Zoledronate Treatment in OS2006 Trial for Osteosarcoma Patients

Zoledronate does not reduce the risk of treatment failure in osteosarcoma: results of the French multicentre OS2006 randomised trial L Brugi res, MC Le Deley, F R dini, P Marec-B rard, H Pacquement, C Lervat, JC Gentet, N Entz-Werl , B Bui, N Corradini, G de Pinieux, P Petit, K Buffard, JY Blay, S Piperno-Neumann 15-18 October 2014, Berlin

Disclosures Novartis Chuga 15-18 October 2014, Berlin

Zoledronate in osteosarcoma Preclinical models Lung metastases model in mice (IV injection of POS-1 murine osteosarcoma cells) 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 - 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 J0 J7 J14 J21 J28 J35 Z OL (100 g/kg) implantation sacrifice 4 4 Progression tumorale Tumor Progression 3 3 *** *** (V42/V25) (V42/V25) C Z 2 2 1 1 *** *** *** *** 0 0 I+Z I CT CT ZOL ZOL IFO IFO IFO+ZOL IFO+ZOL Ory et al, Cancer (2005) 15-18 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 15-18 October 2014, Berlin

OS2006 - 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 15-18 October 2014, Berlin

OS2006 - Chemotherapy > 25 years <18 years 18-25 years left to the choice of each center MTX-ETO-IFO API-AI according to OS94 protocol according to FSG protocol (Assi et al Curr Oncol 2010, Piperno-Neumann et al ASCO 2006) (Le Deley et al Eur J Cancer 2007) 15-18 October 2014, Berlin

OS2006 - Treatment plan MTX-ETO-IFO Surgery GR* PR** A: Adriamycin 37.5 mg/m D1-D2 Etoposide (Eto) 75mg/m D1-D4 MTX 12 g/m D1 120 mg/m D1 P: Cis-platinum - Ifosfamide (Ifo) 3g/m D1-D4 * : GR = Good histological response (< 10% viable cells ) **: PR = Poor histological response ( 10% viable cells) and patients with non resectable primary tumor or metastatic disease API-AI Surgery GR* PR** Etoposide 100 mg/m D1-D3 A: Adriamycin 60 mg/m D1 P: Cis-platinum 100 mg/m D1 A: Adriamycin 60 mg/m D1 15-18 October 2014, Berlin P: Cis-platinum 100 mg/m D1 I: Ifo 3 g/m D1 -D2 I: Ifo 3 g/m D2-D3 I: Ifo 4g/m D1-D3 - I: Ifo 3 g/m D2-D3 Lenograstim 263 g 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) 18-25 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 15-18 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 15-18 October 2014, Berlin

Participant flow (Apr 2007-Feb 2014) Assessed for eligibility N=521 Did not meet eligibility criteria N=70 Suspension of randomisation N=17 Potentially eligible N=434 Not included in the randomised trial N = 116 including 69 refusal Included in the randomised trial N=318 (73%) No zoledronate (Z-) N=158 zoledronate (Z+) N=160 15-18 October 2014, Berlin

Baseline characteristics Z- Z+ Total N=158 N=160 N=318 % Age and planned chemotherapy Less than 18y MTX-Eto-Ifo 18-25 years MTX-Eto-Ifo 18-25 years API-AI > 25 years API-AI Risk group Non metastatic and primary resectable Non metastatic and primary non resectable 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) 109 18 12 19 110 19 11 20 219 37 23 39 69 12 7 12 132 1 25 129 3 28 261 4 53 82 1 17 130 13 132 10 262 23 92 8 76 62 58 78 134 140 49 51 80 59 73 65 153 124 55 45 78 54 79 49 157 103 60 40 15-18 October 2014, Berlin

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 1stinjection Zoledronate dose = protocol dose (+/-10%) for 851/1013 injections (84%) No patient allocated to Z- arm received Zoledronate 15-18 October 2014, Berlin

Toxicity during treatment 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 15-18 October 2014, Berlin

Surgery and histological analysis of the primary tumour 15-18 October 2014, Berlin

OS2006 Event-Free (EFS) and Overall Survival (OS) 3-y OS= 78.3% Median follow-up 3.1 years 3-y EFS= 60.3% 15-18 October 2014, Berlin

Impact of Zoledronate on outcome Z-, N=158 Z+, N=160 Total, N=318 Number of events 49 57 106 Local progression/relapse 4 6 10 Metastatic progression/relapse 28 34 62 Combined 16 15 31 Progression/relapse NOS 1 1 2 Death as 1st event 0 1 1 Z-, 3-y OS= 83.3% (75-89) Z-, 3-y EFS= 62.3% (53-71) Z+, 3-y OS=73.2% (64-81) Z+, 3-y EFS=58.3% (49-67) HR=1.42 (CI: 0.70-2.88), p=0.21 HR=1.31 (CI: 0.79-2.18) p=0.17 15-18 October 2014, Berlin

Impact of Zoledronate on EFS Stability of the results Group No. Events / No. Entered Z+ Hazard Ratio HR [95% CI] Interaction Z- Age and chemotherapy group <18y MTX-Eto-Ifo 18-25y MTX-Eto-Ifo 18-25y API-AI >25y API-AI P=0.80 38/111 6/19 6/11 7/20 31/109 6/18 6/12 6/19 1.29 [0.70;2.38] 0.99 [0.19;5.08] 2.35 [0.44;12.6] 1.17 [0.28;4.92] P=0.30 Risk group Non metastatic Metastatic or non resectable 16/32 41/129 33/132 16/26 1.50 [0.82;2.73] 0.94 [0.36;2.45] P=0.49 Histologic response Good responder Poor responder 26/84 23/44 21/88 22/45 1.62 [0.73;3.58] 1.20 [0.55;2.61] Overall 57/161 49/158 1.31 [0.79;2.18] 0.1 1.0 14.0 | Z- better Z+ better 15-18 October 2014, Berlin

OS 2006 Futility analysis Probability of demonstrating a benefit with zoledronate after inclusion of the 470 pts initially planned <0.0001 Decision to close the trial and to release the results Final analysis in a few months after updating follow-up of all patients 15-18 October 2014, Berlin

OS 2006 - 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 15-18 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, Chuga To investigators, and data managers 15-18 October 2014, Berlin

Backslides 15-18 October 2014, Berlin

Outcome of patients with a localised disease, by chemotherapy group and histological response EFS MTX GR versus PR EFS API-AI GR versus PR OS MTX GR versus PR OS API-AI GR versus PR 15-18 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 Stop for efficacy No heterogeneity across the different strata at the time of randomisation Boundaries defining a significant harm not crossed Stop for futility current statistic test Recommendation of early stopping for futility Probability of demonstrating a benefit <0.0001 (even under H1) Stop for harm 15-18 October 2014, Berlin