First results of the EURAMOS-1 Good Response randomization

Transcription

1 plus maintenance pegylated interferon -2b (ifn) versus alone in patients with resectable high-grade osteosarcoma and good histological response to preoperative : First results of the EURAMOS-1 Good Response randomization S Bielack, S Smeland, JS Whelan, N Marina, JM Hook, G Jovic, M Krailo, T Butterfass-Bahloul, T Kühne, M Eriksson, L Teot, H Gelderblom, L Kager, K Sundby Hall, R Gorlick, RL Randall, PCW Hogendoorn, G Calaminus, MR Sydes, M Bernstein on behalf of the EURAMOS investigators E UROPEAN O STEOSARCOMA I NTERGROUP

2 Osteosarcoma Multi-disciplinary approach = worldwide standard Same strategy Same drugs Same results chemo surgery chemo (MTX, ADR, DDP); IFOS, others little improvement >25 years Rare cancer 2-3 cases per million per year Answering (any) question in RCT only feasible with (very) large scale cooperation Presented by: Stefan Bielack on behalf of EURAMOS investigators

3 European and American Osteosarcoma Study COG Childrens Oncology Group COSS Cooperative Osteosarcoma Study Group EOI European Osteosarcoma Intergroup SSG Scandinavian Sarcoma Group

4 Osteosarcoma Histologic response = prognostic factor Poor 3 year EFS 45%, 5 year OS 45% Good 3 year EFS 70%, 5 year OS 70% Ask questions stratified by response? Poor Good intensive salvage chemotherapy? introduction of biologic agents? (option: interferon- maintenance)

5 Rationale for interferon- maintenance Relatively favorable prognosis in good responders Toxicity of chemo intensification hard to justify Most recurrences soon after chemo Maintenance concept attractive Interferon- Growth inhibition in osteosarcoma cell lines and animal models Suggested effect as single adjuvant in early Scandinavian series Studied extensively in other tumors as a maintenance therapy Safety profile in children well established from other diseases Pegylated preparation with extended half-life

6 Design and eligibility Biopsy-proven diagnosis of resectable osteosarcoma REGISTER (induction) Surgery Histological response assessment Poor Good Registration Resectable high-grade osteosarcoma Extremity or axial Localized or metastatic Age 40 yrs No pretreatment for osteosarcoma No previous chemo for any disease No contraindication to treatment RANDOMIZE RANDOMIZE Registration & chemo 30 days after biopsy IE ifn Written informed consent

7 Design and eligibility Biopsy-proven diagnosis of resectable osteosarcoma REGISTER (induction) Surgery Histological response assessment Poor RANDOMIZE Good RANDOMIZE IE ifn Randomization Good response <10% viable tumor Assessment by reference pathologist if possible Age 5 yrs No disease progression If mets, complete removal feasible Recovery from prior therapy Randomization 35 days post-op Written informed consent

8 Interventions Primary tumor resection R MA MA M Methotrexate 12gm/m 2 A Doxorubicin 75mg/m 2 P Cisplatin 120mg/m 2 MA MA ifn wk 1-10 wk 11 wk wk Pegylated interferon -2b Timing Weekly after chemo until wk 104 Dosing Starting at 0.5 μg/kg/wk (max. 50 μg) x 4 wks if well tolerated Escalation to 1.0 μg/kg/wk (max. 100 μg) Protocol guidelines for Monitoring, mandatory tests, supportive care, dose adaptation

9 Outcome Measures Primary Event-free survival (EFS) Death Local recurrence New metastatic disease Progression of existing metastases Secondary malignancy Secondary include Overall survival Short & long-term toxicity Quality of life

10 Sample size 3yr EFS 70% for 80% for ifn Target HR = 0.63 Power 80%, type I error 0.05 More than 147 EFS events required 567 Good Response randomizations over 5 years Around 2000 registrations required Sample size change - Dec2008 needed ~2000 registrations, not 1400 as planned, to randomize 1260

11 Recruitment: Apr2005 Nov2011 Registration 2260 Confirmed Good Responder 1041 Randomized Not Good Responder 1059 Confirmed Poor Response 160 Response not reported 326 Not Randomized 206 Non-consent 39 Histology reported outside trial timelines 33 Not 2 cycles induction 14 Progression (local or distant) 34 Other SSG ifn EOI COG COSS

12 Baseline characteristics ifn Age Median (IQR) (min-max) Sex Male Female Site of tumor Proximal femur/humerus Other limb site Axial Primary metastases Yes No/possible 14 (11-16) [5-38] (12-16) [5-38] Total

13 Post-operative chemotherapy Doses received Drug Scheduled Median (IQR) ifn Median (IQR) M methotrexate (g/m 2 ) A doxorubicin (mg/m 2 ) P cisplatin (mg/m 2 ) Chemotherapy toxicity As expected Balanced by arm

14 Starting interferon 1.00 Time from randomisation to starting interferon cumulative incidence Proportion started Ifn (76%) report starting ifn 82 (23%) report never starting, main reason is refusal (63) 0.00 N Median start = 5.4 months (95% CI ) months from randomisation 353 (219) 132 (51) 79 (0) 72 (1) 62 4 no ifn data yet

15 Interferon toxicity Worst toxicity grade reported during ifn Max grade N % 0,1 or % % % 5/Fatal 0 0% Missing 3 n/a Total % Grade 4 toxicities 13 Hematologic (leucocytes or platelets), 2 with infection 3 Cardiac 2 new left ventricular systolic dysfunction (LVSD) during ifn 1 worsening of pre-existing LVSD 1 Dyspnea + pleural effusion (post-thoracotomy) 1 Mood alteration (depression + agitation) 1 Amylase

16 Duration of interferon Proportion still on interferon Time from starting to stopping Ifn Median duration ifn 14.9 mo (IQR ) 234/271 stopped ifn (55%) completed ifn (45%) terminated early 44 Toxicity 25 Progression 17 Refusal 20 Other - 37 still on ifn at data freeze N months from starting ifn 270 (67) 202 (24) 163 (116) 39 (26) 8

17 EFS - intention to treat 1.00 Proportion event-free (n=358) ifn (n=357) Events, n (%) 93 (26%) 81 (23%) 3 year EFS 74% (69%-79%) 77% (72%-81%) Hazard ratio* (95%CI) p-value 0.82 ( ) p= % at 3yr 74% at 3yr N ifn Time from randomisation (months) 358 (32) 318 (38) 231 (13) 167 (5) 106 (3) 58 (1) (25) 323 (41) 235 (9) 184 (4) 112 (0) 62 (2) 22 ifn *Cox model adjusted for data center, metastases status, site and location of tumor on bone

18 EFS - exploratory sub-group analyses Subgroup Study HR* (95%CI) Test for heterogeneity ID ES (95% CI) Child** Adolescent Adult 0.78 (0.39, 1.56) 0.66 (0.44, 0.97) 1.10 (0.56, 2.17) Male Female 0.84 (0.57, 1.23) 0.81 (0.49, 1.31) Proximal femur/humerus Other limb site Axial/skeletal 0.58 (0.27, 1.25) 0.83 (0.60, 1.16) 1.96 (0.22, 17.46) No/poss mets Yes mets 0.83 (0.59, 1.16) 0.93 (0.49, 1.77) *adjusted Cox model **Collins et al, J Clin Oncol, 2013 May 13:doi: /JCO

19 Overall Survival 1.00 intention-to-treat population 92% at 3yr Proportion event-free (n=358) ifn (n=357) Deaths, n (%) 46 (13%) 38 (11%) 3 year survival 90% (86%-93%) 92% (88%-94%) Hazard ratio* (95%CI) p-value 0.77 ( ) p= % at 3yr N ifn Time from randomisation (months) 358 (3) 345 (9) 283 (15) 209 (14) 130 (3) 69 (2) (2) 346 (10) 279 (12) 217 (6) 131 (7) 67 (1) 24 ifn *Cox model adjusted for data center, metastases status, site and location of tumor on bone

20 Conclusions (1) Large, multinational RCTs are needed in rare diseases EURAMOS-1 shows such RCTs are feasible Largest reported randomized comparison in osteosarcoma Presented by: Stefan Bielack on behalf of EURAMOS investigators

21 Conclusions (2): vs ifn in good responders Planned analysis of EFS (HR 0.82; 95% CI ) Point estimate of primary outcome measure Favors ifn Observed effect size smaller than targeted CI includes 1 Interpretation complicated by Proportion not starting ifn Proportion not completing ifn Presented by: Stefan Bielack on behalf of EURAMOS investigators

22 Conclusions (3): vs ifn in good responders Preliminary survival data (HR 0.77; 95% CI ) Consistent with EFS Planned survival analysis at 147 deaths follow-up continues for secondary outcome measure Presented by: Stefan Bielack on behalf of EURAMOS investigators

23 Acknowledgments Investigators & research staff at all 326 trial sites & data centers National co-ordinating investigators J Anninga, M Capra, C Dhooge, H Mottl, OS Nielsen, Z Papai, M Tarkkanen Members of the IDMC, TSC, TMG and trial advisory panels Funding bodies National Cancer Institute, USA ; European Science Foundation (ESF) under the EUROCORES Program European Clinical Trials (ECT), through contract No. ERASCT of the European Commission, DG Research, FP6 (Ref No MM/NG/EMRC/0202); Fonds National de la Recherche Scientifique & Fonds voor Wetenschappelijk Onderzoek-Vlaanderen; Danish Medical Research Council; Academy of Finland; Deutsche Forschungsgemeinschaft; Deutsche Krebshilfe; Federal Ministry of Education and Research, Germany, BMBF 01KN1105; Semmelweis Foundation; Netherlands Council for Medical Research; Research Council of Norway; Scandinavian Sarcoma Group; Swiss Paediatric Oncology Group; Cancer Research UK, CRUK/05/013; UK Medical Research Council Merck for providing pegylated interferon- 2b All patients who participated in EURAMOS-1