Farmacogenetica del lenvatinib nei pazienti affetti da carcinoma tiroideo avanzato: correlazione con gli eventi avversi e l'outcome clinico

Introduction: Differentiated thyroid cancer (DTC) usually has an excellent prognosis following initial therapy. However, around 5% of patients with DTC are diagnosed with locally advanced disease and around 10% with distant metastases, which significantly reduces their overall survival (OS). Therapy with 131I is still the standard treatment for patients with distant metastases, however, only about 40% of these patients achieve disease control and remission. Multikinase inhibitors (MKIs) represent the first therapeutic option in this context. However, the clinical benefits and toxicities experienced by patients can vary significantly, reflecting differences in tumour biology and potential variations in drug exposure. Recent data suggest that pharmacogenomic factors may influence variability in lenvatinib plasma levels and tolerability. However, the evidence is scattered and frequently based on small cohorts, which limits its clinical application. Aim: To investigate possible correlations between individual pharmacogenetic profiles, assessed by analysing polymorphisms in the genes encoding cytochromes CYP3A4 and CYP3A5, the transport proteins P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), and the development of treatment-related adverse events and clinical outcome in a cohort of patients with locally advanced or distant metastatic radioiodine refractory differentiated thyroid cancer (RAI-R DTC), treated with lenvatinib. Patients and methods: We conducted a retrospective analysis of a consecutive cohort of patients with RAI-R DTC treated with lenvatinib and enrolled at referral centres in Siena, Pisa and Milan. Clinical and treatment-related data were collected from electronic medical records over a 12-month observation period. Adverse events were graded according to the CTCAE v5.0, while radiological response was evaluated using the RECIST 1.1 criteria. All patients were genotyped for CYP3A4 20230G>A (rs2242480), CYP3A5 6986A>G (rs776746), ABCB1 2677G>T/A (rs2032582), 3435C>T (rs1045642), 3435+22C>T (rs2235048), and ABCG2 421C>A (rs2231142). Results: A total of 48 patients were included (median age: 65.5 years; 56.2% females). The majority had a DTC (72.9%) with distant metastases (87.5%). Molecular profiling, revealed alterations in HRAS/KRAS/NRAS (24%), BRAF (22%), TERT (22%), and less frequently TP53, EGFR, or NTRK fusions. The initial lenvatinib dose was 24 mg/day in 56.2% of patients, decreasing significantly over 12 months due to toxicity (p=0.001); 18.8% maintained the full dose, and 91.7% remained on treatment at 12 months. No significant associations were found between genotypes and lenvatinib dose intensity. Maximum tolerated lenvatinib dose was independently associated with the body weight (β=0.093; p=0.019). The most frequent adverse events (AEs) were fatigue (75%) and hypertension (75%), diarrhea (64.6%), anorexia (58.3%), oral mucositis (50%). ABCB1 rs2032582 GT/TT genotype was associated with a higher incidence of mucositis (OR 5.32, 95%CI: 1.56-20.67; p=0.01), the CYP3A4 GG genotype with a longer duration of oral mucositis (>4 months in 66.7%) and the ABCB1 rs2235048 CT/TT genotype with increased risk of anorexia (OR 6.82, 95%CI: 1.68-35.5; p=0.01). Older age (≥65 years) was associated with fatigue (OR 4.90, 95%CI: 1.22–19.69; p=0.04) and higher body weight was associated with dysgeusia (OR 1.06, 95%CI: 1.01–1.12; p=0.022). Partial response was achieved in 64.6% of patients, disease stabilization in 33.3%, and progression in 2.1%. At a median follow-up of 47.7 months, median OS was not reached. Worse OS was independently associated with both age at the start of lenvatinib treatment and ECOG PS (HR 1.05; 95%CI: 1.00-1.10, p=0.04 and HR 10.7 95%CI: 2.72-42.2; p<0.001, respectively). Discussion and conclusion: Our findings support the inclusion of readily available clinical variables, particularly body weight, in initial dosing strategies to personalise treatment and minimise adverse events. Additionally, age at therapy initiation and ECOG PS appear to be significant prognostic factors, consistent with previous reports. Meanwhile, as demonstrated by other studies, the pharmacogenetic profile of drug transport and metabolism could help to predict and prevent specific adverse events that often lead to the temporary or permanent discontinuation of treatment. Nevertheless, further prospective studies that integrate therapeutic drug monitoring with pharmacogenomics are required to validate genotype-guided dosing and clarify exposure-response-toxicity relationships.