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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
15-18 October 2014, Berlin
Disclosures
Novartis Chugaï
15-18 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)
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CT ZOL IFO IFO+ZOL
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implantation Z OL (100 µg/kg) sacrifice
J0 J7 J14 J21 J28 J35
C Z
I I+Z
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
MTX-ETO-IFO
according to OS94 protocol
API-AI
according to FSG protocol
<18 years 18-25 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)
15-18 October 2014, Berlin
OS2006 - Treatment plan
15-18 October 2014, Berlin
MTX-ETO-IFO
API-AI
MTX 12 g/m² D1 Ifosfamide (Ifo) 3g/m² D1-D4
Etoposide (Eto) 75mg/m² D1-D4 A: Adriamycin 37.5 mg/m² D1-D2
P: Cis-platinum - 120 mg/m² D1
Surgery GR*
PR**
A: Adriamycin 60 mg/m² D1
P: Cis-platinum 100 mg/m² D1
I: Ifo 3 g/m² D2-D3-
Surgery GR*
PR**
A: Adriamycin 60 mg/m² D1
I: Ifo 3 g/m² D1 -D2
P: Cis-platinum 100 mg/m² D1 I: Ifo 3 g/m² D2-D3 I: Ifo 4g/m² D1-D3
Etoposide 100 mg/m² D1-D3
* : GR = Good histological response (<10% viable cells) **: PR = Poor histological response (≥10% viable cells)
and patients with non resectable primary tumor or metastatic disease
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)• 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)
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 trialN = 116 including 69 refusal
Assessed for eligibilityN=521
Included in the randomised trialN=318 (73%)
Potentially eligibleN=434
15-18 October 2014, Berlin
15-18 October 2014, Berlin
Z- Z+ TotalN=158 N=160 N=318 %
Age and planned chemotherapy
109 110 219 69 Less than 18y – MTX-Eto-Ifo 18-25 years – MTX-Eto-Ifo 18 19 37 12 18-25 years – API-AI 12 11 23 7 > 25 years – API-AI 19 20 39 12Risk group
132 129 261 82 Non metastatic and primary resectable Non metastatic and primary non resectable 1 3 4 1 Metastatic disease 25 28 53 17Site of the primary (MD=33) Limb 130 132 262 92 Axial 13 10 23 8Size of the primary (MD=44) <10 cm 76 58 134 49 >10 cm 62 78 140 51Alkaline phosphatases (MD=41) Normal level 80 73 153 55 Above the upper limit (> 1xULN) 59 65 124 45LDH (MD=58) Normal level 78 79 157 60 Above the upper limit (> 1xULN) 54 49 103 40
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 1st injection
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
15-18 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
15-18 October 2014, Berlin
OS2006Event-Free (EFS) and Overall Survival (OS)
3-y OS= 78.3%
3-y EFS= 60.3%
15-18 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 outcomeZ-, 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
HR=1.31 (CI: 0.79-2.18) p=0.17
15-18 October 2014, Berlin
HR=1.42 (CI: 0.70-2.88), p=0.21
15-18 October 2014, Berlin
Impact of Zoledronate on EFSStability of the results
Age and chemotherapy group
Group No. Events / No. EnteredZ+ Z-
Hazard Ratio HR [95% CI]
Z+ better | Z- better
<18y – MTX-Eto-Ifo 38/111 31/109 1.29 [0.70;2.38]18-25y – MTX-Eto-Ifo 6/19 6/18 0.99 [0.19;5.08]18-25y – API-AI 6/11 6/12 2.35 [0.44;12.6]>25y – API-AI 7/20 6/19 1.17 [0.28;4.92]
Risk groupNon metastatic 41/129 33/132 1.50 [0.82;2.73]Metastatic or non resectable 16/32 16/26 0.94 [0.36;2.45]
Histologic responseGood responder 26/84 21/88 1.62 [0.73;3.58]Poor responder 23/44 22/45 1.20 [0.55;2.61]
Overall 57/161 49/158 1.31 [0.79;2.18]
0.1 1.0 14.0
Interaction
P=0.80
P=0.30
P=0.49
OS 2006Futility 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, Chugaï 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
OS MTX GR versus PR
EFS API-AI 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
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 <0.0001 (even under H1)
current statistic test
15-18 October 2014, Berlin
Stop for efficacy
Stop for harm
Stop for futility