Lorlatinib-associated weight gain and dyslipidaemia: A retrospective analysis and implications for future care.

Objectives: The objective of our study was to benchmark the incidence and severity of lorlatinib-related weight gain and dyslipidaemia in a real-world context, to guide future therapeutic strategies to mitigate these toxicities.

Methods: We conducted a retrospective, observational analysis of patients with ALK and ROS1-positive NSCLC at a single institution in the UK who were commenced on lorlatinib from 11/2016 to 11/2022. Non-small cell lung cancer (NSCLC) patients prescribed lorlatinib were identified through institutional electronic pharmacy records. Descriptive analyses were conducted. Patients without recorded baseline weight were excluded from the analysis. Changes in weight, body mass index (BMI), triglycerides, and total/low-density lipoprotein (LDL)/high-density lipoprotein (HDL) cholesterol were calculated from serial measurements and graded in accordance with CTCAE v5.0.

Results: 43 patients were evaluated. 81 % of patients developed weight gain on lorlatinib (median: 4.5 kg, 6.5 % increase from baseline); Grade < 1 in 37 % (n = 16/43), Grade 1 in 23 % (n = 10/43), Grade 2 in 12 % (n = 5/43), and Grade ≥ 3 in 9 % (n = 4/43). BMI increase was observed in 79 % of patients. 35 % of patients with healthy baseline BMI moved into overweight/obese categories. Of patients with recorded baseline lipid levels, 91 % developed increase in total cholesterol, and 68 % an increase in triglycerides, respectively. 7 % (n = 1/15) patients with normal baseline total cholesterol developed Grade ≥ 3 elevated cholesterol; no patients with normal baseline triglycerides developed Grade ≥ 3 elevated hypertriglyceridaemia (n = 12). Median time to onset of total cholesterol elevation was 21 days. Lipid-lowering therapy was required in most patients (86 %). One patient developed a non-ST elevation myocardial infarction (NSTEMI) which may have been attributable to lorlatinib.

Conclusion: Weight gain and dyslipidaemia are commonly observed with lorlatinib, highlighting the need for effective pharmacologic and non-pharmacologic strategies to manage these toxicities. Rates were similar to those reported in the CROWN trial. Given the 60 % 5-year progression-free survival (PFS) demonstrated in CROWN, mitigation of treatment-related toxicities is paramount to minimise impact on patient quality of life (QOL) and cancer-independent morbidity in this subgroup of NSCLC patients with favourable outcomes.