Overt thyroid dysfunction and anti-thyroid antibodies predict response to anti-PD-1 immunotherapy in cancer patients.

Thyroid dysfunction is among the most common adverse effects during anti-PD-1 immunotherapy, and alongside correlations with elevated anti-thyroid antibodies (ATAb), studies have found correlations with survival. However, the exact relations remain to be clarified. We therefore aimed to clarify the relationship between thyroid dysfunction, ATAbs and survival in anti-PD-1 treated cancer patients.We included 168 patients with non-small-cell lung carcinoma, renal cell carcinoma, and metastatic melanoma treated with nivolumab or pembrolizumab. TSH and free T4 (FT4) levels were measured before each anti-PD-1 infusion. ATAb levels (anti-thyroid peroxidase (TPO) and anti-thyroglobulin (Tg)) were measured at baseline and after 2 months of treatment. Although the vast majority of patients had detectable levels of ATABs, only few patients had positive ATAbs when using conventional cut-offs. To study the consequences of detectable ATABs, the cut-off levels were a priori set at the median concentrations at baseline in the study population. Tumor progression was classified according to RECIST v1.1.Patients who acquired overt thyroid dysfunction during treatment had significantly higher overall survival (OS) (HR=0.18 [95%CI: 0.04-0.76]; p=0.020) and progression free survival (PFS) (HR=0.39 [0.15-0.998]; p=0.050) than patients without thyroid dysfunction with one-year OS rates of 94% vs 59% and one-year PFS rates of 64% vs 34%. During treatment, patients with ATAb levels above the median had a higher OS (HR=0.39 [0.21-0.72]; p=0.003) and PFS (HR=0.52 [0.33-0.81]; p=0.004) than patients with ATAb levels below the median, with one-year OS rates of 83% vs 49% and PFS rates of 54% vs 20%, respectively. When analyzing ATAb levels over time, patients with a persistent ATAb level above the median had a higher OS (HR=0.41 [0.19-0.89], p=0.025) and PFS (HR=0.54 [0.31-0.95], p=0.032) compared to patients with a persistent ATAb level below the median. Patients whose ATAb levels increased above the median during treatment had an improved OS (HR=0.27 [0.06-1.22], p=0.088) and PFS (HR=0.24 [0.07-0.77], p=0.017) compared to patients whose ATAb levels decreased below the median.Acquired overt thyroid toxicity and above median ATAb levels during anti-PD-1 treatment are associated with improved PFS and OS. Additionally, our results suggest that ATAb levels at baseline are of clinical relevance for PFS and OS.