A Le Cesne1, P Marec-Berard2, J-Y Blay3, N Gaspar4, F Bertucci5, N Penel6, E Bompas7, S Cousin8, M Toulmonde8, A Bessede9, W H Fridman10, C Sautes-Fridman10, M Kind11, F Le Loarer12, M Pulido13, A Italiano14. 1. Department of Medical Oncology, Gustave Roussy, Villejuif, France. 2. Department of Pediatric Oncology, Centre Léon Bérard, Lyon, France. 3. Department of Medical Oncology, Centre Léon Bérard, Lyon, France. 4. Department of Pediatric Oncology, Gustave Roussy, Villejuif, France. 5. Department of Medical Oncology, Institut Paoli Calmettes, Marseille, France. 6. Department of Medical Oncology, Centre Oscar Lambret, Lille, France. 7. Department of Medical Oncology, Institut de Cancérologie de L'Ouest, Nantes, France. 8. Department of Medical Oncology, Institut Bergonié, Bordeaux, France. 9. Immusmol, Bordeaux, France. 10. INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Team "Cancer, Immune Control and Escape", 75006, Paris, France; Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, University Paris Descartes Paris 5, 75006, Paris, France; UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne University, 75006, Paris, France. 11. Department of Medical Imaging, Institut Bergonié, Bordeaux, France. 12. Department of Pathology, Institut Bergonié, Bordeaux, France. 13. Unité de Recherche et D'Epidémiologie Cliniques, Institut Bergonié, Bordeaux, France; INSERM CIC 1401, Bordeaux, France. 14. Department of Medical Oncology, Gustave Roussy, Villejuif, France; University of Bordeaux, Bordeaux, France; INSERM, Unité ACTION U1218, Bordeaux, France. Electronic address: a.italiano@bordeaux.unicancer.fr.
Abstract
PURPOSE: There are some lines of evidence suggesting a potential role of immunotherapy for treating patients with osteosarcomas. PATIENTS AND METHODS: This was an open-label, multicentre, phase 2 study of pembrolizumab in combination with metronomic cyclophosphamide in patients with advanced osteosarcomas. All patients received 50 mg b.i.d. of cyclophosphamide one week on and one week off and 200 mg of intravenous pembrolizumab (every 3 weeks). There was a dual primary end-point, encompassing both the non-progression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. An objective response rate of 20% and/or a 6-month non-progression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from the patients' tumour samples. RESULTS: Between October 13 2015 and July 3 2017, 17 patients were included. Fifty were assessable for the efficacy end-point. Four patients experienced tumour shrinkage, resulting in a partial response (PR) in one patient (6.7%). The 6-month non-progression rate was 13.3% (95% confidence interval [CI]: 1.7-40.5). The most frequent adverse events were grade I or II nausea, anaemia, anorexia and fatigue. programmed death-ligand 1 (PD-L1) expression rate was low, observed in only 2 cases of 14 with available tumour material. The only patient who experienced PR had a PD-L1-negative tumour. CONCLUSION: Programmed cell death 1 (PD-1) inhibition has limited activity in osteosarcomas. Further studies investigating PD-1 inhibitor in combination with agents modulating the microenvironment are warranted. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT02406781.
PURPOSE: There are some lines of evidence suggesting a potential role of immunotherapy for treating patients with osteosarcomas. PATIENTS AND METHODS: This was an open-label, multicentre, phase 2 study of pembrolizumab in combination with metronomic cyclophosphamide in patients with advanced osteosarcomas. All patients received 50 mg b.i.d. of cyclophosphamide one week on and one week off and 200 mg of intravenous pembrolizumab (every 3 weeks). There was a dual primary end-point, encompassing both the non-progression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. An objective response rate of 20% and/or a 6-month non-progression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from the patients' tumour samples. RESULTS: Between October 13 2015 and July 3 2017, 17 patients were included. Fifty were assessable for the efficacy end-point. Four patients experienced tumour shrinkage, resulting in a partial response (PR) in one patient (6.7%). The 6-month non-progression rate was 13.3% (95% confidence interval [CI]: 1.7-40.5). The most frequent adverse events were grade I or II nausea, anaemia, anorexia and fatigue. programmed death-ligand 1 (PD-L1) expression rate was low, observed in only 2 cases of 14 with available tumour material. The only patient who experienced PR had a PD-L1-negative tumour. CONCLUSION: Programmed cell death 1 (PD-1) inhibition has limited activity in osteosarcomas. Further studies investigating PD-1 inhibitor in combination with agents modulating the microenvironment are warranted. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT02406781.
Authors: M J Melake; H G Smith; D Mansfield; E Davies; M T Dillon; A C Wilkins; E C Patin; M Pedersen; R Buus; A A Melcher; K Thway; A B Miah; S H Zaidi; A J Hayes; T R Fenton; K J Harrington; M McLaughlin Journal: Oncoimmunology Date: 2022-05-09 Impact factor: 7.723