Immune-checkpoint inhibitors (ICI) are monoclonal antibodies which target molecules to enhance antitumor response. Several adverse events have been described and the major ICI-related endocrinopathies are thyroid dysfunction and hypophysitis. Its occurrence has been associated with increased survival.
A retrospective study of adult patients treated with ICI between March 2014 and September 2019 at an oncologic centre was performed to evaluate the impact of thyroid function test abnormalities (TFTA) in their prognosis. We excluded patients without regular monitoring of thyroid function, with previous thyroid or pituitary disease (including medical and surgical treatments), previous head/neck radiotherapy and who performed only one ICI cycle. Clinical data of all patients were examined independently by two Endocrinologists. Survival analysis was performed using the Kaplan-Meier method. Cox regression was used to evaluate associations between the occurrence of TFTA and the outcome of overall survival (OS). It was adjusted for sex, age, primary neoplasm, tumor staging and ICI. All analyses were performed using IBM-SPSS v.25 and a level of significance α=0.05 was noted.
We included 161 of 205 patients, with a median age of 65 years [Interquartile range (IQR) 15] and 67% male. Most patients had melanoma (52%) and lung cancer (43%). Globally, 86, 59 and 25 patients were under pembrolizumab, nivolumab and ipilimumab, respectively. Median duration of ICI treatment was 4.4 months (IQR 7.7) and median total follow‐up was 11.4 months (IQR 11.2). New onset TFTA was diagnosed in 18% of patients, at median age of 65 years (IQR 20) and 55% male. Almost half (45%) had primary hypothyroidism, 28% had central hypothyroidism and 13.8% had biphasic thyroiditis and thyrotoxicosis, each. Most TFTA (79%) occurred under pembrolizumab and nivolumab. Grade 2 CTCAE was the most frequently reported. None of the events led to ICI suspension.
Patients with TFTA underwent a significant higher number of ICI cycles than control group [median 11 cycles (IQR 20) vs 7 (IQR 11), p=0.017] and had a higher period under ICI (median of 7.6 months (IQR 13.8) vs 4.2 (IQR 7.7), p=0.026). Comparison between TFTA patients and control group did not reveal statistical differences in patients’ age and sex, primary neoplasm, tumor staging and ICI.
Overall survival was significantly higher in patients that developed TFTA during treatment with ICI, comparing to the control group (mean OS 3.62 years vs 1.92 years, p=0.033). The risk of mortality was higher for the control group, approximately 3 times, considering the adjustment for the covariates (HR 2.94, 95%CI=1.18 to 7.34, p=0.021). Overall survival was not affected by the covariates.
Our study shows that patients under ICI that develop primary or central thyroid dysfunction had an improved survival. In these patients, the occurrence of TFTA could be a marker of a better response to ICI.