Patricia Pautier1, Anne Floquet2, Christine Chevreau3, Nicolas Penel4, Cécile Guillemet5, Corinne Delcambre6, Didier Cupissol7, Frédéric Selle8, Nicolas Isambert9, Sophie Piperno-Neumann10, Antoine Thyss11, François Bertucci12, Emmanuelle Bompas13, Jerôme Alexandre14, Olivier Collard15, Sandrine Lavau-Denes16, Patrick Soulié17, Maud Toulmonde2, Axel Le Cesne18, Benjamin Lacas19, Florence Duffaud20. 1. Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France. Electronic address: patricia.pautier@gustaveroussy.fr. 2. Department of Medical Oncology, Institut Bergonié, Bordeaux, France. 3. Department of Medical Oncology, Institut Claudius-Regaud, Toulouse, France. 4. Department of Medical Oncology, Centre Oscar-Lambret, Lille, France. 5. Department of Medical Oncology, Centre Henri-Becquerel, Rouen, France. 6. Department of Medical Oncology, Centre François-Baclesse, Caen, France. 7. Department of Medical Oncology, Centre Val d'Aurelle, Montpellier, France. 8. Department of Medical Oncology, Hôpital Tenon, Paris, France. 9. Department of Medical Oncology, Centre GF Leclerc, Dijon, France. 10. Department of Medical Oncology, Institut Curie, Paris, France. 11. Department of Medical Oncology Centre Antoine Lacassagne, Nice, France. 12. Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France. 13. Department of Medical Oncology, Centre René Gauducheau, Saint Herblain, France. 14. Department of Medical Oncology, Hôpital Cochin, Paris, France. 15. Department of Medical Oncology, Institut de Cancérologie de la Loire, Saint Priest en Jarez, France. 16. Department of Medical Oncology, Centre Hospitalo-Universitaire Dupuytren, Limoges, France. 17. Department of Medical Oncology, Centre Paul Papin, Angers, France. 18. Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France. 19. Department of Biostatistics, Institut Gustave Roussy, Villejuif, France. 20. Department of Medical Oncology, La Timone University Hospital, Marseille, France.
Abstract
BACKGROUND: Metastatic leiomyosarcomas of uterine or soft-tissue origin have poor prognosis and moderate chemosensitivity. Trabectedin has shown activity in pretreated leiomyosarcoma. We did a single-group, multicentre, phase 2 trial (LMS-02) to assess the effect of first-line doxorubicin and trabectedin combination on disease control and survival. METHODS: Adults (18 years to physiological age ≤70 years) with measurable metastatic or unresectable uterine leiomyosarcoma or soft-tissue leiomyosarcoma who had not received any previous chemotherapy were enrolled at 19 centres in France. Treatment consisted of 60 mg/m(2) intravenous doxorubicin followed by 1·1 mg/m(2) trabectedin in a 3 h intravenous infusion on day 1, both by the central venous route, and 6 mg subcutaneous pegfilgrastim on day 2, repeated every 3 weeks for up to six cycles. Surgery for residual disease was permitted. The primary endpoint was the proportion of patients achieving disease control, defined as complete or partial response or stable disease. Stratification was done by anatomical site and analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT02131480. FINDINGS: Between July 28, 2010, and May 10, 2013, 109 patients were enrolled and treated, of whom 108 were assessable for response: 47 in the uterine leiomyosarcoma group and 61 in the soft-tissue leiomyosarcoma group. 32 (68%) patients in the uterine leiomyosarcoma group and 45 (74%) in the soft-tissue leiomyosarcoma group received all six cycles of treatment. Of 47 patients with uterine leiomyosarcoma, 28 (59·6%, 95% CI 44·3-73·6) achieved a partial response and 13 (27·7%, 15·6-42·6) stable disease; 41 (87·2%, 74·3-95·2) patients achieved disease control. Of 61 patients with soft-tissue leiomyosarcoma, two (3·3%, 95% CI 0·4-11·7) achieved a complete response, 22 (36·1%, 25·0-50·8) had a partial response, and 32 (52·5%, 40·8-67·3) had stable disease; 56 (91·8%, 81·9-97·3) of patients achieved disease control. The most common grade 3-4 treatment-associated adverse events were neutropenia (84 [78%] of 108 patients), increased alanine aminotransferase concentration (42 [39%]), thrombocytopenia (40 [37%]), anaemia (29 [27%]), febrile neutropenia (26 [24%]), and fatigue (21 [19%]). INTERPRETATION: Despite expected but manageable toxic effects, these results support the activity of doxorubicin plus trabectedin as first-line treatment for uterine leiomyosarcoma and soft-tissue leiomyosarcoma. This combination should be developed further in a phase 3 trial against the present standard of care. FUNDING: Pharmamar and Amgen.
BACKGROUND: Metastatic leiomyosarcomas of uterine or soft-tissue origin have poor prognosis and moderate chemosensitivity. Trabectedin has shown activity in pretreated leiomyosarcoma. We did a single-group, multicentre, phase 2 trial (LMS-02) to assess the effect of first-line doxorubicin and trabectedin combination on disease control and survival. METHODS: Adults (18 years to physiological age ≤70 years) with measurable metastatic or unresectable uterine leiomyosarcoma or soft-tissue leiomyosarcoma who had not received any previous chemotherapy were enrolled at 19 centres in France. Treatment consisted of 60 mg/m(2) intravenous doxorubicin followed by 1·1 mg/m(2) trabectedin in a 3 h intravenous infusion on day 1, both by the central venous route, and 6 mg subcutaneous pegfilgrastim on day 2, repeated every 3 weeks for up to six cycles. Surgery for residual disease was permitted. The primary endpoint was the proportion of patients achieving disease control, defined as complete or partial response or stable disease. Stratification was done by anatomical site and analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT02131480. FINDINGS: Between July 28, 2010, and May 10, 2013, 109 patients were enrolled and treated, of whom 108 were assessable for response: 47 in the uterine leiomyosarcoma group and 61 in the soft-tissue leiomyosarcoma group. 32 (68%) patients in the uterine leiomyosarcoma group and 45 (74%) in the soft-tissue leiomyosarcoma group received all six cycles of treatment. Of 47 patients with uterine leiomyosarcoma, 28 (59·6%, 95% CI 44·3-73·6) achieved a partial response and 13 (27·7%, 15·6-42·6) stable disease; 41 (87·2%, 74·3-95·2) patients achieved disease control. Of 61 patients with soft-tissue leiomyosarcoma, two (3·3%, 95% CI 0·4-11·7) achieved a complete response, 22 (36·1%, 25·0-50·8) had a partial response, and 32 (52·5%, 40·8-67·3) had stable disease; 56 (91·8%, 81·9-97·3) of patients achieved disease control. The most common grade 3-4 treatment-associated adverse events were neutropenia (84 [78%] of 108 patients), increased alanine aminotransferase concentration (42 [39%]), thrombocytopenia (40 [37%]), anaemia (29 [27%]), febrile neutropenia (26 [24%]), and fatigue (21 [19%]). INTERPRETATION: Despite expected but manageable toxic effects, these results support the activity of doxorubicin plus trabectedin as first-line treatment for uterine leiomyosarcoma and soft-tissue leiomyosarcoma. This combination should be developed further in a phase 3 trial against the present standard of care. FUNDING: Pharmamar and Amgen.
Authors: Rebecca C Arend; Michael D Toboni; Allison M Montgomery; Robert A Burger; Alexander B Olawaiye; Bradley J Monk; Thomas J Herzog Journal: Oncologist Date: 2018-08-23
Authors: Amani Arthur; Edward W Johnston; Jessica M Winfield; Matthew D Blackledge; Robin L Jones; Paul H Huang; Christina Messiou Journal: Front Oncol Date: 2022-07-01 Impact factor: 5.738