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
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
European and American Osteosarcoma Study COG Childrens Oncology Group COSS Cooperative Osteosarcoma Study Group EOI European Osteosarcoma Intergroup SSG Scandinavian Sarcoma Group
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)
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
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
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
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 12-29 wk 30-104 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
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
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
Recruitment: Apr2005 Nov2011 Registration 2260 Confirmed Good Responder 1041 Randomized 715 1219 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 358 357 COSS
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] 210 148 42 306 10 45 313 14 (12-16) [5-38] 210 147 41 310 6 41 316 Total 358 357
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 ) 96 95 84-98 95 84-98 300 298 289-303 298 288-303 240 239 234-241 239 235-241 Chemotherapy toxicity As expected Balanced by arm
Starting interferon 1.00 Time from randomisation to starting interferon cumulative incidence Proportion started Ifn 0.75 0.50 0.25 271 (76%) report starting ifn 82 (23%) report never starting, main reason is refusal (63) 0.00 N Median start = 5.4 months (95% CI 5.2-5.5) 0 6 12 18 24 months from randomisation 353 (219) 132 (51) 79 (0) 72 (1) 62 4 no ifn data yet
Interferon toxicity Worst toxicity grade reported during ifn Max grade N % 0,1 or 2 187 70% 3 62 23% 4 19 7% 5/Fatal 0 0% Missing 3 n/a Total 271 100% 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
Duration of interferon Proportion still on interferon 1.00 0.75 0.50 0.25 0.00 Time from starting to stopping Ifn Median duration ifn 14.9 mo (IQR 4.6-15.1) 234/271 stopped ifn - 128 (55%) completed ifn - 106 (45%) terminated early 44 Toxicity 25 Progression 17 Refusal 20 Other - 37 still on ifn at data freeze N 0 6 12 18 24 months from starting ifn 270 (67) 202 (24) 163 (116) 39 (26) 8
EFS - intention to treat 1.00 Proportion event-free 0.75 0.50 0.25 0.00 (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 (0.61-1.11) p=0.201 77% at 3yr 74% at 3yr N ifn 0 12 24 36 48 60 72 Time from randomisation (months) 358 (32) 318 (38) 231 (13) 167 (5) 106 (3) 58 (1) 8 356 (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
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) 0.087 Male Female 0.84 (0.57, 1.23) 0.81 (0.49, 1.31) 0.914 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) 0.499 No/poss mets Yes mets 0.83 (0.59, 1.16) 0.93 (0.49, 1.77) 0.751.2.5 1 2 4 *adjusted Cox model **Collins et al, J Clin Oncol, 2013 May 13:doi: 10.1200/JCO.2012.43.8598
Overall Survival 1.00 intention-to-treat population 92% at 3yr Proportion event-free 0.75 0.50 0.25 0.00 (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 (0.50-1.19) p=0.240 90% at 3yr N ifn 0 12 24 36 48 60 72 Time from randomisation (months) 358 (3) 345 (9) 283 (15) 209 (14) 130 (3) 69 (2) 11 356 (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
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
Conclusions (2): vs ifn in good responders Planned analysis of EFS (HR 0.82; 95% CI 0.61-1.11) 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
Conclusions (3): vs ifn in good responders Preliminary survival data (HR 0.77; 95% CI 0.50 1.19) 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
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-2003-980409 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 www.euramos.org