PD‑1 inhibitors combined with tyrosine kinase inhibitor‑associated hypothyroidism is a predictive factor for antitumor effectiveness in male patients with hepatocellular carcinoma

Tyrosine kinase inhibitors (TKIs) and programmed cell death protein‑1 (PD‑1) inhibitors are well‑established first‑line systemic therapies for hepatocellular carcinoma (HCC), with hypothyroidism as a prominent immune‑related adverse event. However, the female sex is a known risk factor for thyroid dysfunction associated with TKIs. The present study aimed to determine whether PD‑1 inhibitor plus TKIs‑induced hypothyroidism predicts treatment efficacy in male patients with HCC. A retrospective cohort study enrolled 77 male patients with confirmed HCC who received PD‑1 inhibitor‑TKIs combination therapy at Nanjing Second Hospital (Nanjing, China). According to the evaluation of thyroid function, patients were divided into normal thyroid function and hypothyroidism groups, based on serial thyroid function evaluations. The primary endpoint of the present study was progression‑free survival (PFS). Baseline serum thyroid‑­stimulating hormone (TSH) and thyroglobulin antibody (TgAb) levels were significantly higher in the hypothyroidism group compared with the group with normal thyroid function [TSH, 4.2 mIU/l; 95% confidence interval (CI), 2.0‑4.6 mIU/l vs. 1.7 mIU/l (95% CI, 1.2‑3.1 mIU/l); P<0.001; TgAb, 12.4 IU/ml (95% CI, 2.1‑18.2 IU/ml) vs. 1.4 IU/ml (95% CI, 0.8‑5.0 IU/ml); P=0.007]. The group with hypothyroidism had a median PFS of 8.0 months, which was longer compared with the group with normal thyroid function (6.1 months; P<0.001). Cox regression analysis demonstrated that PD‑1 inhibitors plus TKIs‑induced hypothyroidism [hazard ratio (HR)=0.320; 95% CI, 0.160‑0.641; P=0.001] and baseline serum α‑fetoprotein >200 ng/ml (HR=2.354; 95% CI, 1.277‑4.340; P=0.008) were independent prognostic factors of PFS in male patients with HCC. In conclusion, de novo hypothyroidism during PD‑1 inhibitors combined with TKIs is associated with prolonged PFS in male patients with HCC.