Thyroid Dysfunction after Atezolizumab and Bevacizumab Is Associated with Favorable Outcomes in Hepatocellular Carcinoma

Abstract

<b><i>Introduction:</i></b> Atezolizumab and bevacizumab (Ate/Bev) combination has become the new first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). Although several studies reported thyroid dysfunction after treatment with immune checkpoint inhibitors, the clinical and immunological significance of thyroid dysfunction in patients treated with Ate/Bev has not been comprehensively addressed. We aimed to comprehensively evaluate the clinical and immunological implications of thyroid dysfunction in unresectable HCC patients treated with Ate/Bev. <b><i>Methods:</i></b> We enrolled 208 patients with unresectable HCC treated with Ate/Bev from three Korean cancer centers. Thyroid adverse events (AEs) were reviewed, and cytokines and T cells in the blood samples were analyzed at baseline. For external validation, we analyzed clinical outcomes according to thyroid AEs in patients treated with Ate/Bev in the IMbrave150 study. <b><i>Results:</i></b> Forty-one (19.7%) out of 208 patients experienced thyroid dysfunction (hypothyroidism [17.3%] and thyrotoxicosis [5.8%]) after Ate/Bev treatment. Median time to onset of hypothyroidism and thyrotoxicosis after Ate/Bev treatment was 3.5 and 1.3 months, respectively. Patients with thyroid AEs demonstrated significantly better progression-free survival, overall survival, and objective response rate than those without thyroid AEs. These findings were still consistent even after adjusting for confounding factors. Furthermore, favorable survival outcomes in patients with thyroid AEs were also validated in a cohort of IMbrave150 patients. While patients with thyrotoxicosis showed a significantly lower level of baseline IL-6, those with hypothyroidism did not show significant differences in circulating cytokine levels and CD8<sup>+</sup> T-cell fractions. <b><i>Conclusions:</i></b> A fraction of patients with HCC treated with Ate/Bev experienced thyroid dysfunction, and the development of thyroid AEs was associated with favorable clinical outcomes.

Analysis of Immune-Related Adverse Events of Atezolizumab and Bevacizumab in Patients with Hepatocellular Carcinoma: A Multicentre Cohort Study

“…The most commonly documented irAE in our study was an endocrinological disorder, which mainly comprised thyroid-related irAEs. A recent study showed that thyroid-related irAEs occurred in 19.7% of the A + B-treated patients with HCC, which closely aligns with our results of 18% [28]. Given that thyroid-related irAEs require hospitalization to be classified as grade 3 according to the CTCAE criteria, all occurrences of endocrine disorders in our study were categorized as mild irAEs.…”

“…Bevacizumab-Treated HCC Liver Cancer 2024;13:413-425 DOI: 10.1159/000535839 meticulously explored the frequency and severity of various types of irAEs that can be encountered in real clinical practice among patients with HCC treated with A + B. In this regard, a recent study suggested an association between thyroid-related irAEs and favourable outcomes in HCC patients treated with A + B [28]. Our study further extends this finding by revealing that the occurrence of mild-grade irAEs, encompassing thyroidrelated irAEs, is independently associated with favourable outcomes in terms of OS, PFS, and TTD.…”

Complications of immunotherapy in advanced hepatocellular carcinoma

“…This finding suggests that the development of thyroiditis may be associated with improved outcomes following atezolizumab/bevacizumab therapy in patients with HCC. 41 In the study by Pinato et al, 42 the steroid dose or duration of use did not significantly affect the survival time or PFS of patients with HCC undergoing immunotherapy.…”

“…TrAEs of grade 2 or higher were identified as a predictor of improved OS (hazard ratio [HR], 0.55; 95% CI, 0.34-0.88) and PFS (HR, 0.51; 95% CI, 0.35-0.74) and were associated with a higher ORR of ICI (27% vs. 16%). 40 According to Song et al, 41 patients with thyroid AEs demonstrated significantly better PFS, OS, and ORR than those without thyroid AEs, even after adjusting for confounding factors. This finding suggests that the development of thyroiditis may be associated with improved outcomes following atezolizumab/bevacizumab therapy in patients with HCC.…”

Immune-Related Adverse Events Associated with Atezolizumab: Insights from Real-World Pharmacovigilance Data

“…Hypophysitis is rare following anti-PD-L1 therapy, though reports exist and our RR was elevated [ 29 , 30 ]. Disorders of the thyroid are common following immunotherapy and have been found to show a favourable outcome in hepatocellular carcinoma following atezolizumab treatment [ 31 ]. The incidence of hyperthyroidism and hypothyroidism following anti-PD-L1 therapy is reported to be 0.7% and 3.8–5.5%, respectively, and multiple cases of thyroid disorder post-atezolizumab have been reported [ 32 , 33 , 34 ].…”