Investigational drugs for the treatment of thymic cancer: a focus on phase 1 and 2 clinical trials

ABSTRACT

Introduction

Thymic epithelial tumors (TETs) are rare tumors of thymic epithelial cells. Treatment options for advanced disease patients who failed standard platinum-based chemotherapy are limited.

Areas covered

Phase I and II trials published in the last five years testing new systemic treatments for advanced TET patients are discussed, as well as ongoing trials. A PubMed database literature review was conducted for articles published between January 2016 and December 2021, and ongoing clinical trials were retrieved from ClinicalTrials.gov database.

Expert opinion

The most promising classes of new drugs in TET patients are angiogenesis inhibitors and immune checkpoint antibodies (ICIs). Sunitinib and Lenvatinib showed response rates of 26% and 38%, respectively, and ICIs showed durable responses in 20–25% in thymic carcinoma (TCs). Both approaches are mainly active in TCs, therefore new treatment options for thymomas are an unmet medical need.

Two major new therapeutic strategies are ICI combinations with other drugs and drugs that target pathways that are dysregulated in TETs.

Future challenges include the development of preclinical models to help identify novel targets and test new treatment strategies, and randomized clinical trials to provide reliable evidence based on survival endpoints.

KEYWORDS:

• Thymic epithelial tumors
• thymomas and thymic carcinomas
• phase I and II trials
• immune checkpoint inhibitors
• anti-angiogenic drugs

Article highlights

• Antitumor activity has been reported in several trials testing anti-PD(L)1 antibodies: however, only a minority of patients achieve long-lasting responses, and at the cost of increased risk of severe immune-related adverse events.

• Small molecule inhibitors of angiogenesis including Regorafenib, Sunitinib, and Lenvatinib showed response rates ranging from 0 to 38% in patients with advanced TCs.

• Two new promising immune therapeutic strategies are under evaluation in several phase II trials: the combination of anti-PD(L)1 antibodies with angiogenesis inhibitors, or with anti-CTLA4 antibodies.

• The following emerging drug targets are under evaluation in TETs: the mediator of nucleus-cytoplasmic shuttling XPO1; the PI3K/mTOR pathway; the cyclin-dependent kinase (CDK)/Rb pathway; neurotrophic tyrosine receptor kinase genes (NTRK 1/2/3) and the methylthioadenosine phosphorylase (MTAP) enzyme.

• The rarity of TETs has so far been responsible for relatively small phase II studies. Larger phase II studies and randomized clinical trials will require a coordinated multicenter effort.

• Preclinical research focused on discovery of new therapeutic targets and biomarkers of response is hampered by the lack of representative preclinical models. New in-vitro and in-vivo models will be necessary to develop and test specific treatments for TETs.

Declaration of interest

G. Giaccone has a research contract agreement with Karyopharm. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors have no funding to report.