Параллельные клинические испытания селинксора у пациентов с продвинутой тимомой и тимической карциномой.

Introduction

Thymic epithelial tumors (TETs) are rare thoracic malignancies, comprising thymomas and thymic carcinomas. Although the prognosis of TETs is better than other epithelial tumors, the tendency to invade nearby structures or metastasize results in significant morbidity and mortality. Platinum-based chemotherapy remains the standard first-line treatment 1 for advanced disease. However, there are no approved systemic therapies for patients with disease progression after first-line platinum-based chemotherapy. There is an unmet need to develop novel therapeutics to improve outcomes in patients with advanced TETs.

Selinexor is an oral, slowly reversible, covalent-selective inhibitor of nuclear export that specifically blocks the karyopherin protein Exportin 1 (XPO1/Exportin 1), also called chromosome region maintenance 1 (CRM1). Preclinical studies have demonstrated that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins and induces p53-dependent and p53-independent antitumor activity in vitro in TET cells. 2 In addition, selinexor suppressed the growth of TET xenograft tumors in athymic nude mice. In a phase I trial of selinexor in patients with advanced solid tumors, one complete and six partial responses were observed among 157 patients assessable for efficacy. One of the responders had thymoma, and treatment with selinexor continued for almost 2 years for this patient. 3 Selinexor was granted approval for multiple myeloma by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) and for relapsed/refractory diffuse large B-cell lymphoma by the FDA. 4 , 5

To evaluate the efficacy and safety of selinexor in patients with advanced thymoma and thymic carcinoma, we launched two phase II parallel clinical trials. The trials were investigator-initiated, and due to budget considerations, two nearly identical trials were coordinated to run in parallel—one in the United States and the other in Europe—rather than conducting a single large study. Here, we report the results of these clinical trials.

Methods

Study Design and Objectives

The study consisted of two parallel nonrandomized, open-label, two-arm, phase II trials conducted in the United States ( NCT03193437 ) and Europe ( NCT03466827 ). The protocols were developed together and harmonized. Regular teleconferences between investigators were held to assess the progress of the study. Arm A included patients with thymoma (T), and arm B involved patients with thymic carcinoma (TC). The final analysis was carried out on data pooled from both trials.

The primary objective of the study was to determine the efficacy of selinexor in patients with TETs by overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. ORR was defined as the percentage of patients who achieved either a complete or partial response as best response. Secondary end points included progression-free survival (PFS), overall survival (OS), and adverse events (AEs) per Common Terminology Criteria for Adverse Events (CTCAEs) version 4.03.

Study Population

Patients with advanced, inoperable TETs who had progressive disease after treatment with at least one platinum containing chemotherapy were eligible. Other inclusion criteria included age above or equal to 18 years, measurable disease per RECIST 1.1, ECOG performance status less than or equal to 2, and adequate bone marrow and other organ function. Key exclusion criteria included symptomatic brain metastasis requiring corticosteroids, uncontrolled autoimmune disorders, and significantly diseased or obstructed gastrointestinal tract/malabsorption/uncontrolled vomiting or diarrhea/inability to swallow oral medications. Written informed consent was obtained from all patients.

Study Treatment

Patients received selinexor 60 mg twice weekly (Monday/Wednesday, Tuesday/Thursday, or Wednesday/Friday). Patients were given selinexor 3 weeks on and 1 week off in 4-week cycles (6 doses/cycle). Treatment continued until disease progression or the development of unacceptable toxicities or until deemed without benefit to the patient. To improve tolerability, the starting dose was later reduced to 40 mg twice weekly during the study. Patients received prophylactic antiemetics, but steroids were not included as part of the antiemetic regimen.

Safety and Response Evaluation

Computed tomography (CT) scans of the chest and abdomen were performed every 2 cycles for tumor evaluation. Safety was monitored through physical examinations, which included vital signs and weight measurements, performance status evaluation, assessment of concomitant medication use, and laboratory parameter analysis. Information regarding adverse events (AEs) was collected, and each AE was graded, starting from the day of the first administration of the study drug, throughout the treatment period, and, where possible, up to 30 days after the last dose of the study drug.

Statistical Considerations

Simon's two-stage minimax design was used separately for T and TC. A response rate of 10% was considered clinically irrelevant, and a response rate of 30 % was considered promising and clinically relevant for both T and TC cohorts. In the first stage, 15 evaluable patients were included. If response according to RECIST 1.1 was observed in two of 15 patients in the first stage, accrual of 10 evaluable patients continued in the second stage. If responses were observed in five of 25 patients, the alternative hypothesis was accepted, and selinexor was considered active and appropriate for further evaluation. This design yielded a type I error rate of 5% and power of 80% when the true response rate was 30%. ORR was summarized by each cohort, along with their two-sided exact 95% confidence interval (CI). OS, PFS, and DOR were estimated using the Kaplan-Meier method. The median OS, PFS, DOR were calculated for each or whole cohort and presented with two-sided 95% CIs, respectively.

Results

Patient Characteristics

A total of 31 patients were enrolled: 16 with T and 15 with TC ( Table 1 ). Accrual was from November 2017 to October 2019. Four institutions were involved in accrual. The median age was 57 (range: 41–81) years, with 17 men and 14 women. The median number of previous systemic therapies was 2 (range: 1–9). Most patients had previous thymectomy (67.7%) and previous radiation (77.4%). A total of 10 patients (32.3%) had an autoimmune disorder associated with their TET, six of which were myasthenia gravis, two glomerulonephritis, one Crohn’s disease, and one rheumatoid arthritis. Furthermore, most patients had either ECOG 0 (45.2%) or ECOG 1 (51.6%). The most prevalent subtype of T was B2 (six patients), and the most prevalent subtype of thymic carcinoma was squamous (10 patients). Most of the patient had either Masaoka stage IVA (48.4%) or stage IVB (48.4%) disease. The starting dose was 60 mg twice weekly for 29 patients (93.5%) and 40 mg twice weekly for two patients (6.5%). Table 1 Baseline Demographics Variable All Patients (N = 31) Median age 57 (range: 41–81) Gender Male 17 (54.8%) Female 14 (45.2%) Race African American 3 (9.7%) Caucasian 17 (54.8%) Hispanic 1 (3.2%) Unknown 10 (32.3%) Country of enrollment United States of America 8 (25.8%; 5T, 3TC) Denmark 12 (38.7%; 5T, 7 TC) France 11 (35.5%; 6T, 5 TC) Tumor type Thymoma 16 (51.6%) Thymic carcinoma 15 (48.4%) Median previous number of previous therapies 2 (range 1–9) Previous thymectomy No 10 (32.3%) Yes 21 (67.7%) Previous chest radiation No 7 (22.6%) Yes 24 (77.4%) History of autoimmune disease No 19 (61.2%) Yes 10 (32.3%) Myasthenia gravis 6 Crohn’s disease 1 Glomerulonephritis 2 Rheum. arthritis 1 Unknown 2 (6.5%) ECOG/WHO status at enrollment 0 14 (45.2%) 1 16 (51.6%) 2 1 (3.2%) Subtype of thymoma B1 3 B1/B2 1 B2 6 B3 5 Unknown 1 Subtype of thymic carcinoma Squamous 10 Unknown/Other 5 Disease stage (Masaoka) III 1 (3.2%) Iva 15 (48.4%) IVb 15 (48.4%) Starting dose of selinexor 60 mg 29 (93.5%) 40 mg 2 (6.5%) T, thymoma; TC, thymic carcinoma.

Efficacy of Selinexor

The median duration of selinexor therapy was 4.5 (range: 0.1–44.3) months. The overall response rate in the entire study population was 9.7% (95% CI: 2.0%–25.8%), including two patients who received study treatment for less than or equal to 2 weeks and did not undergo subsequent tumor imaging. In the TC group, there was one complete response in a patient with squamous subtype (ORR 6.7%; 95% CI: 1.2%–29.8%), with the response ongoing for more than 5 years at the time of data cutoff. In the T group, there were two partial responses (ORR 12.5% 95% CI: 3.5%–36.0%), both in patients the B2 subtype. Of the patients with T who achieved a partial response, one was able to maintain disease control for 44.9 months with a duration of response of 14.2 months, whereas the other had disease control for 13.8 months with a duration of response of 3.1 months. Stable disease as the best response was observed in 11 patients (68.6%) with T and 12 patients (80%) with TC. Two patients in the T subgroup had progressive disease (12.5%), and one patient in the TC subgroup had progressive disease (6.7%) as the best response ( Table 2 ). Most patients had stable disease per RECIST, but 71% had some decrease in their target lesions as their best response ( Fig. 1 ). Figure 2 illustrates the variety of tumor responses over time. Representative images from responders are found in Figure 3 . Table 2 Tumor Response Response Thymoma (n = 16) n (%) Thymic Carcinoma (n = 15) n (%) CR 0 (0) 1 (6.7) PR 2 (12.5) 0 (0) SD 11 (68.8) 12 (80) PD 2 (12.5) 1 (6.7) Unevaluable 1 (6.3) 1 (6.7) Note: Response was assessed per RECIST 1.1. Responses were confirmed with subsequent imaging. Patients were deemed unevaluable if no postbaseline tumor assessments were performed. CR, complete response; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. Figure 1 The waterfall plot illustrates the change in tumor size for each individual patient in response to selinexor. Each bar represents a patient, with the length of the bar indicating the percentage change in tumor size from baseline. The dashed line indicates the threshold for defining response (30% reduction). In red are patients with thymoma and in black are patients with thymic carcinoma. Sq, squamous; Unk, unknown. Figure 2 The spider plot depicts the treatment response profiles of individual patients. Each line represents a patient, with the line indicating the change in tumor size over time. The numbers on the X-axis indicate each time point for tumor assessment, as defined by the protocol. Figure 3 Three responses. In a patient with B2 thymoma, a mass abutting the heart (arrow) demonstrated reduction in size after 5.5 months of treatment ( B ) compared with before treatment ( A ). Another patient with B2 thymoma experienced shrinkage of a target lesion (arrow) with images taken at baseline ( C ) and after 25.4 months after treatment ( D ). An anterior mediastinal mass (arrow) in a patient with thymic carcinoma demonstrated a complete response, images are before treatment ( E ) and after 14 months of treatment ( F ).

In the T group, the median PFS was 13.6 months (95% CI: 6.3–44.3) and the median OS was not reached ( Fig. 4 A and B ). In the TC group, the median PFS was 7.8 months (95% CI: 4.3–15.5) and the median OS was 15.5 months (95% CI: 13.0–29.9). The TC group did not meet the criteria to move to the second stage (1/15 response), and accrual to this cohort was closed. The T group however met the criteria for the second stage (2/15), and one additional patient was subsequently enrolled. However, due to the low ORRs and budgetary constraints, the trials were halted early. Figure 4 Kaplan-Meier analysis of PFS ( A ) and OS ( B ) with selinexor in patients with thymoma (black) and thymic carcinoma (red).

Safety and Tolerability of Selinexor

The most common treatment-related adverse events (TRAEs) for both T and TC are found in Table 3 : nausea (83.8%), vomiting (45.2%), anemia (41.9%), fatigue (38.7%), asthenia (38.7%), anorexia (35.5%), and diarrhea (29.0%). The TRAEs were similar between the T and TC cohorts. In the T group, any-grade nausea occurred in 81.3%, anemia in 56.3%, vomiting in 43.8%, fatigue in 37.5%, asthenia in 37.5%, thrombocytopenia in 37.5%, anorexia in 31.3%, diarrhea in 25.0%, and visual impairment in 18.8%. In the TC group, nausea occurred in 86.7%, vomiting in 46.7%, fatigue in 40.0%, asthenia in 40.0%, anorexia in 40.0%, visual impairment in 40.0%, diarrhea in 33.3%, anemia in 26.7%, and thrombocytopenia in 20.0%. Most of the TRAEs were grade 1 or 2. The most common grade 3 or higher TRAEs were anemia (16.1%), thrombocytopenia (12.9%), and asthenia (12.9%). One grade 5 TRAEs of pancytopenia was observed. Table 3 Treatment-Related Adverse Events Adverse Event Any Grade n (%) Grade 1 n (%) Grade 2 n (%) Grade 3 n (%) Grade 4 n (%) Nausea 26 (83.9) 12 (38.7) 12 (38.7) 1 (3.2) 0 (0) Vomiting 14 (45.2) 7 (22.6) 5 (16.1) 1 (3.2) 0 (0) Anemia 13 (41.9) 5 (16.1) 3 (9.7) 4 (12.9) 1 (3.2) Fatigue 12 (38.7) 4 (12.9) 7 (22.6) 1 (3.2) 0 (0) Asthenia 12 (38.7) 5 (16.1) 3 (9.7) 4 (12.9) 0 (0) Anorexia 11 (35.5) 6 (19.4) 4 (12.9) 1 (3.2) 0 (0) Diarrhea 9 (29) 6 (19.4) 2 (6.5) 1 (3.2) 0 (0) Thrombocytopenia 9 (29) 5 (16.1) 0 (0) 2 (6.5) 2 (6.5) Visual impairment 9 (29) 9 (29) 0 (0) 0 (0) 0 (0) Weight loss 8 (25.8) 7 (22.6) 0 (0) 1 (3.2) 0 (0) Dysgeusia 8 (25.8) 5 (16.1) 3 (9.7) 0 (0) 0 (0) Dehydration 5 (16.1) 3 (9.7) 1 (3.2) 1 (3.2) 0 (0) Dyspnea 5 (16.1) 2 (6.5) 2 (6.5) 1 (3.2) 0 (0) Headache 5 (16.1) 5 (16.1) 0 (0) 0 (0) 0 (0) Neutropenia 5 (16.1) 3 (9.7) 2 (6.5) 0 (0) 0 (0) Mucositis 5 (16.1) 3 (9.7) 1 (3.2) 1 (3.2) 0 (0) Dizziness 4 (12.9) 3 (9.7) 1 (3.2) 0 (0) 0 (0) Cough 3 (9.7) 2 (6.5) 1 (3.2) 0 (0) 0 (0) Dry eye 3 (9.7) 3 (9.7) 0 (0) 0 (0) 0 (0) Periorbital edema 3 (9.7) 2 (6.5) 1 (3.2) 0 (0) 0 (0) Leukopenia 3 (9.7) 0 (0) 3 (9.7) 0 (0) 0 (0) Cataract 2 (6.5) 0 (0) 0 (0) 1 (3.2) 1 (3.2) Fever 2 (6.5) 2 (6.5) 0 (0) 0 (0) 0 (0) Abdominal pain 2 (6.5) 1 (3.2) 1 (3.2) 0 (0) 0 (0) Transaminitis 2 (6.5) 2 (6.5) 0 (0) 0 (0) 0 (0) Hypomagnesemia 2 (6.5) 2 (6.5) 0 (0) 0 (0) 0 (0) Hyponatremia 2 (6.5) 1 (3.2) 0 (0) 1 (3.2) 0 (0) Acute kidney injury 2 (6.5) 2 (6.5) 0 (0) 0 (0) 0 (0) Rash 1 (3.2) 0 (0) 0 (0) 1 (3.2) 0 (0)

Furthermore, 20 patients (64.5%) required dose reductions due to TRAEs. Overall, 20 patients (64.5%) required dose interruptions, 18 due to TRAEs and two due to pneumonia unrelated to selinexor. Selinexor treatment was discontinued due to TRAEs in 11 patients (35.5%). In addition, 12 patients (38.7%) discontinued selinexor due to disease progression, two patients (6.5%) stopped due to pulmonary infections unrelated to study treatment, one patient (3.2%) chose to stop the treatment due to complete response, one patient (3.2%) stopped due to physician choice, one patient (3.2%) stopped due to personal preference, and three patients (9.7%) for reasons unknown.

At time of data cutoff (December 2023), 15 of the patients had died and 16 were still alive. One death was related to TRAE of pancytopenia, five died due to disease progression, one due to pancytopenia thought to be associated with thymoma, one due to aspergillus infection during treatment with subsequent cytotoxic chemotherapy, and seven of unknown reasons.

Discussion

In this study, selinexor demonstrated modest ORRs in both T and TC groups. The response rate was insufficient for the TC cohort to proceed to the second stage of the trial. Although the study was halted prematurely for the T cohort, a subset of patients experienced extended periods of stable disease. Although this may suggest the potential utility of XPO1 inhibitors in the treatment of advanced TETs, the indolent behavior of thymoma may be a confounding factor. The differences in PFS and OS, between patients with T and those with TC, reflect biological differences.

The safety profile of selinexor is consistent with previous studies, with no new safety concerns identified. However, safety and tolerability data from this study highlight the need for careful management of treatment-related adverse events, with a substantial proportion of patients requiring dose modifications and/or interruptions. The incidence of TRAEs suggests that patient selection and supportive care strategies including the prophylactic use of antiemetics such as 5-HT3 antagonists and olanzapine used in this study are critical for maintaining treatment adherence and quality of life.

Biomarkers of resistance to selinexor that have been reported in hematological malignancies include XPO1 mutations, XPO1 overexpression, E2F1 overexpression, and activation of bypass signaling mechanisms, among others. 6 , 7 Preclinical research on selinexor in TETs indicated that resistance to selinexor was associated with loss of p53 activity or amplification of XPO1 . 2 Additional research is required to discover predictive biomarkers for both response and resistance to selinexor, aiming to refine patient selection strategies, ideally through the analysis of clinical samples.

Studies of targeted therapies and immunotherapies conducted in the past decade have revealed varying degrees of activity in TETs. Anti-angiogenesis therapies, such as sunitinib and lenvatinib, have demonstrated clinically meaningful activity especially in TC with ORRs ranging from 21% to 38%. 8 , 9 Anti–programmed cell death protein 1 therapy, including pembrolizumab, has demonstrated activity with durable responses in a subset of patients with TC 10 , 11 , 12 ; however, serious immune-related adverse events occurred in approximately 15% of patients, indicating the need for close monitoring and patient selection. The use of immunotherapy is discouraged in patients with thymoma outside of a clinical trial. The results of a phase II clinical trial of palbociclib, an inhibitor of CDK4 and CDK6, were reported with the ORR of 12.5% in advanced TET, 13 similar to the ORR observed in this study. However, the rates of dose interruption (29.2%) and dose reduction (16.7%) were much lower with palbociclib compared with selinexor, suggesting better tolerability.

Our study is limited by the small number of patients evaluated and by lack of randomization. However, given the rarity of TETs, randomized studies are challenging if not impossible. Beyond being the first study in the field to assess an XPO1 inhibitor, one of the unique aspects of our study is the conduct of two IITs designed to run in parallel with collaboration across continents. This approach may help reduce the cost of international studies, especially investigator-initiated trials.

In conclusion, selinexor demonstrated modest anticancer activity in patients with pretreated advanced TET. The treatment was complicated by high rates of TRAEs, leading to frequent dose reductions and interruptions.

CRediT Authorship Contribution Statement

Chul Kim: Conceptualization, Data curation, Formal analysis, Investigation, Supervision, Writing - original draft, review & editing.

Vanya Aggarwal: Data curation, Formal analysis, Writing - original draft, review & editing.

Gedske Daugaard: Data curation, Formal analysis, Investigation, Writing - review & editing.

Tianzhi Tang: Data curation, Formal analysis, Writing - review & editing.

Jaeil Ahn: Formal analysis, Writing – review & editing.

Benjamin Besse: Data curation, Formal analysis, Investigation, Writing - review & editing.

Nicolas Girard: Data curation, Formal analysis, Investigation, Writing - review & editing.

Giuseppe Giaccone: Conceptualization, Data curation, Formal analysis, Investigation, Supervision, Writing - original draft, review & editing.

Peter Meidahl Petersen: Conceptualization, Data curation, Formal analysis, Investigation, Supervision, Writing - original draft, review & editing.

Disclosure

Dr. Kim reports receiving research funding (to institution) from Karyopharm , 10.13039/100004325 AstraZeneca , 10.13039/100004336 Novartis , Regeneron, Janssen, Genentech, Lyell, Daiichi Sankyo, Gilead, Macrogenics, Boehringer Ingelheim, Black Diamond Therapeutics, and ORIC Pharmaceuticals; providing consulting for Jazz Pharmaceuticals, Arcus Biosciences, AstraZeneca, Eisai, Daiichi Sankyo, Regeneron, Sanofi, Takeda, J&J, Pinetree, Boehringer Ingelheim, Bristol Myers Squibb, Bicycle, Bayer, Onviv, and Bio-Thera. Dr. Daugaard reports providing consulting for Astellas, Bayer, Merck Sharp & Dohme, and Janssen; receiving support for attending meetings and/or travel from Merck; having participation on a data safety monitoring board or advisory board from Bayer. Dr. Besse reports receiving research funding (to institution) from AstraZeneca, 10.13039/100006483 AbbVie , 10.13039/100002429 Amgen , Sanofi, Daiichi Sankyo, Janssen Oncology, Roche/Genentech, Ellipses Pharma, Genmab, MSD Oncology, PharmaMar, Taiho Pharmaceutical, Nuvalent, Inc., Enliven Therapeutics, Prelude Therapeutics, Takeda, BeiGene, GlaxoSmithKline, OSE Immunotherapeutics, and AnHeart Therapeutics; honoraria from AbbVie, Roche, Janssen, Merck Sharp & Dohme, AstraZeneca, Chugai Pharma, Daiichi Sankyo, Hedera Dx, Sanofi/Aventis, and Springer Healthcare Ltd. (Inst); consulting or advisory role from Chugai Pharma (Inst), Daiichi Sankyo (Inst), F. Hoffmann LaRoche (Inst), PharmaMar (Inst), Sanofi/Aventis (Inst), AbbVie (Inst), Da Volterra (Inst), Lilly (Inst), Ellipses Pharma (Inst), Janssen (Inst), OSE Immunotherapeutics (Inst), Taiho Oncology (Inst), Turning Point Therapeutics (Inst), BioNTech SE (Inst), Bristol Myers Squibb (Inst), CureVac (Inst), Regeneron (Inst), Genmab (Inst), Immunocore (Inst), MSD Oncology (Inst), and Owkin (Inst). Dr. Girard reports receiving research grants/support from AbbVie, Amgen, AstraZeneca, 10.13039/100017239 BeiGene , Boehringer Ingelheim , Bristol Myers Squibb, Daiichi Sankyo, Gilead, Hoffmann-La Roche, Janssen, LeoPharma, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Sanofi, and Sivan; consultative services for AbbVie, Amgen, AstraZeneca, Beigene, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Ipsen Hoffmann-La Roche, Janssen, LeoPharma, Lilly, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Pierre Fabre, Sanofi, and Sivan Takeda; participation on a data safety monitoring board for Hoffmann-La Roche; employment of a family member with AstraZeneca. Dr. Petersen reports receiving grants from Capital Region , Denmark, The Danish Cancer Society; consulting for Novartis; payment or honoraria for lectures from Bayer; support for attending meetings and/or travel from Merck Sharp & Dohme; and participation on a data safety monitoring board or advisory board from Bayer. The remaining authors declare no conflict of interest.

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Supplementary Data

Supplementary Table 1

Cite this article as: Kim C, Aggarwal V, Daugaard G, et al. Parallel phase II clinical trials of selinexor in patients with advanced thymoma and thymic carcinoma. JTO Clin Res Rep 2025;6:100848.

Note: To access the supplementary material accompanying this article, visit the online version of the JTO Clinical and Research Reports at www.jtocrr.org and at https://doi.org/10.1016/j.jtocrr.2025.100848 .