Adverse events associated with sequential immune checkpoint inhibitor and alectinib in patients with ALK-rearranged...

ALK tyrosine kinase inhibitors (TKIs) are the standard first-line therapy for ALK-rearranged [ALK fusion-positive (ALK+)] advanced non-small-cell lung cancer (NSCLC). In real-world practice, patients may receive immune checkpoint inhibitors (ICIs) before initiating ALK TKIs. We aimed to assess the frequency of treatment-related adverse events (TRAEs) associated with this sequential approach.

We retrospectively analyzed alectinib-associated TRAEs in patients with advanced ALK+ NSCLC who received alectinib as their first TKI, with or without prior ICI exposure.

We identified 166 patients, of whom 12 had prior ICI exposure. From alectinib initiation, the 12-month cumulative incidence in patients with versus without prior ICI was as follows: all-grade pneumonitis, 25.0% versus 4.6%; transaminase elevation, 25.0% versus 14.4%; and rash, 43.3% versus 5.9%. Competing-risks regression detected a higher risk of all-grade pneumonitis [hazard ratio (HR) 5.2], all-grade rash (HR 7.8), and grade ≥3 rash (HR 8.9) in patients with versus without prior ICI. Alectinib required discontinuation or hospitalization for TRAEs in 25.0% and 16.7% of patients with prior ICI, respectively, compared with 7.8% and 3.2% of patients without prior ICI.

Alectinib after ICI was associated with higher risks of pneumonitis and rash, and numerically higher risk of grade ≥3 hepatotoxicity, leading to increased rates of alectinib interruption and steroid use. These findings underscore the importance of expedited genotyping to guide treatment selection and avoid unwarranted ICI exposure.