zoledronate does not reduce the risk of treatment failure in osteosarcoma: results of the french...

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


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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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


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)


OS2006 - Treatment plan


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


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


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



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


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

Surgery and histological analysis of the primary tumour


OS2006Event-Free (EFS) and Overall Survival (OS)

3-y OS= 78.3%

3-y EFS= 60.3%


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


HR=1.42 (CI: 0.70-2.88), p=0.21


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


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


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


Backslides


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


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


Stop for efficacy

Stop for harm

Stop for futility

zoledronate does not reduce the risk of treatment failure in osteosarcoma: results of the french...

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