Thyroid Dysfunction and Nivolumab Reponse in NSCLC

Cohort characteristics

The patients' characteristics were collected from medicals records: age, gender, smoking status (absent, current or weaned), WHO performance index, neoplastic characteristics (tumor histology, history of brain metastasis, prior radiotherapy treatment, prior therapy lines (defined by the number of chemotherapy or immunotherapy regimens used before Nivolumab® treatment) We also recorded data about expression of tumor PD-L1, LDH levels and the lymphocyte to neutrophil ratio (dNLR) summarized in the LIPI score (Lung immune prognostic index), which distinguishes three categories: good prognosis (normal LDH, dNLR <3), intermediate prognosis (abnormal LDH or dNLR> 3), poor prognosis (abnormal LDH and dNLR> 3),

Treatment schedule and morphological monitoring

Nivolumab® (3mg/kg mg) was administered as an IV infusion for 30 minutes every 2 weeks until disease progression, unacceptable toxicity, or death. Tumor assessment was performed every 2 months until disease progression. Tumor assessment was based on the results of the computerized tomodensitometry (CT) + injection of a radioiodine contrast agent and/or 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) (18FDG-PET/CT), according to the RECIST 1.1 or iRECIST 1.1 ((immune) Response Evaluation Criteria in Solid Tumors) criterion. In case of a dissociated response (response of a lesion associated with a progression of another lesion) or in case of suspicion of pseudo-progression (increase in size or appearance of new lesions linked to the influx of immune cells within the tumor), a new morphological evaluation after two additional cycles was taken into account.

Thyroid function screening and classification of thyroid dysfunction

Thyroid function screening was performed before (<3 months) and during treatment with Nivolumab® (TSH, free T4 (fT4), free T3 (fT3) ± Anti-thyroid peroxidase antibodies (TPOAb) and/or TSH receptor antibodies (TRAbs) were measured by electrochemiluminescence (Reference laboratory values were: TSH, 0.27-4.20 mIU/L; fT4, 11.6-22.0 pmol/L; fT3, 4.0-6.8 pmol/L; TPOAb, <34 kIU/L; and TRAb, <1.75 U/L

For classification of thyroid dysfunction, the CTCAE classification was not taken into account because it is not adapted to thyroid dysfunction that is often asymptomatic. Only abnormalities of the thyroid function tests were considered as follow:

• Patients with abnormalities of TSH level were classified in the group "Thyroid Dysfunction +" and those with normal TSH level were classified in the group "Thyroid Dysfunction -". In case of normal TSH with isolated abnormality of peripherical hormone fT4 and/or fT3, the patient was classified in the "Thyroid Dysfunction -" group;
• Depending on the level of peripheral thyroid hormones (i.e. fT3 and fT4): subclinical thyroid dysfunction was defined by an abnormal TSH without abnormality of the peripheral hormones and overt thyroid dysfunction was defined by an abnormal TSH associated with at least one abnormality of the peripheral hormones T3 or T4L;
• Depending on the TSH level: moderate thyroid dysfunction was defined by a TSH level between 0.1 mIU/L and 0.27 mIU/L or between 4.2 mIU/L and 10 mIU/L, and severe thyroid dysfunction was defined in case of TSH ≤ 0.1 mUI/L or ≥ 10 mUI/L, respectively for hyperthyroidism and hypothyroidism;
• Depending on the type of thyroid dysfunction, we classified each patient in three categories isolated hypothyroidism, isolated thyrotoxicosis and thyroiditis (thyrotoxicosis then hypothyroidism).

Inclusion criteria

• patients at least 18 years old and had histologically confirmed locally advanced stage (IIIB) or metastatic (IV) non-small cell lung cancer with disease progression;
• treated with Nivolumab® as second or more therapeutic line
• in the oncologic department university hospital of Brest
• during the inclusion period between July 20, 2015 to June 30, 2018.

Exclusion criteria

• patients whose primary tumor was not from bronchopulmonary origin
• patients with a history of total thyroidectomy and/or having previously treated with levothyroxine and/or having a thyroid dysfunction previously to the introduction of Nivolumab®
• patients not having any thyroid monitoring during Nivolumab® treatment, and those for which data were missing
• patients who expressed their opposition to participate in the study