Malignant Pleural Mesothelioma (MPM) is a rare neoplasm that is typically diagnosed in a locally advanced stage, making it not eligible for radical surgery and requiring systemic treatment. Chemotherapy with platinum compounds and pemetrexed has been the only approved standard of care for approximately 20 years, without any relevant therapeutic advance until the introduction of immune checkpoint inhibitors. Nevertheless, the prognosis remains poor, with an average survival of only 18 months. Thanks to a better understanding of the molecular mechanisms underlying tumor biology, targeted therapy has become an essential therapeutic option in several solid malignancies. Unfortunately, most of the clinical trials evaluating potentially targeted drugs for MPM have failed. This review aims to present the main findings of the most promising targeted therapies in MPM, and to explore possible reasons leading to treatments failures. The ultimate goal is to determine whether there is still a place for continued preclinical/clinical research in this area.

Background: Thymic epithelial tumors (TETs) are rare malignancies with a limited therapeutic armamentarium. Enrollment in prospective clinical trials involving novel agents or new treatment combinations represents a therapeutic opportunity for patients with TETs. However, the availability to such trials is often limited due to poor engagement by pharmaceutical companies in rare cancer research. This study retrospectively investigated the proportion of Italian patients with metastatic TETs treated with experimental systemic therapy (any lines) in prospective clinical trials. Methods: Clinicoradiological, histopathological, and oncological data were retrospectively collected for 135 patients with unresectable metastatic TETs who received systemic therapy between January 2000 and December 2020. Data were sourced from the large multicenter database of the Italian collaborative group for ThYmic MalignanciEs (TYME). Survival analyses were performed using the Kaplan-Meier method and stratified by histology. Results: A total of 135 patients were included: 73 (54%) treated within clinical trials (any lines of therapy) and 62 (46%) treated outside of trials. Among the trial group, 59 patients (80.8%) had thymoma B3 or thymic carcinoma (TC), and 14 (19.2%) had other thymoma subtypes. In the non-trial group, 35 patients (56.4%) had thymoma B3 or TC, and 27 (43.5%) had other thymoma subtypes. Overall, 46 out of 63 patients (73%) treated in a protocol study received experimental drugs in the second or third-line setting. At 36 months, the overall survival (OS) rate was 75.8% in the trial group and 83.5% in the non-trial group. Stratifying by histology, patients with TC or thymoma B3 had a 36-month OS rate of 71.5% in the trial group and 73.7% in the non-trial group. Among patients with other thymoma subtypes, the 36-month OS was 92.8% in the trial group and 95.8% in the non-trial group. Conclusions: Our analysis showed that, within the Italian TYME network, the majority of patients with metastatic TETs were treated with systemic therapy in the context of a clinical trial. Moreover, these patients presented a higher proportion of histologies associated with a poor prognosis compared to those not treated with experimental drugs. Further data collection is needed to explore whether meaningful differences exist between patients treated within and outside.

Background: Thymic epithelial tumors (TETs) are rare cancers, and limited data are available in the literature regarding the management of metastatic disease. In particular, for patients with metastatic oligo-recurrent disease, the use of local treatments instead of systemic therapy is sometimes considered by clinicians, although the supporting evidence is weak. We aim to retrospectively evaluate a series of patients with metastatic oligo-recurrent TETs treated with local therapy. Methods: A monocentric retrospective trial was conducted selecting patients with TETs who were treated with local therapy (surgery or radiotherapy) for metastatic oligo-recurrent disease following radical surgery of the primary tumor. Data were collected on clinical characteristics, date and localization of recurrences, type of local treatments, date of disease progression after local therapy, and follow-up. The data were analyzed using Statistical Analysis System (SAS) version 9.4. Results: A total of 38 patients with TETs (30 thymomas; 8 thymic carcinomas) were included. Disease recurrence was detected in a single site in 18 patients (47.4%), in two sites in 14 patients (36.8%), and in three or more sites in 6 patients (15.8%). The most frequent sites of recurrence were pleura alone in 14 patients (36.8%), chest wall in 14 patients (36.8%), and lung in 10 (26.3%). Oligo-recurrent disease was confined to a single organ in 25 patients (65.8%) and to multiple organs in 13 patients (34.2%). Local therapy for oligo recurrence consisted of surgery alone in 15 patients (39.5%), radiotherapy alone in 7 (18.4%), radiotherapy plus surgery in 6 (15.8%), surgery plus chemotherapy in 6 (15.7%), radiotherapy plus chemotherapy in 2 (5.3%), and surgery combined with both radiotherapy and chemotherapy in 2 (5.3%). Following local therapy, 26 patients (68.4%) experienced progression of disease. Among them, 16 patients (61.5%) received an additional local therapy, while 10 (38.5%) received systemic treatment. The median progression-free survival (PFS) was 26.5 months [95% confidence interval (CI): 16–41]. The 6- and 12-month PFS rates were 85.9% and 79.7%, respectively. The median overall survival (OS) was 100.3 months (95% CI: 84–not reached) with the 1- and 5-year OS rates of 100% and 89%, respectively. Conclusions: Local treatment of metastatic oligo-recurrent TETs seems to be associated with prolonged survival. An enlargement of the case study and a prospective evaluation could provide stronger evidence to support this therapeutic approach.