardio-Oncology clinic. The CV toxicity profile varied among individual ALK-i: Lorlatinib exhibited the highest rate of CV toxicity, with dyslipidemia affecting nearly all treated patients (18/20, 90%). However, no MACE occurred during follow-up (median drug-time exposure months: 13). Brigatinib was associated with a higher incidence of hypertension, leading to temporary treatment discontinuation in three patients (median drug-time exposure months: 14). Alectinib appeared to have the most favorable CV safety profile, with only 3 patients (11,1%) experiencing any form of cardiotoxicity (drug-time exposure months: 10,5). Conclusion While ALK-i demonstrate an overall manageable CV safety profile, they are associated with a notable risk of dyslipidemia and hypertension. Given the expected long-term survival of patients receiving ALK-targeted therapies, CV monitoring and risk management should be an integral part of patient care.