Denosumab et Tumeurs à Cellules Géantes:

Transcription

1 Denosumab et Tumeurs à Cellules Géantes: «La preuve du concept» Axel Le Cesne Institut Gustave Roussy, Villejuif Strasbourg, 27 Juin 2013

2 GCT of bone Common bone tumour Typically in young adults More in females Results in pain and impaired mobility and function GCT has limited treatment options Most amenable to surgery Recurrence in 10-75% 5% small bones 13% axial 2

3 /07/13

4 RANK-RANKL: médiateur de la destruction osseuse dans les TCG osseuses RANK RANKL

5 Objective To investigate whether denosumab, a fully human monoclonal antibody against RANKL, could inhibit bone destruction and eliminate giant cells Screening/ Randomization Denosumab 120 mg SC Every 28 Days (Loading Doses on Day 8 & 15 of Month 1) Daily Supplements of Calcium and Vitamin D Denosumab Treatment Continued Until: 1) Complete Tumor Resection 2) Lack of Clinical Benefit Primary Endpoint: Proportion of subjects with a tumor response, defined as - the elimination of 90% of giant cells or - no radiologic progression of the target lesion for up to week 25 Secondary Endpoints: Suppression of the bone turnover marker urine N-telopeptide (untx), safety profile, incidence of serum anti-denosumab antibody formation

6 Results: Denosumab Treatment Resulted in an 86% Tumor Response 30 of 35 (86%; 95% CI 70%-95%) subjects responded to denosumab treatment 20/20 by histology 10 by radiology J1 Week 19 Among 31 evaluable subjects 26 (84%) had substantial clinical benefit, including reduced pain, increased range of motion, and return to work

7 Denosumab in Giant Cell Tumor of Bone Updated Results with Independent Assessment of Response (ESMO 2012) Jean-Yves Blay, Sant Chawla, Edwin Choy, Robert Grimer, Stefano Ferrari, Peter Reichardt, Piotr Rutkowski, David Thomas, Yi Qian, Ira Jacobs Lancet Oncol, 2013, submitted

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9 Investigator determined disease status 9

10 Independent Imaging Assessment: Objective Tumor Response and Tumor Control Patients with objective tumor response % Median time to OR (months) Patients with OR sustained 24 weeks % Patients with tumor control 24 weeks % Overall RECIST EORTC Modified Choi 72% (136/190) 25% (47/187) 96% (25/26) 76% (134/176) (76/111) 98 (109/111) not reached 24 (26/109) 99 (108/109) (11/12) 100 (12/12) 3 75 (76/102) 99 (101/102)

11 Response to denosumab D1 M4 D1 M7

12 Investigator determined clinical benefit 12

13 Less frequent and less extensive surgery Surgical Procedure, n* Baseline Planned (N =100) Actual Total (N = 26) Total number of surgeries * Major surgeries 44 3 Hemipelvectomy 4 0 Amputation 17 0 Joint/prosthesis replacement 9 1 Joint resection 14 2 En bloc resection 37 6 En bloc excision 4 0 Marginal excision 1 0 Curettage Other 1 1 No surgery N/A 74 90% of patients (26/269) had no surgery or underwent a less morbid procedure compared with the baseline planned surgical procedure by the analysis cut-off date The estimated median time to surgery was 23.8 months.

14 Adverse events

15 IGR Cochin Arago - KB Patient Localisation SAM Tibia G YOM Humérus D cures Date chir Type de chirurgie Histo C viables 6 injections après 4 Exérèses 27 03/11 Curetage > 80% Oui Exérèse 19 01/11 Reduction tumorale 0% sur R2 Oui 2 curetages 15 11/11 Curetage + allo-auto greffe Quelques CGs Oui Antécédents SIL Tibia D LOP L3 RAS 21 09/12 Résection 0% (RC) En cours KOT Sacrum RAS 22 08/12 Curetage Riche en CGs En cours CHA ischio-pubis G RAS 21 02/13 Resection + Curetage 0% (RC) En cours CAV Fémur D RAS 19 12/12 Curetage + allogreffe Riche en CGs En cours FAL Radius D 2 curetages 17 11/12 Curetage + allogreffe 0% (RC) En cours JUL Tibia D RAS 12 07/12 Resection+ prothese 0% (RC) En cours THI Radius G Curetage 17 10/12 Resection Autogreffe 0% (RC) Grossesse DES Tibia D Ostéotomie 15 04/13 Curetage 0% (RC) En cours Moy RC/10

16 Denosumab in GCT Clearly one of the most effective drugs in oncology Clinical improvement Disease progression was halted in 99% of subjects Less and less morbid surgery Histologic results showed near complete or complete elimination of giant cells in all subjects for whom histology was available Third proof of concept in mesenchymal tumors (GIST/DFSP) Challenges remain: FDA/EMA approval based on the just closed to inclusion trial (N=500) Can we stop treatment? Stop vs continuation in locally advanced non resectable patients, stop vs continuation in resected patients? What is the correct dose? Adjuvant treatment? Planned EORTC trial Does it work in other giant cell rich lesions?