Weight, BSA, Toxicity, and Efficacy of Tyrosine Kinase Inhibitors for ALK-Mutated NSCLC

ALK tyrosine kinase inhibitors (ALK TKIs) are started at a standard dose regardless of patients' weight and body surface area (BSA). In this retrospective analysis, the authors explored whether body size variables were associated with toxicity and efficacy.

Retrospective data for ALK-positive patients at the Princess Margaret Cancer Centre were extracted from electronic health records. Associations between BSA/weight quartiles and dose reductions (DRs), temporary interruptions (TIs), and permanent discontinuation due to toxicity were evaluated using generalized linear mixed modeling. Survival analysis was conducted using Kaplan-Meier curves and log-rank tests.

Among 142 patients with ALK-positive NSCLC treated between July 2012 and March 2024, the median age was 58 years, 54% were female, 78% never-smokers, 49% were Asian, and 37% were Caucasian. A significantly higher proportion of males were in the highest BSA Q4 (89%, p < 0.001), whereas more females (91%, p < 0.001) and Asians were in the lowest BSA Q1 (80%, p < 0.001).Higher weight at ALK TKI initiation was associated with an increased likelihood of DR at any time (adjusted odds ratio [aOR] = 1.20 per 10-kg increase, 95% confidence interval: 1.0-1.4, p = 0.04), as was having higher BSA (aOR = 2.00 per 0.5-U increase, 95% confidence interval: 1.0-3.9, p = 0.04). TIs were associated with higher weight (10-kg increase, aOR = 1.28, p = 0.006), BMI (5-U BMI increase, aOR = 1.40, p = 0.02), and BSA (0.5-U increase, aOR = 2.59, p = 0.005). These weight/BSA results were statistically significant in patients during alectinib or lorlatinib treatment. In contrast, permanent discontinuation was associated with higher weight/BSA in brigatinib/ceritinib/crizotinib-treated patients. In multivariable analysis, older age and male sex were independently associated with more DRs and TIs. Weight and BSA quartiles were not associated with progression-free survival (p = 0.4) or overall survival (p = 0.6).

Higher weight and larger BSA at the start of ALK TKI treatment were associated with higher likelihood of toxicity, leading to more DRs and TIs-particularly in males and patients receiving alectinib and lorlatinib. However, weight and BSA were not associated with treatment outcomes.