Weight Gain on Lorlatinib Is Associated With Accumulation of Visceral Adipose Tissue

Lorlatinib exposure is associated with metabolic effects, including weight gain. Anatomical distribution (i.e., visceral versus subcutaneous) of the gained adipose tissue remains poorly characterized.

Body composition was retrospectively analyzed using computed tomography images at baseline, 3 months, 6 months, and 12 months for patients with anaplastic lymphoma kinase-positive (ALK+) lung cancer treated with later-line lorlatinib in prospective trials at the Massachusetts General Hospital. Longitudinal trends were assessed in the overall cohort and compared across lorlatinib doses. Body composition analysis was also performed for a patient receiving first-line lorlatinib.

Between 2014 and 2020, 67 patients received lorlatinib 100 mg (n = 37) or 50 to 75 mg (n = 30). Overall, the skeletal muscle index, visceral adipose tissue index (VATI), and body mass index (BMI) increased from baseline to 3 months and from 3 months to 6 months (e.g., baseline to 3 mo skeletal muscle index: 0.77 cm²/m² [95% confidence interval or CI: 0.08, 1.45; p value = 0.028]; VATI: 4.23 cm²/m² [95% CI: 2.37, 6.19; p value < 0.001]; BMI: 0.97 kg/m² [95% CI: 0.59, 1.35 kg/m²; p value < 0.001]). There was insufficient evidence of change in the subcutaneous adipose tissue index in the study period. When adjusted for dose, the trends persisted but did not reach statistical significance. Analysis of a patient receiving first-line lorlatinib reported a 16-kg weight gain and increased BMI and VATI during the initial 3 years, with a decrease in BMI and VATI after initiating dulaglutide.

Weight gain during treatment with lorlatinib is preferentially associated with accumulation of visceral rather than subcutaneous adipose tissue. Future interventions to address lorlatinib-related weight gain should focus on mitigating visceral adiposity.