Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy

Abstract

Purpose No effective salvage treatments are available for patients with advanced/recurrent thymoma (T) or thymic carcinoma (TC) who have progressed after platinum-based chemotherapy. This study evaluated the activity of everolimus in patients with advanced/recurrent T or TC previously treated with cisplatin-containing chemotherapy. Patients and Methods This was a single-arm, single-stage, open-label, multicenter, phase II trial. Patients received oral everolimus 10 mg/d until disease progression, unacceptable toxicity, or patient refusal. A Fleming phase II trial was designed. The null hypothesis of a true disease control rate (DCR) of 40% was tested against a one-sided alternative of a true DCR of 60% (α = β = 0.10): If disease control were achieved in ≥ 21 of the first 41 evaluable patients, everolimus could be recommended for further evaluation. Progression-free survival, overall survival, and safety were also evaluated. Results From 2011 to 2013, 51 patients were enrolled (T, n = 32; TC, n = 19). Complete remission was observed in one patient with TC, partial response in five patients (T, n = 3; TC, n = 2), and stable disease in 38 patients (T, n = 27; TC, n= 11), with a DCR of 88% (T,: 93.8%; TC, 77.8%). With a median follow up of 25.7 months, median progression-free survival was 10.1 months (T,: 16.6 months; TC, 5.6 months), and median overall survival was 25.7 months (T, not reached; TC, 14.7 months). Fourteen patients had a serious drug-related adverse event; of these patients, nine permanently discontinued treatment. Three patients died of pneumonitis while in the study. Immunohistochemical positivity for p4E-BP1 or insulin-like growth factor-1 receptor was statistically significantly related to a shorter survival. Conclusion Everolimus may induce durable disease control in a high percentage of patients with T or TC, albeit with a potential high risk of fatal pneumonitis.

Thymic Carcinoma Management Patterns among International Thymic Malignancy Interest Group (ITMIG) Physicians with Consensus from the Thymic Carcinoma Working Group

“…The role of molecular-targeted therapy in the treatment of unresectable thymic carcinoma has been evaluated in phase II clinical trials 14,15 . Further efforts are needed to identify additional molecular targets in thymic carcinoma and evaluate the role of immunotherapy.…”

Activation of the mTOR/ Akt pathway in thymic epithelial cells derived from thymomas

“…Interestingly, only one of our cases harbored a GTF2I mutations, that was associated at RPPA analysis in this cohort, with lower expression of the apoptosis, cell cycle, DNA damage response, hormone receptor signaling, breast hormone signaling, RAS/MAPK, RTK, and TSC/mTOR pathways [38]. Our findings related to the activation of the Akt-mTOR pathway in a majority of specimens from patients with thymomas are of significant clinical relevance, given the recent results of a phase II study of everolimus in advanced thymic epithelial tumors, reporting on a disease control rate of 88%, with median progression-free survival of 10.1 months and median overall survival of 25.7 months [34]. Everolimus is currently available and may represent an off-label option for refractory tumors [3].…”

“…Exposure of thymic carcinoma cells to HSP90 inhibitors led to cell cycle arrest and apoptosis, and blocked invasiveness, through the downregulation of HSP90 oncogenic clients, including insulin-like growth factor 1 receptor (IGF-1R), a transmembrane tyrosine kinase receptor frequently overexpressed in thymic carcinomas, CDK4, and PI3K/Akt [32]. Taken together, these data were of significant therapeutic relevance: while pictilisib is mostly developed in breast cancers, which more frequently harbor PI3K alterations, phase II trials dedicated to thymic epithelial tumors were conducted with the IGF-1R inhibitor cixutumumab [33], the mTOR inhibitor everolimus [34] reporting on clinical antitumor activity in advanced, refractory cases. The IU-TAB-1-cell line was established from type AB thymoma, with phenotypic and molecular profiling but limited information of derivation protocol and success rate, and subsequent analysis of molecular pathways of interest [35].…”

<p>Optimal management of thymic malignancies: current perspectives</p>

“…Targeted agents, approved in other solid tumors, have then been evaluated in thymic malignancies. First of all, mTOR inhibitors (such as Everolimus) showed encouraging results in a Phase II trial 77 with a median progression-free survival at 10.1 months and median overall survival at 25.7 months. One of the most severe adverse effects was fatal pneumonitis and caution before instituting this treatment should be considered.…”