Antitumor Activity of Lurbinectedin, a Selective Inhibitor of Oncogene Transcription, in Patients with Relapsed Ewing Sarcoma: Results of a Basket Phase II Study

Vivek Subbiah, Irene Braña, Alessandra Longhi, Valentina Boni, Jean-Pierre Delord, Ahmad Awada, Pascaline Boudou-Rouquette, John Sarantopoulos, Geoffrey I Shapiro, Anthony Elias, Ravin Ratan, Cristian Fernandez, Carmen Kahatt, Martin Cullell-Young, Mariano Siguero, Ali Zeaiter, Sant P Chawla, Vivek Subbiah, Irene Braña, Alessandra Longhi, Valentina Boni, Jean-Pierre Delord, Ahmad Awada, Pascaline Boudou-Rouquette, John Sarantopoulos, Geoffrey I Shapiro, Anthony Elias, Ravin Ratan, Cristian Fernandez, Carmen Kahatt, Martin Cullell-Young, Mariano Siguero, Ali Zeaiter, Sant P Chawla

Abstract

Purpose: Lurbinectedin suppresses the oncogenic transcription factor EWS-FLI1 through relocalization to the nucleolus, and delays tumor growth in mice bearing Ewing sarcoma xenografts. On the basis of this rationale, lurbinectedin was evaluated in patients with relapsed Ewing sarcoma.

Patients and methods: This open-label, single-arm, Basket phase II trial included a cohort of 28 treated adult patients with confirmed Ewing sarcoma, measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1, Eastern Cooperative Oncology Group performance status ≤2, adequate organ function, no central nervous system metastasis, and pretreated with ≤2 chemotherapy lines for metastatic/recurrent disease. Patients received lurbinectedin 3.2 mg/m2 as a 1-hour infusion every 3 weeks. Primary endpoint was overall response rate (ORR) as per RECIST v.1.1. Secondary endpoints included time-to-event parameters and safety profile.

Results: ORR was 14.3% [95% confidence interval (CI), 4.0%-32.7%], with median duration of response of 4.2 months (95% CI, 2.9-5.5 months). Median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months), clinical benefit rate was 39.3%, and disease control rate was 57.1%. With 39% censoring, median overall survival was 12.0 months (95% CI, 8.5-18.5 months). Most common grade 3/4 adverse events were neutropenia (57%), anemia, thrombocytopenia, and treatment-related febrile neutropenia (14% each). No deaths or discontinuations were due to toxicity.

Conclusions: Lurbinectedin was active in the treatment of relapsed Ewing sarcoma and had a manageable safety profile. Lurbinectedin could represent a valuable addition to therapies for Ewing sarcoma, and is currently being evaluated in combination with irinotecan in advanced Ewing sarcoma in a phase Ib/II trial.

Trial registration: ClinicalTrials.gov NCT02454972.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
A, PFS. Each numbered bar represents a patient with Ewing sarcoma treated with lurbinectedin (n = 28). The times when each patient experienced disease progression as per RECIST, and response to treatment, are shown with triangles and asterisks, respectively. B, Maximum variation of target lesions in patients with measurable disease and at least one radiologic tumor assessment. Each patient is identified using the same number as in A. PD, progressive disease; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease.
Figure 2.
Figure 2.
A, Tumor shrinkage observed in a 54-year-old male with osseous Ewing sarcoma who achieved PR with lurbinectedin. The patient had been pretreated with two lines of chemotherapy for advanced disease. Three target lesions were present at baseline: two in the lung and one in a right hilar lymph node. B, After two cycles of treatment with lurbinectedin all target lesions were smaller, with the sum of longest diameters decreasing from 76 to 35 mm (i.e., a tumor shrinkage of 53.9%). In both images, the red arrow shows the location of the lesions. PR, partial response.

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