Thymic carcinoma is a rare neoplasm with a dismal prognosis, and there are no established therapeutic regimens for metastatic or recurrent disease. Immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies, are widely approved in several human cancers, contributing to prolonging survival in thoracic tumors. Thymic carcinoma exhibits histologic properties of squamous cell carcinoma (SQC), and resembles the SQC of the lung. ICIs are not approved in thymic carcinoma. Thus, several clinical trials have been undertaken to demonstrate if they are therapeutically effective for patients with thymic carcinoma.
- thymic carcinoma
- immunotherapy
- immune checkpoint inhibitor
- PD-1 blockade
- pembrolizumab
- nivolumab
1. Introduction
Thymic carcinoma (TC) is a rare neoplasm with a poor outcome. If early detected, surgical resection is suitable for its curability, whereas systemic chemotherapy (platinum-based regimens) is usually indicated for patients with metastatic or recurrent disease. However, chemotherapy yielded limited benefits to the outcome and efficacy of TC. Currently, there are no established regimens for the treatment of patients with advanced TC.
In fact, the assessment of chemotherapeutic agents for TC is limited to single-arm phase II trials or retrospective studies with small samples. Recently, Okuma et al. reported a systemic review and pooled analysis of anthracycline-, carboplatin-, or cisplatin-based chemotherapy in patients with TC [1]. Their results revealed that the objective response rates (ORRs) of anthracycline-based and non-anthracycline-based chemotherapy for advanced TC were 41.8% and 40.9%, respectively (p < 0.91), whereas those of cisplatin-based and carboplatin-based chemotherapy were 53.6% and 32.8%, respectively (p = 0.0029) in 206 patients collecting 10 studies. They concluded that cisplatin-based chemotherapy was better in patients with TC than carboplatin-based chemotherapy. Anthracycline-based regimens, such as ADOC (doxorubicin, cisplatin, vincristine, and cyclophosphamide), CODE (adriamycin, cisplatin, vincristine, and etoposide) and carboplatin plus amrubicin, and non-anthracycline-based chemotherapy, such as carboplatin plus paclitaxel, cisplatin plus docetaxel, and cisplatin plus irinotecan, are selected based on the judgment of chief-physicians. In fact, promising drugs, such as molecular targeting agents or immunotherapy aside from anthracycline or platinum-based regimens, are not available, although clinical trials have been conducted in different countries.
Recently, immune checkpoint inhibitors (ICIs), such as anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) antibodies, have been administered to patients with several different kinds of neoplastic types. In particular, PD-1 blockade (nivolumab, pembrolizumab, and atezolizumab) show significant efficacy in patients with advanced non-small-cell lung cancer (NSCLC). Varying efficacies of these antibodies according to PD-L1 expression within tumor cells have been reported. PD-1 blockade monotherapy, or a combination of PD-1 blockade with platinum-based regimens, have been identified as first-line standard treatments [2][3][4][5]. By recent investigation, Kaplan-Meier curves of overall survival (OS) exhibited an estimated 5-year rate of 34.2% among patients with melanoma, 27.7% among patients with renal cell carcinoma, and 15.6% among patients with NSCLC [6]. Although the possibility of long-term survivors after PD-1 blockade treatment has been confirmed in several reports [7][8], ICIs have been identified as a curative modality in limited cancer types.
2. Discussion
Currently, PD-1 blockade is approved in patients with several types of human neoplasms. In particular, it has been found to improve the therapeutic efficacy of PD-1 blockade combined with cytotoxic agents or angiogenetic drugs
. Therefore, we expect that PD-1 blockade is therapeutically effective for patients with TC as rare cancer. In our review, three prospective phase II studies and several case series regarding TC were discussed, and we found that the ORR, DCR, and median PFS in PD-1 blockade monotherapy were approximately 20%, 73%, and four months, respectively. Compared with the clinical trial of nivolumab in previously treated NSCLC, the therapeutic outcome of PD-1 blockade monotherapy in TC seemed favorable, and the increased frequency of irAEs was not found. Although the expression of PD-L1 within tumor cells is known to predict the efficacy of PD-1 blockade in patients with NSCLC, two exploratory investigations indicated that PD-L1 has the potential to precisely predict PD-1 blockade in TC
. Cho et al. and Giaccone et al. described that the clinical benefit according to the expression level of PD-L1 seems to be apparent for predicting the efficacy of PD-1 blockade in patients with thymic carcinoma
. Several case reports have also been reviewed, and the treatment content discussed. In clinical practice, nivolumab or pembrolizumab is active for patients with previously treated TC. Moreover, their clinical effectiveness was confirmed to persist in the long-term. Further studies are required to confirm the efficacy of PD-1 blockade according to the expression level of PD-L1.
To improve the therapeutic efficacy of TC, the development of new regimens, such as tyrosine kinase inhibitors (TKIs), ICIs, and their combination, is necessary, and many studies are ongoing. As clinical trials of PD-1 blockade monotherapy in patients with thymic epithelial tumors, three phase II studies are currently ongoing. Atezolizumab was investigated in 34 patients with pretreated TC, with the primary endpoint of ORR and secondary endpoint of PFS, OS, duration of objective response (DOR), DCR, adverse events, and distribution of PD-L1 and TMB expression (NCT04321330). Nivolumab was examined in 55 patients with previously treated TC and thymoma type B3 after platinum-based chemotherapy, with the primary endpoint of PFS rate at six months and secondary endpoint of PFS, OS, ORR, DCR, and DOR (NCT03134118). Avelumab was investigated for 55 patients with previously treated TC and thymoma after platinum-based chemotherapy, with a primary endpoint of ORR and safety and secondary endpoint of immune-related PFS, OS, and DOR (NCT03076554). The PFS, OS, and DOR were common in these three studies, but primary outcome measures were different among these studies, PFS or ORR.
In addition, combination therapy of TKIs with PD-1 blockade has also been examined as a targeted treatment for thymic epithelial tumors. A phase II study evaluating the ORR of pembrolizumab plus sunitinib is currently ongoing in 40 patients with TC who are resistant to platinum-based regimens (NCT03463460). The primary objective of this study is ORR and secondary objectives are to evaluate safety profile, PFS and OS. As exploratory investigations, it is planning to determine whether sunitinib leads to an increase in PD-L1 expression, TILs, and decrease in myeloid-derived suppressor cells (MDSC) in both tumor and peripheral blood. In the CAVEATT study, 33 patients with TC and thymoma type B3 treated with platinum-based chemotherapy are registered and received avelumab combined with axitinib (an oral VEGFR-1/2/3 kinase inhibitor) for the primary endpoint of ORR. In phase I/II trials, nivolumab plus vorolanib, an oral VEGFR/PDGFR kinase inhibitor, is in progress for the aim of safety and ORR in 177 patients with pretreated thoracic tumors, including TC (NCT03583086). The primary objectives of this study are safety and tolerability of nivolumab plus vorolanib as a phase I study and efficacy as a phase II study, and secondary objectives are PFS and OS. Finally, pembrolizumab with or without SC-C101 (a superagonist fusion protein of interleukin-15) is currently ongoing as a phase 1/Ib study for 96 patients with pretreated solid tumors, including thymic epithelial tumors (NCT04234113). The primary objective of this study is to determine dose-limiting toxicities and treatment-related adverse events, and secondary objectives are ORR, BOR, PFS, and clinical benefit rate. These clinical trials are promising and are expected to provide future perspectives.
3. Conclusions
Very few prospective studies have evaluated the efficacy of PD-1 blockade monotherapy (pembrolizumab or nivolumab) in patients with pretreated TC. The therapeutic efficacy of PD-1 blockade monotherapy is still limited in such patients, similar to the therapeutic results of advanced NSCLC. Although it remains unclear whether PD-L1 expression could predict the efficacy of PD-1 blockade monotherapy in TC, an exploratory investigation suggests an increased response of PD-1 blockade in patients with high PD-L expression. We believe that PD-L1 appears predictive in such patients. Future perspectives focusing on the therapeutic implication of TKIs plus ICIs or new experimental agents plus ICIs, and several experimental studies are currently ongoing.
References
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