Head and Neck Cancer
Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial
2Veterans Health Service Medical Center, Seoul, South Korea
3Samsung Medical Center, Sunghyunkwan University School of Medicine, Seoul, South Korea
4Merck Research Laboratories, Boston, MA
Limited treatment options exist for patients with thymic epithelial tumor (TET) whose disease progresses after platinum-based chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate its efficacy and safety.
Patients with histologically confirmed TET whose disease progressed after at least one line of platinum-based chemotherapy were eligible for the study. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past year or documented history of clinically severe autoimmune disease. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The primary objective of response rate was assessed every 9 weeks by investigators.
Of 33 patients enrolled, 26 had thymic carcinoma and seven had thymoma. Of seven thymoma, two (28.6%; 95% CI, 8.2% to 64.1%) had partial response, and five (71.6%) had stable disease. Of 26 thymic carcinoma, five (19.2%; 95% CI, 8.5% to 37.9%) had partial response and 14 (53.8%) had stable disease. The median progression-free survival was 6.1 months for both groups. The most common adverse events of any grade included dyspnea (11; 33.3%), chest wall pain (10; 30.3%), anorexia (seven; 21.2%), and fatigue (seven; 21.2%). Five (71.4%) of seven patients with thymoma and four (15.4%) of 26 patients with thymic carcinoma reported grade ≥ 3 immune-related adverse events, including hepatitis (four; 12.1%), myocarditis (three; 9.1%), myasthenia gravis (two; 6.1%), thyroiditis (one; 3.0%), antineutrophil cytoplasmic antibody–associated rapidly progressive glomerulonephritis (one; 3.0%), colitis (one; 3.0%), and subacute myoclonus (one; 3.0%).
Thymic epithelial tumors (TETs), classified as either thymoma (T) or thymic carcinoma (TC), are rare in adults, but are the most common types among tumors of the anterior mediastinum.1 Complete surgical resection is the only potentially curative option for TETs, but for metastatic disease palliative chemotherapy is indicated.2 TETs are known to be sensitive to platinum-based combination chemotherapy as first-line therapy.3-5 However, there are limited treatment options after failure of platinum-based chemotherapy, and only a few prospective studies have investigated potential therapies. Previous studies with most conventional chemotherapy and novel biologic agents have documented modest antitumor activity in patients with refractory or recurrent TETs, except everolimus and sunitinib, in TC.6-8
Programmed cell death 1 (PD-1) is a negative costimulatory receptor expressed primarily on the surface of activated T cells.9 Binding of PD-1 to one of its ligands, programmed cell death ligand 1 (PD-L1) or PD-L2, inhibits a cytotoxic T-cell response, resulting in downmodulation of antitumor immunity.10 Pembrolizumab is a selective, humanized, monoclonal antibody designed to bind to PD-1 and thus block the interaction between PD-1 and its ligands.11 Pembrolizumab has shown notable clinical benefits in various types of advanced solid and hematologic malignancies.12-14 Recent studies have reported that PD-L1 is expressed in up to 70% of patients with TETs, but the effect of PD-L1 expression on clinical outcomes remains unclear.15-17 High PD-L1 expression on TETs suggests that anti PD-1/PD-L1 agents could be a promising alternative treatment option for these tumors. Predicated on this hypothesis, we conducted a phase II study to assess the efficacy and safety of pembrolizumab in patients with TETs who had progressive disease after at least one line of systemic treatment with platinum-based chemotherapy.
This is an open-label, single-arm, phase II study at a single center (Samsung Medical Center) in Korea. The study protocol and all amendments were approved by the institutional review boards. The study protocol is available in the Data Supplement. Eligible patients were ≥ 18 years of age, with histologically confirmed T or TC not amenable to potentially curative treatments, disease progression after failure of at least one line of platinum-based chemotherapy, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status ≤ 2, and adequate organ and bone marrow function. We did not exclude patients with controlled brain metastases. Exclusion criteria included patients with immunosuppression, active autoimmune disease that required systemic treatment within the past year or documented history of clinically severe autoimmune disease, interstitial lung disease, active infection requiring systemic therapy, known history of HIV infection, active hepatitis B virus or hepatitis C virus infection, radiation therapy within 2 weeks of first pembrolizumab dose, or previous treatment with any other anti–PD-1 or anti–PD-L1 therapy. All patients provided written informed consent.
Pembrolizumab was administered intravenously at a fixed dose of 200 mg every 3 weeks until disease progression, death, unacceptable toxicity, withdrawal of consent, or at the discretion of the investigators up to 24 months. Baseline assessments included patient history, physical examination, computed tomography scan or magnetic resonance imaging, and laboratory tests (hematology, urinalysis, coagulation, blood chemistry, and pregnancy test if indicated). Physical examination and laboratory tests were performed every 3 weeks, and tumor assessments by computed tomography scan or magnetic resonance imaging of disease-involved site were done every 9 weeks (three cycles of pembrolizumab) according to RECIST version 1.1. If disease progression was radiographically detected, patients who were clinically stable were permitted to continue receiving pembrolizumab until progressive disease was confirmed on a second scan. Dose reduction was not permitted. All adverse events were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Immune-related adverse events (irAEs) were defined as events of clinical interests with potentially drug-related immunologic causes. Pembrolizumab was withheld if patients showed prespecified drug-related adverse events, which included diarrhea or colitis (grade 2 or 3), increased AST, ALT, or bilirubin (grade 2), type I diabetes mellitus (if new onset), or grade 3 or 4 hyperglycemia, hypophysitis (grade 2 or 3), hyperthyroidism (grade 3), pneumonitis (grade 2), renal failure or nephritis (grade 2), or all other drug-related toxicity (grade 3). Pembrolizumab was discontinued if adverse events did not resolve within 12 weeks of the last dose, or inability to reduce corticosteroid dose to 10 mg or less, or equivalent dose of prednisone per day within 12 weeks. The rechallenge of pembrolizumab was allowed once adverse events were resolved at physicians’ discretion.
Archival tumor tissues were required from all patients for study participation. PD-L1 expression was assessed at baseline using the PD-L1 IHC 22C3 pharmDx assay kit (Dako North America, Carpinteria, CA), as previously described.18 Formalin-fixed, paraffin embedded (FFPE) tumor tissue sections were deparaffinized with xylene and rehydrated with ethanol. After antigen retrieval and blocking, prepared slides were stained using the primary mouse antihuman PD-L1 antibody (clone 22C3). Signal was visualized with 3,3′ diaminobenzidine, and slides were counterstained with hematoxylin and cover slipped. PD-L1 positivity was defined by membranous PD-L1 expression in ≥ 1% of tumor and associated inflammatory cells or positive staining of stroma. PD-L1 expression was classified as high if at least 50% of the tumor cells, inflammatory cells, or stroma cells stained positive. PD-L1 expression in 0% to 49% of cells was classified as low expression.
RNA was isolated from FFPE tissue sections using miRNease FFPE kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. RNA concentration was assessed using the Nanodrop (Thermo Fisher Scientific, Waltham, MA). Total RNA (200 ng) was analyzed using the nCounter PanCancer Immune Profiling Panel (Nanostring Technologies, Seattle, WA). The experimental procedures were carried out on the Nanostring preparation station and digital analyzer according to manufacturer’s instructions, as previously reported.19
The primary end point was the overall response rate (ORR), defined as the proportion of patients with a complete or partial response at any point by the investigator assessment. Secondary end points included progression-free survival (PFS), overall survival (OS), duration of response (DOR), the association between candidate efficacy biomarkers (PD-L1 immunostaining and mRNA expression), and safety profiles. PFS was defined as the time from the date of first dose to first documented disease progression per RECIST v1.1 or death as a result of any cause, whichever occurred first. OS was defined as the time from the date of first dose to death as a result of any cause. DOR was defined as the time from the date of first documented objective response (complete or partial response) until disease progression.
Given the rarity of TETs, this study was planned to include patients with T and TC in a single cohort. The statistical design of the study was based on Simon’s two-stage phase II optimal design (power of 90% and one-sided α of 0.05) to rule out a 5% objective response and to target a 25% objective response.20 Nine patients were to be enrolled in the first stage, and if one or more responses were seen, a total of 21 patients were to be treated. Among them, four or more objective responses were necessary for this drug to be evaluated in further study. Considering a 10% dropout rate, a total of 33 patients were enrolled.
The Kaplan-Meier method was used to estimate the median values of time-to-event variables, such as PFS, OS, and DOR. χ2 test and Mann-Whitney test were used to assess the association between the clinical outcomes and the PD-L1 expression or PD-L1 mRNA expression. Data were considered statistically significant from P < .05.
Between March 2016 and July 2016, a total of 33 patients were enrolled, 26 with TC and seven with T (Table 1). The median age was 57 years (range, 26 to 78 years), and 21 (63.6%) of 33 patients were male. Sixteen (48.5%) had stage IVA disease and 17 (51.5%) had stage IVB according to the Masaoka staging system. Nineteen (73.1%) of 26 patients with TC had squamous cell carcinoma. Of 33 patients, 19 (57.3%) had received at least two prior lines of systemic chemotherapy including platinum regimen, whereas 10 (30.3%) had received three or more lines of chemotherapy. Three (9.1%) had a previous history of myasthenia gravis without receiving immunosuppressive treatment at least 1 year before enrollment.
All enrolled patients received at least one dose of pembrolizumab. The median follow-up duration was 14.9 months (interquartile range, 6.25-20.7). As listed in Table 2, of seven patients with T, two (28.6%) had partial response and five (71.6%) had stable disease, resulting in an ORR of 28.6% (95% CI, 8.2% to 64.1%) and a disease control rate of 100% (95% CI, 64.6% to 100%). The median DOR was not reached for patients with T. Of 26 patients with TC, five (19.2%) achieved partial response and 14 (53.8%) had stable disease (including one unconfirmed partial response), resulting in an ORR of 19.2% (95% CI, 8.5% to 37.9%) and a disease control rate of 73.1% (95% CI, 53.9% to 86.3%). The median DOR was 9.7 months (95% CI, 0.0% to 19.8%) for patients with TC. One patient who achieved a partial response after six cycles of pembrolizumab could not be re-evaluated because of follow-up loss, resulting in unconfirmed partial response.
Reduction in tumor size from baseline in target lesions was observed in five (71.4%) of seven patients with T and 12 (46.2%) of 26 patients with TC (Fig 1). One (14.3%) of seven patients with T and five (19.2%) of 26 patients with TC were still receiving pembrolizumab treatment at the time of data cutoff (January 18, 2018). The median PFS was 6.1 months for both T (95% CI, 4.3 to 7.9 months) and TC (95% CI, 5.1 to 7.1 months). The median OS was 14.5 months for TC and not reached for T (Appendix Fig A1, online only).
As of January 18, 2018, the median number of cycles was eight for both T and TC. Twenty-eight (84.8%) patients had disease progression and 17 (51.5%) patients had died—16 (48.5%) from disease progression and one from systemic cytomegalovirus infection. The major reason for treatment discontinuation was disease progression (17 patients [51.5%]). Treatment was also discontinued in eight patients (24.2%) because of severe irAEs and in two patients (6.1%) because of loss of follow-up. Four patients with TC had continued pembrolizumab treatment beyond progression. Among those four patients, one patient is still receiving pembrolizumab treatment without additional disease progression.
Of the 33 enrolled patients, the most frequently observed adverse events of any grade, regardless of their causality to pembrolizumab, were dyspnea (11; 33.3%), chest wall pain (10; 30.3%), anorexia (seven; 21.2%), fatigue (seven; 21.2%), and cough (six; 18.1%; Table 3). As listed in Table 4, five (71.4%) of seven patients with T reported grade 3 or 4 irAEs, such as myocarditis (three; 42.9%), hepatitis (two; 28.6%), thyroiditis (one; 14.3%), colitis (one; 14.3%), conjunctivitis (one; 14.3%), and nephritis (one; 14.3%). Four (15.4%) of 26 patients with TC reported grade 3 or 4 irAEs, including hepatitis (two; 7.7%), myasthenia gravis (two; 7.7%), and subacute myoclonus (one; 3.8%). Three patients who had a previous history of autoimmune syndrome eventually developed severe irAEs during pembrolizumab treatment. Five patients (71.4%) with T and three patients (11.5%) with TC discontinued pembrolizumab treatment because of grade 3 or 4 irAEs (Table 5). Of eight patients who discontinued pembrolizumab treatment because of irAEs, six experienced severe irAEs after the first or second cycle of pembrolizumab treatment. Seven (87.5%) of eight patients who discontinued treatment fully recovered from irAEs with administration of high-dose corticosteroids and other immunosuppressive agents. However, a 66-year-old woman with a WHO B2 T died as a result of superimposed cytomegalovirus infection during immunosuppressive treatment of co-occurrence of grade 4 autoimmune hepatitis, grade 3 colitis, and grade 2 dermatitis. In eight patients who discontinued treatment because of severe irAEs, the median PFS was 6.1 months (95% CI, 1.8 to 10.4 months) and median DOR was 5.0 months (95% CI, 0.0 to 12.4 months). The median time to progression from the time point of study discontinuation because of severe irAEs was 4.7 months (95% CI, 1.6 to 7.8 months). Given the high incidence of irAEs at the early stage of the study, study protocol was revised to halt the inclusion of patients with T or patients who had a previous history of autoimmune syndrome regardless of severity and histologic subtype during the study.
Tumor samples were evaluable for PD-L1 immunostaining in 24 patients (72.7%). Among them, 14 (58.3%) had high PD-L1 immunohistochemistry expression of ≥ 50% tumor proportion score (Fig 2A). Five (35.7%) of 14 patients whose tumor expressed high PD-L1 achieved a partial response, whereas none of the patients with low PD-L1 expression had a response (P = .034). In contrast, there was no significant difference in the development of severe irAEs on the basis of the status of PD-L1 immunostaining when the cutoff value was 50% (hazard ratio, 3.0; P = .242). Nineteen (57.6%) of 33 patients had tumor samples available for assessment of PD-L1 mRNA expression using the nCounter PanCancer Immune Profiling Panel. There was a strong correlation between PD-L1 expression by immunohistochemistry and PD-L1 mRNA expression (Fig 2B). Four responders had relatively high PD-L1 mRNA expression on tumor compared with nonresponders (P = .049). We did not find any significant correlation between clinical outcomes and mRNA expression for the other evaluated genes, including interferon-γ–related genes (Appendix Fig A2, online only).
In this phase II study, pembrolizumab demonstrated encouraging antitumor activity with durable response among patients with TETs. ORR was similar in patients with T and those with TC (28.6% and 19.2%, respectively). These treatment responses are clinically meaningful, given that most novel agents to date have failed to demonstrate considerable antitumor activity in both T and TC.6,7 Furthermore, an ORR of 19.2% suggests its potential clinical use in refractory TC, considering poor response to previous salvage therapy in this population.6,22-25 Recently, as targeted agent, a phase II study of sunitinib showed relatively high antitumor activity with an ORR of 26% in 23 pretreated patients with TC, which made sunitinib a promising salvage treatment option in this population. More recently, Giaccone et al26 reported that pembrolizumab in pretreated patients with TC showed a 22.5% (nine of 40) response rate, with a median PFS of 4.2 months (95% CI, 2.9 to 10.3 months), which is quite similar to our study. Although cross-trial comparisons should be made with caution, pembrolizumab demonstrated comparable response rate with sunitinib in patients with TC.
Despite our limited sample size, high PD-L1 immunohistochemistry expression was significantly associated with better response to pembrolizumab in patients with TET, which is consistent with previous reports in other malignancies.18,27,28 Among 24 evaluable patients, the ORR was 35.7% in 14 (58.3%) patients whose tumor expressed ≥ 50% tumor proportion score of PD-L1 immunostaining, whereas no response was observed in all 10 patients with < 50% of PD-L1 immunostaining (P = .034). Similarly, Giaccone et al26 also reported a significant correlation between high PD-L1 expression and better response to pembrolizumab in TC. Furthermore, PD-L1 mRNA expression was also relatively higher in responders compared with nonresponders (P = .049) in our study.
The safety profile of pembrolizumab in this study was noteworthy because of a high rate of irAEs. Among total patients, nine patients (27.3%) reported grade 3 or 4 irAEs, and eight (24.2%) discontinued pembrolizumab treatment. irAEs were more prevalent in patients with T compared with patients with TC (71.4% v 15.4%, respectively). Furthermore, five out of nine patients (four with T and one with TC) experienced multiple autoimmune adverse events simultaneously, which were not commonly observed in other malignancies treated with pembrolizumab. Of note, severe immune-related myocarditis, which is a quite rare autoimmune syndrome, even in TET, developed in three patients with T, but all have fully recovered with high-dose corticosteroids and intravenous immunoglobulin. Giaccone et al26 also observed a relatively high rate of irAEs for TC, with six patients (15%) developing grade 3 or 4 irAEs, such as myocarditis, hepatitis, myasthenia gravis, bullous pemphigoid, and type 1 diabetes mellitus. Similarly, Rajan et al29 reported that three (37.5%) of eight patients with TET treated with avelumab, an anti–PD-L1 antibody, developed grade 3 or 4 irAEs, including myositis, indicating that irAEs are more frequent in patients with T and even TC compared with other solid malignancies treated with a single agent of immune checkpoint inhibitors. Given the high incidence of severe irAEs in TET, especially in T, immune checkpoint inhibitors should be avoided in patients with T or those who have a previous history of autoimmune syndrome. In patients with TC, careful monitoring should be emphasized to detect and manage irAEs at the early period of treatment, because these adverse events can be severe.
In patients with TET treated with pembrolizumab, the development of irAEs seemed to be associated with better tumor response, with four (44.4%) of nine patients who developed severe irAEs achieving partial response. However, we did not observe any significant correlation between irAEs and PD-L1 expression or interferon-γ gene signature. Such association with autoimmunity and better response to immune checkpoint inhibitors has been previously described in patients with melanoma.30 The PD-1/PD-L1 pathway is a key regulator in T-cell activation and self-tolerance and plays a crucial role in autoimmunity.31 In normal thymus, PD-L1 is expressed broadly on the thymic cortex and thymocytes.32 It has been reported that PD-1/PD-L1 interactions modulate positive and negative selection from CD4−CD8− to CD4+CD8+ during the thymic development stage.33 Although the exact mechanisms by which TET induces autoreactivity still remain unclear, one possible explanation is that the damage induced by tumor growth within the thymus diminishes its ability to maintain self-tolerance. Furthermore, it can be hypothesized that immune checkpoint inhibitors could enhance the loss of immune regulation, resulting in high prevalence of irAEs.34
Several immunologic biomarkers for the prediction and early identification of irAEs are currently being investigated.35,36 IL-17, immune gene expression, or peripheral eosinophil counts were reported to be associated with the development of irAEs in solid tumors. Considering the high incidence of irAEs in patients with TET treated with immune checkpoint inhibitors, additional biomarker studies are warranted to identify those who can benefit from immune checkpoint inhibitors without irAEs.
In conclusion, to our knowledge, this study is the first prospective investigation of pembrolizumab in patients with T and TC. Pembrolizumab showed encouraging antitumor activity in patients with refractory or relapsed TETs. However, given the relatively high incidence of irAEs, especially in patients with T, treatment with an immune checkpoint inhibitor should be avoided in patients with T. Early detection and management of irAEs is also critical in pembrolizumab treatment adherence and retention of patients with TC.
Supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea, Grant No. HI16C1984. Pembrolizumab was provided by Merck.
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Conception and design: Jinhyun Cho, Hae Su Kim, Myung-Ju Ahn
Provision of study materials or patients: Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Collection and assembly of data: Jinhyun Cho, Bo Mi Ku, Yoon-La Choi, Joungho Han
Data analysis and interpretation: Jinhyun Cho, Bo Mi Ku, Razvan Cristescu, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Employment: Merck Sharpe & Dohme
Honoraria: AstraZeneca/MedImmune, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme
Consulting or Advisory Role: Pfizer, Novartis, AstraZeneca, Bristol-Myers Squibb
Research Funding: Merck Sharp & Dohme
Travel, Accommodations, Expenses: Novartis
Honoraria: Amgen, Pfizer, AstraZeneca, Menarini, Roche, Eisai, Bristol-Myers Squibb, Janssen, Boehringer Ingelheim
Consulting or Advisory Role: Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Eli Lilly, Hanmi, Kyowa Hakko Kirin, Novartis, Ono Pharmaceutical, Roche, Bristol-Myers Squibb, MSD
Speakers' Bureau: Boehringer Ingelheim, AstraZeneca
Research Funding: AstraZeneca
Honoraria: AstraZeneca, Genentech, Bristol-Myers Squibb, MSD
Consulting or Advisory Role: AstraZeneca, Eli Lilly, MSD, Lyzz
No other potential conflicts of interest were reported.
We thank all patients who participated in this study and their families.
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