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Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer.

ABSTRACT: Purpose: Drugs that blockade interaction between programmed cell-death protein 1 (PD-1) and its ligand (PD-L1) are promising. Immune-related adverse events (irAEs) might be associated with favorable clinical outcomes, and thyroid dysfunction is one of the most common irAE. We evaluated the association of thyroid dysfunction during PD-1 blockade with the treatment efficacy in patients with non-small cell lung cancer (NSCLC). Experimental Design: A total 58 patients with stage IV NSCLC treated with PD-1 blockade were enrolled. Patients were categorized into thyroid dysfunction and euthyroid groups. Overall survival (OS) and progression-free survival (PFS) of the two groups were compared. Patients, tumor, and medication factors were adjusted using Cox proportional hazard modeling. Objective response rate (RR) and durable control rate were assessed according to the severity of thyroid dysfunction. Results: OS [median 118.0 (73.0-267.0) vs. 71.0 (28.0-160.0) days, log-rank P = 0.025] and PFS [118.0 (73.0-267.0) vs. 61.0 (28.0-130.0), log-rank P = 0.014] were longer in the thyroid dysfunction group. After adjustment, thyroid dysfunction was an independent predictive factor for favorable outcome [adjusted HR = 0.11 (95% CI) 0.01-0.92 for overall death; 0.38 (0.17-0.85) for disease progression]. The severity of thyroid dysfunction was associated with durable control rate (P for trend = 0.008). Conclusions: Thyroid dysfunction during PD-1 blockade is associated with treatment response and could provide supplementary information for immune monitoring in patients with advanced NSCLC.

SUBMITTER: Kim HI

PROVIDER: S-EPMC5739550 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer.

Kim Hye In HI Kim Mijin M Lee Se-Hoon SH Park So Young SY Kim Young Nam YN Kim Hosu H Jeon Min Ji MJ Kim Tae Yong TY Kim Sun Wook SW Kim Won Bae WB Kim Sang-We SW Lee Dae Ho DH Park Keunchil K Ahn Myung-Ju MJ Chung Jae Hoon JH Shong Young Kee YK Kim Won Gu WG Kim Tae Hyuk TH

Oncoimmunology 20170921 1

<b>Purpose:</b> Drugs that blockade interaction between programmed cell-death protein 1 (PD-1) and its ligand (PD-L1) are promising. Immune-related adverse events (irAEs) might be associated with favorable clinical outcomes, and thyroid dysfunction is one of the most common irAE. We evaluated the association of thyroid dysfunction during PD-1 blockade with the treatment efficacy in patients with non-small cell lung cancer (NSCLC). <b>Experimental Design:</b> A total 58 patients with stage IV NSC ...[more]

PMID: 29296533

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Project description:BackgroundProgrammed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described.Patient and methodsPatients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n?=?51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated.ResultsOf 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P?<?0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P?=?0.04).ConclusionsThyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.

Project description:Background: Despite remarkable success of immunotherapies with checkpoint blockade antibodies targeting programmed cell death protein 1 (PD-1), the majority of patients with non-small-cell lung cancer (NSCLC) have yet to receive durable benefits. We used the metabolomic profiling of early on-treatment serum to explore predictors of clinical outcomes of anti-PD-1 treatment in patients with advanced NSCLC. Methods: We recruited 74 Chinese patients who had stage IIIB/IV NSCLC-proven tumor progression and were treated with PD-1 inhibitor. The study was comprised of a discovery cohort of patients treated with nivolumab and two validation cohorts of patients receiving tislelizumab or nivolumab. Serum samples were collected 2-3 weeks after the first infusion of PD-1 inhibitor. Metabolomic profiling of serum was performed using ultrahigh performance lipid chromatograph-mass spectrometry. The serum metabolite biomarkers were identified using an integral workflow of nontargeted metabolomic data analysis. Results: A serum metabolite panel consisting of hypoxanthine and histidine was identified and validated as a predictor of response to PD-1 blockade treatment in patients with advanced NSCLC. High levels of both hypoxanthine and histidine in early on-treatment serum were associated with improved progression-free survival [hazard ratio (HR) = 0.078, 95% confidence interval (CI), 0.027-0.221, p < 0.001] and overall survival (HR = 0.124, 95% CI, 0.039-0.397, p < 0.001) in the discovery cohort. The serum metabolite panel showed a high sensitivity and specificity in distinguishing responders and non-responders in the validation cohorts 1 and 2, with an area under the receiver-operating characteristic curve of 0.933 and 1.000, respectively. High levels of serum hypoxanthine and histidine were correlated with improved progression-free survival in the validation cohort 1 (HR = 0.137, 95% CI, 0.040-0.467, p = 0.001) and in the validation cohort 2 (HR = 0.084, 95% CI, 0.009-0.762, p = 0.028). Conclusion: Our results revealed that hypoxanthine and histidine in early on-treatment serum are predictive biomarkers of response to PD-1 blockade therapy in patients with advanced NSCLC. The serum biomarker panel would enable early identification of NSCLC patients who may benefit from PD-1 blockade therapy.

Dataset Information

Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer.

Publications

Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer.

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