Nivolumab-induced thyroid dysfunction in patients with lung cancer

Abstract

Background

Nivolumab is an anti-cancer monoclonal antibody that inhibits PD1 and modulates T-cell response. It has been shown to significantly improve survival in several types of cancer, but clinical trials have also reported an increased risk of developing immune-related adverse events (IRAEs). Endocrine IRAEs may be particularly relevant.

Objective

To comprehensively evaluate the clinical presentation of endocrine IRAEs in patients with lung cancer treated with nivolumab. Potential risk factors are analyzed, and strategies for IRAE management are proposed.

Methods

Forty consecutive patients treated with nivolumab for advanced non-small cell lung cancer (NSCLC) were studied, paying particular attention to development of endocrine IRAEs (thyroid, hypophyseal, adrenal, or pancreatic) and clinical outcome.

Results

Thyroid function changes were found in 9 patients (22.5%), of which six developed hypothyroidism and three had hyperthyroidism after a median of 3.8 and 2.3 cycles of nivolumab respectively. Only one patient had thyroid-related symptoms. Thyroid autoimmunity was negative in all cases. Hyperthyroid patients showed no uptake in iodine scintigraphy, and their hormone values returned to normal in less than six months. Nivolumab was discontinued for toxicity in one patient. One patient with hyperthyroidism also developed autoimmune diabetes, and one patient with hypothyroidism also had hypogonadism. After a median follow-up of 7.6 months, 25 patients (62.5%) showed response to nivolumab. Univariate and multivariate analyses showed no differences between patients who developed thyroid changes and those who did not.

Conclusions

Thyroid changes after treatment with nivolumab are common and warrant active laboratory monitoring. The underlying mechanisms and their relevance deserve further research.

Resumen

Introducción

Nivolumab es un anticuerpo monoclonal que ejerce acción anti-tumoral mediante la inhibición de PD1 y modulación de la respuesta de las células T. Ha demostrado un aumento significativo en la supervivencia de distintos tipos de cáncer, pero también se ha reportado un incremento en el riesgo de desarrollar eventos adversos relacionados con la inmunidad (IRAEs). Los IRAEs endocrinos son particularmente relevantes.

Objetivos

Evaluar de forma detallada la presentación clínica de los IRAEs endocrinos en pacientes con cáncer de pulmón refractario tratados con nivolumab. Se analizan potenciales factores de riesgo y se proponen estrategias para su manejo.

Material y métodos

Se estudiaron 40 pacientes consecutivos con cáncer de pulmón de células no pequeñas (NSCLC) tratados con nivolumab. Se realizó el seguimiento prestando especial atención al desarrollo de los IRAEs endocrinos (tiroides, hipófisis, adrenal o páncreas) y su evolución clínica.

Resultados

Se detectaron alteraciones de la función tiroidea en 9 casos (22,5%): 6 hipotiroidismo y 3 hipertiroidismo, tras una mediana de 3,8 y 2,3 ciclos de nivolumab, respectivamente. Solo un paciente desarrolló síntomas relacionados. La autoinmunidad tiroidea fue negativa en todos los casos. La gammagrafía fue negativa en todos los casos de hipertiroidismo y los valores hormonales volvieron a la normalidad en menos de 6 meses. Se suspendió nivolumab en un caso debido a toxicidad. Uno de los pacientes con hipertiroidismo también desarrolló diabetes autoinmune, y uno de los pacientes con hipotiroidismo también presentaba hipogonadismo. Tras una mediana de seguimiento de 7,6 meses, 25 pacientes (62,5%) presentaron respuesta favorable al nivolumab. El análisis uni y multivariante no mostró diferencias entre los pacientes que desarrollaron alteraciones tiroideas y los que no.

Conclusiones

Las alteraciones tiroideas tras el tratamiento con nivolumab son frecuentes y requieren una vigilancia activa. Los mecanismos subyacentes y su relevancia aún no se conocen en profundidad.

Introduction

With recent advances in the knowledge and understanding of immunology and cancer biology, there has been an increase in the use of immune checkpoint inhibitors (ICPI) for the treatment of malignancies. Specifically, these therapies are commonly based on mechanisms of boosting the negative immunoregulatory receptors on T cell surface to enhance the host immunity against tumor cells. In this regard, nivolumab is a monoclonal antibody that binds and blocks the activation of the programmed cell-death-1 (PD1) receptor, which is expressed on T-cells and binds to its ligands PD-L1 and PD-L2 on cancer cells and other immune and non-immune cells. Thus, it increases the anti-tumor T-cell response by blocking the interaction of PD1 and PD-L1 to prevent T-cell inactivation at the tumor site. In fact, a significant improvement in survival outcomes has been demonstrated with nivolumab in several types of solid tumors, including melanoma and lung cancer, in comparison to chemotherapy.1, 2, 3, 4, 5

As a counterpart to this antineoplastic activity, ICPI may contribute to the development of a unique set of mechanism-based toxicities, termed immune-related adverse events (IRAEs), as a consequence of impaired self-tolerance from loss of T-cell inhibition.⁶ Endocrine IRAEs, although less acknowledged at the beginning, are emerging as a topic of increasing relevance and interest, especially given their potential highly symptomatic nature, the availability of treatments to ameliorate them if they occur, and the interest in discovering the underlying mechanisms involved.4, 6, 7, 8, 9

Most of the information available on these potential side effects derives from preclinical and laboratory-funded randomized studies,10, 11 and only recently there have been publications regarding post-commercial and observational clinical real world data in case reports and case-series.12, 13

The aim of this study is to present a comprehensive evaluation of the clinical presentation of endocrine IRAEs in a large cohort of patients with refractory lung cancer from a single center treated with nivolumab. We use clearly defined criteria to establish the occurrence of endocrine IRAEs, we provide detailed longitudinal follow-up, and we suggest potential risk factors for the development of IRAE, specifically regarding the thyroid, and devise strategies for their approach and clinical management, including the consideration of continuing to receive these ICPI.