Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study

Summary

Background

Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma.

Methods

We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0–2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis.

Findings

41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14–26). The proportion of patients who achieved a response was 22·5% (95% CI 10·8–38·5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity.

Interpretation

Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential.

Funding

Merck & Co.

Introduction

Thymic epithelial tumours are rare malignancies of thymic epithelial cells, and approximately 500 new cases are diagnosed each year in the USA.¹ Thymic carcinomas are the most aggressive subtype of thymic epithelial tumours and constitute just over 10% of thymic epithelial tumours.² They are often not resectable, tend to metastasise to many locations, and are associated with a shorter overall survival than are thymomas. The recommended treatment of localised disease is surgery, whenever feasible, and radiation with or without chemotherapy. For unresectable and metastatic thymic carcinomas, the standard treatment is chemotherapy with cisplatin, doxorubicin, and cyclophosphamide, or carboplatin and paclitaxel, although the proportion of patients who achieve a response is less than 50%.³ Targeted therapies against thymic carcinoma have been unsuccessful, except for sunitinib, a multikinase inhibitor, which led to a response in 25% of patients.⁴ Novel, effective treatments are needed for this rare disease.

Immunotherapy has been crucial in the treatment of several malignancies in the past few years and has included the use of immune checkpoint inhibitors, such as antibodies against CTLA-4, PD-1, and PD-L1.5, 6 Thymic carcinomas have a high expression of PD-L1,7, 8 which is correlated with a better response to PD-1 and PD-L1 antibodies in several studies.5, 9, 10 When PD-1, which is predominantly present on the surface of activated T cells, binds to PD-L1 on tumour cells, the cytotoxic T-cell response is downregulated.¹¹ The thymus is involved in T-cell development, and although thymomas are associated with myasthenia gravis and other autoimmune diseases, thymic carcinomas are infrequently associated with autoimmune disorders.³ On the basis of these considerations, we conducted an investigator-initiated, single-arm, phase 2 study of pembrolizumab, an anti-PD-1 antibody, in patients with advanced refractory or recurrent thymic carcinomas.

Research in context

Evidence before this study

At the time of planning our study in 2014, we searched PubMed and ClinicalTrials.gov with the terms “thymic carcinoma”, “thymic epithelial malignancy”, “pembrolizumab”, and “anti-PD-1”. We searched articles published before Dec 31, 2013. The search was not limited to English language publications. We did not identify any studies of anti-PD-1 therapy for thymic carcinoma. We used the data on PD-L1 expression in thymic carcinomas and the correlation between PD-L1 expression and efficacy of anti-PD-1 therapy observed in other tumour types and the higher mutational burden of thymic carcinoma as compared with thymoma, as the basis for this trial.

Added value of the study

The anti-PD-1 antibody pembrolizumab was active (objective response 22·5%) and led to durable responses in heavily pretreated patients with metastatic thymic carcinoma. Six (15%) patients developed serious autoimmune toxicity.

Implications of all the available evidence

To the best of our knowledge, these findings represent the first prospective data to demonstrate the antitumour activity of anti-PD-1 therapy in pretreated metastatic thymic carcinoma. Given the relative paucity of effective systemic therapies in the setting of metastatic disease, pembrolizumab might represent a new therapeutic option for these patients. Patients with thymic carcinoma have an increased risk of developing serious autoimmune toxicities after treatment with pembrolizumab and therefore close monitoring of patients is necessary.