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10547 Background: Alternative endpoints to overall survival (OS) such as progresion-free survival (PFS), time-to-progression (TTP) or time-to-treatment failure (TTF) are increasingly used to assess treatment efficacy in randomized controlled trials (RCT) to reduce inclusions and trials’ duration. Their properties in terms of surrogate markers need to be assessed to ensure that they can adequately replace OS. Methods: We conducted a literature review to summarize by cancer type studies evaluating surrogate endpoints for OS. In the absence of data for soft-tissue sarcoma (STS), we assessed surrogate properties for OS of PFS, TTP and TTF in advanced STS. We relied on a meta-analytical framework to estimate individual-level association (association between the candidate surrogate endpoint and OS) and trial-level association (association between the treatment effects on the candidate surrogate and on OS). Statistical methods included weighted linear regression (WLR) and the two-stage method introduced by Burzy...

Introduction Dans les essais cliniques randomises (ECR) en cancerologie, les progres therapeutiques ont conduit a l’utilisation de criteres de survie composites autres que la survie globale (SG), tels que la survie sans progression (SSP) ou le temps jusqu’a progression (TP), comme criteres de jugement. Cependant, ces criteres sont souvent mal definis et leurs proprietes de substitution a la SG ont rarement ete evaluees. Nous nous interessons ici aux proprietes de substitution a la SG de criteres de survie composites communement utilises dans les ECR portant sur les sarcomes en situation metastatique (projet Datecan-2, financement INCa). Methodes Nous avons evalue la capacite de substitution a la SG de trois criteres de survie composites a partir d’une meta-analyse d’ECR de phase II–III. La proportion d’effet traitement (PET) expliquee par le critere de survie composite a ete calculee. Pour chaque critere de survie composite, nous avons estime l’association entre celui-ci et la survie globale (association au niveau individuel), ainsi que l’association entre l’effet du traitement sur le critere de survie composite et l’effet du traitement sur la SG (association au niveau de l’essai). Nous nous sommes bases sur des methodes de regression lineaire ponderee et de modelisation conjointe de criteres de survie. Resultats Les donnees individuelles de 2020 patients issus de 10 ECR (promotion EORTC, UNICANCER, Institut Bergonie) ont ete analysees. Le recul median variait entre 15 mois et 93 mois selon l’ECR (mediane : 35 mois). Nous avons evalue la capacite de substitution a la SG a 2 ans de trois criteres : la SSP (temps jusqu’a progression ou deces quelle que soit la cause), le TP (temps jusqu’a progression ou deces lie au cancer) et le temps jusqu’a echec du traitement (TET) (temps jusqu’a progression, deces lie au cancer ou deces toxique) a 1 an. Au centieme pres, la PET estimee est identique pour les trois criteres (–2,69 IC 95 % [–16,29 ; 10,90]). Au niveau individuel, la SSP presente la plus forte association avec la SG (R2 = 0,62 et tau de Kendall = 0,43 IC 95 % [0,40 ; 0,46]). Au niveau de l’essai, la regression lineaire ponderee suggere une plus forte association pour la SSP (R2 = 0,44). Quel que soit le critere composite, la modelisation conjointe ne permet pas de mettre en evidence d’association avec la SG. Conclusion La SSP a 1 an presente les meilleures proprietes de substitution a la SG a 2 ans meme si ces resultats ne permettent pas la validation de la SSP comme critere de substitution a la SG. Des travaux complementaires prevoient le recueil d’ECR additionnels pour affiner nos premieres estimations et valider nos modeles de regression sur donnees independantes. Des analyses de sensibilite sont egalement prevues notamment pour l’etude de criteres de survie composites mesures a 18 mois comme criteres de substitution a la SG a 3 ans.

10500 Background: In 2004 we launched an open-label randomized trial with adjuvant IM for 2 yrs in localized, surgically resected, high/intermediate-risk GIST. Methods: Pts were randomized between 2 yrs of IM, 400 mg daily, and no further therapy after surgery. The primary end-point was OS, while RFS, RFI and toxicity were secondary end-points. Main eligibility criteria were: age >18 yrs, PS 0-2, localized CD117-positive GIST, intermediate or high risk according to the 2002 Consensus classification, R0 or R1 surgical margins, no previous medical therapy. Pts were stratified by risk, tumor site and margins. An accrual of 400 pts was planned, then escalated to 900. Given the prognostic improvement of advanced GIST pts, in 2009 the study IDMC authorized to change the primary end-point into IFS, whose failure was defined as the time when a different tyrosine kinase inhibitor (TKI) is started. We report on a planned interim analysis carried out after 115 events according to the new primary end-point, with a significance level of 1.5%. Hazard ratios (HR) and p-values were adjusted for stratification factors. Results: 908 pts were randomized between 2005 and 2008, 454 to IM and 454 to observation arm; 835 pts were eligible. 17% of pts treated with IM stopped early due to toxicity or refusal. With a median follow-up of 4.7 yrs, 5-yr IFS was 87% in the IM-arm vs 84% in the control arm (HR=0.80, 98.5% CI [0.51; 1.26], p=0.23); RFS was 84% vs 66% at 3 yrs, and 69% vs 63% at 5 yrs (p

Methods Patients (pts) with locally advanced or metastatic, grade 2 or 3 STS aged up to 60 yrs, were randomised to receive either single agent D (75 mg/m2) or D (75 mg/m2) with I (10 g/m2 over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by performance status (0 or 1), age ( Results 455 pts from 38 centres were randomised to D (n = 228) or D-I (n = 227). With median follow-up of 56 months, OS at 1 yr was slightly greater with D-I at 60% (95.5% CI 53 – 66) vs 51% (95.5% CI 44 – 58) with D alone, but the difference was not statistically significant (HR 0.82, 95.5% CI 0.66 – 1.01, stratified log rank test p = 0.061). No difference was seen in the 2-yr OS rate which was 31% (95.5%CI 25 – 38) for D-I vs 28% (95.5%CI 22 – 34) for D. Median PFS was significantly increased at 7.4 months (95% CI 6.6 – 8.3) for D-I vs 4.6 months (95% CI 2.9 – 5.6) for D (HR 0.72, 95% CI 0.59 – 0.88, stratified log rank test p = 0.002). Responses were CR: D = 1, D-I = 4; PR: D = 30 (13.2%), D-I = 56 (24.7%); SD: D = 105 (46.1%), D-I = 114 (50.2%). Febrile neutropenia was more common with D-I (45.9% vs 13.6%) as was anaemia (35.3% vs 4.6%). Conclusions The lack of a significant improvement in OS does not support the routine use of this intensive combination of D + I for STS in the palliative setting. The higher response rate suggests that D-I might be justified in selected pts age Disclosure All authors have declared no conflicts of interest. The EORTC 62012 trial was initiated to address concerns that previous studies comparing single agent doxorubicin (D) versus (vs) doxorubicin plus ifosfamide (I) in soft tissue sarcomas (STS) had used suboptimal doses of I. Non-randomised data suggested that a higher dose of I could increase response rate and progression free survival (PFS).

www.thelancet.com Vol 380 September 1, 2012 801 Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/ Endo and Nielsen are right in stating that genetic subtypes— eg, in adipocytic sarcomas—can aff ect angiogenesis. The decision to exclude all adipocytic soft-tissue sarcomas was mainly based on the design and outcome of the phase 2 study. In this trial as well as in, for example, the trial of eribulin, the four-strata design (leiomyosarcoma, liposarcoma, synovial sarcoma, other) was used to get a better overview of effi cacy than in previous, non-lumped phase 2 studies. Still, this is of course not the way to gain the best insight into therapeutic effi cacy of a drug, given the variety of molecular subtypes in all histological groups. A study with pazopanib is currently recruiting patients with dediff erentiated, myxoid/roundcell, pleomorphic, mixed-type, or not otherwise specifi ed adipocytic sarcoma (NCT01506596), which will yield results that could supplement the conclusions of the PALETTE study.

Background Tumor EGFR and KRas mutations are both predictive and prognostic biomarkers in patients with advanced NSCLC. We analyzed the correlation between these biomarkers and treatment outcomes in a phase III trial of 3rd/4th line sorafenib in patients with NSCLC. Methods The global, randomized, placebo-controlled MISSION trial enrolled 703 patients with advanced relapsed/refractory NSCLC of predominantly non-squamous histology. The primary study endpoint was overall survival (OS). EGFR and KRas mutations were analyzed in archival tumor samples and in circulating tumor DNA isolated from plasma. Results Tumor and/or plasma mutation data were available from 347 patients (49%). EGFR and KRas mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were well balanced between treatment arms. Analysis of the interaction between EGFR mutation status and treatment effect on survival suggested that patients with EGFR mutations (mEGFR) benefitted from sorafenib, while those with wild-type EGFR (wtEGFR) did not (p = 0.023). Median OS was two-fold longer in mEGFR patients receiving sorafenib versus placebo (423 vs 197 days, HR 0.48, p = 0.002). There was no significant difference in OS between patients with wtEGFR receiving sorafenib or placebo (253 vs 256 days, HR 0.92, p = 0.559). An interaction was also seen between EGFR mutation status and the sorafenib effect on PFS (p = 0.015). Patients with mEGFR treated with sorafenib had better outcomes compared to placebo based on Cox regression analysis (HR 0.27, p Conclusion Post-hoc analyses of efficacy outcomes in MISSION suggest that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving 3rd/4th line sorafenib. These results must be interpreted with caution due to the small, non-representative nature of the genetic biomarker subpopulation analyzed in this trial. Further prospective investigation may be warranted. Disclosure T.S.K. Mok: Honoraria: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, and GSK Biologicals Speaker: Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, and Merck Serono Research funding: Astrazeneca. L. Paz-Ares: Dr. Paz-Ares has received honoraria from Bayer HealthCare Pharmaceuticals, Lilly, Roche and Pfizer. Y. Wu: Dr. Wu has received lecture fees from Roche, AstraZeneca, Eli Lilly, and Pfizer. V. Hirsh: Member of the steering committee for the MISSION trial. C. Lathia: Dr. Lathia is an employee of Bayer HealthCare. T.J. Ong: Dr. Ong is an employee of, and owns shares in, Bayer HealthCare. C. Pena: Dr. Pena is an employee of Bayer HealthCare. All other authors have declared no conflicts of interest.

10602 Background: Progressive disease (PD) according to RECIST 1.1 (Eisenhauer et al, 2009) is defined as one or more of (1) PD of measurable target lesions, (2) the presence of a new lesion (NL) or (3) the unequivocal PD of non-target disease (NT-PD). We explored the impact of these components, varying over time, on predicting overall survival (OS) in the RECIST database residing at EORTC (Bogaerts et al, 2009). Methods: Data was selected from 12 randomized clinical trials (3530 patients with breast, lung or colorectal cancer). A maximum of 5 target lesions was used to determine the sum of diameters. The following were calculated or assigned at each measurement time t: best response (BR) was best % improvement from baseline up to t (0% if no improvement - 100% if complete response (CR)); tumor growth (TG) was the weekly rate of increase from nadir to t (0 if no increase; irrespective of prior shrinkage), presence of NL (yes/no), and occurrence of NT-PD (yes/no); categories were not mutually exclusive. OS was analyzed by tumor type using a Cox regression model, adjusting for baseline sum, and including BR, TG, presence of NL and NT-PD as time dependent covariates. Results: Thirty-six percent of patients had NL, 26% had NT-PD, 11% achieved CR and 14% did not have shrinkage of target lesions, while 46% experienced TG (median strongest growth per patient of 0.5 mm/week). Regardless of tumor type, the presence of NL (Hazard Ratio (HR) ranging 1.4-2.5), NT-PD (HR 1.2-2.5) and TG (per 1mm/week increase; HR 1.1-1.4) were associated with worse OS, while achieving CR was associated with a longer OS (HR 0.2-0.8). Further analyses exploring the functional shape of the association between BR and TG, and OS are ongoing. This includes putting TG in contrast with the more usual % cutoff defining target PD. Conclusions: All three components of PD according to RECIST are independently strongly associated with OS. Quantification such as this will enable a better understanding of the role of each component (e.g. clinical aspect of NT-PD assessment) in PD evaluation. Work is ongoing to incorporate this information into an updated RECIST with enhanced prediction of subsequent survival.

10579 Background: Pazopanib has been introduced recently in the treatment for patients with advanced STS. Multiple chemotherapies have been investigated for the treatment of advanced and recurrent ...