Zoledronate does not reduce the risk of treatment failure in osteosarcoma: results of the French multicentre OS2006 randomised trial L Brugières, MC Le Deley, F Rédini, P Marec-Bérard, H Pacquement, C Lervat, JC Gentet, N Entz-Werlé, B Bui, N Corradini, G de Pinieux, P Petit, K Buffard, JY Blay, S Piperno-Neumann October 2014, Berlin

Disclosure s  Novartis  Chugaï October 2014, Berlin

Zoledronate in osteosarcoma Preclinical models Rat -transplantable model of osteosarcoma - Z prevents the formation of bone osteolytic lesions and reduces local tumor growth - IFO+Z enhances tumor regression and tissue repair Lung metastases model in mice (IV injection of POS-1 murine osteosarcoma cells) - Z suppresses lung mets in vivo and prolongs overall survival of osteosarcoma-bearing mice - Z has a direct antitumoral effect on POS-1 cells in vitro Ory et al, Cancer (2005) implantation Z OL (100 µg/kg) sacrifice J0 J7 J14 J21 J28 J35 CZ I I+Z October 2014, Berlin

OS2006 trial  Randomised phase III trial involving all French paediatric oncology and most adult sarcoma centres (overall 48 centres)  Objective: To evaluate the impact of the addition of a 10-month Zoledronate treatment to chemotherapy and surgery on the event-free survival of osteosarcoma patients  Primary endpoint : EFS October 2014, Berlin

OS Inclusion criteria  All newly diagnosed high grade osteosarcoma except : Small cell osteosarcoma Maxillary osteosarcoma Extra-osseous osteosarcoma Patients with primary resection multiple metastases for whom complete removal was not expected to be feasible even after shrinkage with chemotherapy  Age > 5 years and < 50 years October 2014, Berlin

OS Chemotherapy MTX-ETO-IFO according to OS94 protocol API-AI according to FSG protocol <18 years18-25 years > 25 years left to the choice of each center (Assi et al Curr Oncol 2010, Piperno-Neumann et al ASCO 2006) (Le Deley et al Eur J Cancer 2007) October 2014, Berlin

OS Treatment plan October 2014, Berlin MTX-ETO-IFO API-AI Lenograstim 263 µg D6-D12

Zoledronate  Randomisation at diagnosis between 2 arms with or without zoledronate  Dose of Zoledronate 10 monthly IV infusions: 4 before/ 6 after surgery Dose >25 years: 4 mg <18 years : 0.05 mg/kg (max 4 mg/ dose) y: 0.05 mg/kg for the first 2 courses, then 4 mg Dose reduction if gr 3-4 hypocalcemia  Vitamin D3 and calcium supplementation in both arms October 2014, Berlin

Statistical considerations  Randomisation stratified on:  age and type of chemotherapy => 4 strata  risk group : non metastatic and resectable versus metastatic or not resectable  centre  Sample size : 470 patients required to achieve  a 80%-power to detect a 13% improvement of 3 y-EFS (from 55% to 68%) in the Zoledronate arm (HR=0.65),  with a two-sided log-rank test (alpha=5%)  and 3 interim analyses  This is the results of the second interim analysis performed after the inclusion of 318 pts October 2014, Berlin

Participant flow (Apr 2007-Feb 2014) Did not meet eligibility criteria N=70 No zoledronate (Z-) N=158 zoledronate (Z+) N=160 Suspension of randomisation N=17 Not included in the randomised trial N = 116 including 69 refusal Assessed for eligibility N=521 Included in the randomised trial N=318 (73%) Potentially eligible N= October 2014, Berlin

Z-Z+Total N=158N=160N=318% Age and planned chemotherapy Less than 18y – MTX-Eto-Ifo years – MTX-Eto-Ifo years – API-AI > 25 years – API-AI Risk group Non metastatic and primary resectable Non metastatic and primary non resectable 1341 Metastatic disease Site of the primary (MD=33) Limb Axial Size of the primary (MD=44) <10 cm >10 cm Alkaline phosphatases (MD=41) Normal level Above the upper limit (> 1xULN) LDH (MD=58) Normal level Above the upper limit (> 1xULN) Baseline characteristics

Zoledronate - Total administration  In Zoledronate arm:  55 patients had an omission of >1 injection, including 4 patients with no Zoledronate injection 4 patients who stopped Zoledronate after 1 st injection  Zoledronate dose = protocol dose (+/-10%) for 851/1013 injections (84%)  No patient allocated to Z- arm received Zoledronate October 2014, Berlin

Toxicity during treatment October 2014, Berlin  No significant increase of toxicity regarding the most frequent expected toxicities (i.e. hematotoxicity, infection, transfusion, ASAT/ALAT elevation, mucositis…)  Hypocalcemia grade 2-4 significantly more frequent in Z+ arm per course: OR = 7.2, 95%CI, 4.9 – 10.6, p<0.001 decreasing risk over time

Surgery and histological analysis of the primary tumour October 2014, Berlin

OS2006 Event-Free (EFS) and Overall Survival (OS) 3-y OS= 78.3% 3-y EFS= 60.3% October 2014, Berlin Median follow-up 3.1 years

Z+, 3-y EFS=58.3% (49-67) Z-, 3-y EFS= 62.3% (53-71) Z-, 3-y OS= 83.3% (75-89) Z+, 3-y OS=73.2% (64-81) Impact of Zoledronate on outcome Z-, N=158 Z+, N=160Total, N=318 Number of events Local progression/relapse4610 Metastatic progression/relapse Combined Progression/relapse NOS112 Death as 1st event011 HR=1.31 (CI: ) p= October 2014, Berlin HR=1.42 (CI: ), p=0.21

15-18 October 2014, Berlin Impact of Zoledronate on EFS Stability of the results Age and chemotherapy group GroupNo. Events / No. Entered Z+Z- Hazard RatioHR [95% CI] Z+ better | Z- better <18y – MTX-Eto-Ifo38/11131/ [0.70;2.38] 18-25y – MTX-Eto-Ifo6/196/ [0.19;5.08] 18-25y – API-AI6/116/ [0.44;12.6] >25y – API-AI7/206/ [0.28;4.92] Risk group Non metastatic41/12933/ [0.82;2.73] Metastatic or non resectable16/3216/ [0.36;2.45] Histologic response Good responder26/8421/ [0.73;3.58] Poor responder23/4422/ [0.55;2.61] Overall57/16149/ [0.79;2.18] Interaction P=0.80 P=0.30 P=0.49

OS 2006 Futility analysis  Probability of demonstrating a benefit with zoledronate after inclusion of the 470 pts initially planned <  Decision to close the trial and to release the results  Final analysis in a few months after updating follow-up of all patients October 2014, Berlin

OS Conclusion  Zoledronate in association with chemotherapy did not reduce the risk of treatment failure  There was no safety concern apart from the expected higher incidence of hypocalcemia  Overall results (EFS, OS) are consistent with previous studies both in children and adult patients  Translational studies on going to try to understand these unexpected clinical results October 2014, Berlin

Thanks  To patients and families  To Unicancer, SFCE and FSG  To French National Cancer Institute (INca) and La Ligue contre le Cancer  To Novartis, Chugaï  To investigators, and data managers October 2014, Berlin

Backslides October 2014, Berlin

Outcome of patients with a localised disease, by chemotherapy group and histological response EFS MTX GR versus PR OS MTX GR versus PR EFS API-AI GR versus PR OS API-AI GR versus PR October 2014, Berlin

Second interim analysis (26 MARCH 2014)  Trend for a harmful effect of Zoledronate  On EFS and OS  Stable results after exclusion of the 8 patients allocated to Z+ who received 0 to 1 Zoledronate injection  No heterogeneity across the different strata at the time of randomisation  Boundaries defining a significant harm not crossed  Recommendation of early stopping for futility Probability of demonstrating a benefit < (even under H1) current statistic test October 2014, Berlin Stop for efficacy Stop for harm Stop for futility