Outcome of chemotherapy in synovial sarcoma (sys) patients (pts): review of 15 clinical trials from EORTCc involving advanced sys compared to other Soft Tissue Sarcomas (STS) Winette T. van der Graaf, Elisa Rizzo, Alessandro Gronchi, Ian Judson, Hans Gelderblom, Sandrine Marreaud and Saskia Litiere, on behalf of the EORTC Soft Tissue and Bone Sarcoma Group

Disclosures Research grants from Novartis, Pfizer, GSK 2

Background 3 Synovial sarcoma (SyS) represents about 8% of all soft tissue sarcomas SyS is a relatively more common among teenagers and young adults The impression is that it is a more chemosensitive STS As outcome in metastatic session has not been reported to have become significantly better during the last decades, we need new synovial sarcoma specific studies. Therefore we need solid outcome data as basis for the statistical design of new studies.

Aim 4 To evaluate : The clinical presentation of SyS pts The outcome of pts with advanced or metastatic SyS treated with first line chemotherapy.

Patients and Methods 5 Data were used from the EORTC-STBSG database containing information on  chemo-naïve advanced and metastatic STS pts who participated in fifteen chemotherapy trials between 1976 and Pts with SyS were compared with other STS patients. We evaluated overall survival (OS), progression free survival (PFS) and response rate (RR). The chemotherapy in SyS pts was aggregated in 5 categories: A: anthracyclines alone (121 pts), B: ifosfamide alone (42), C: doxorubicin and ifosfamide (112 pts), D: CYVADIC (42 pts) E: Other: Brostallicin, Trabectedin (8pts).

Selection of Synovial sarcoma patients 6 From the 15 EORTC pooled sarcoma trials, 313 patients with SyS sarcoma were identified for analysis patients in the EORTC sarcoma database 192 received prior treatment 313 SyS patients 3171 Other subtypes 3484 received no prior treatment

Characteristics of SyS pts compared to others STS pts 7

8 a Kruskal -Wallis test; b Chi-square test

RESULTS 9 OS PFS RR

OS Synovial vs. other sub-types 10 (months) ONNumber of patients at risk :Tumor site Synovial sarcoma Other types Overall Score test: p=0.009 Tumor site Median (95% CI) (Months) % at 1 Year (95% CI) Synovial sarcoma 15.0 (13.9, 16.4)63.7 (57.9, 68.8) Other types 11.6 (11.1, 12.0)48.0 (46.2, 49.8)

PFS Synovial vs. other sub-types 11 (months) ON Number of patients at risk : Tumor site Synovial sarcoma Other types Overall Score test: p=0.004 Tumor site Median (95% CI) (Months) % at 1 Year (95% CI) Synovial sarcoma 6.3 (5.8, 6.9)18.2 (14.2, 22.6) Other types 3.6 (3.4, 3.9)16.7 (15.4, 18.0)

OS univariate analysis 12

OS by Performance status 13 (months) ONNumber of patients at risk : Performance status PS 0 PS 1 PS 2+ Overall Score test: p<0.0001(df=2) Performance status Median (95% CI) (Months) % at 1 Year (95% CI) PS (15.5, 19.7)75.9 (68.2, 82.0) PS (10.8, 15.6)55.6 (46.6, 63.6) PS >=2 6.1 (3.1, 8.3)14.3 (2.4, 36.3)

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OS multivariate analysis 15 Factor Hazard Ratio 95% Lower CL for Hazard Ratio 95% Upper CL for Hazard Ratio P Performance status PS 1 vs. PS <0.001 PS 2+ vs. PS Metastatic site involved Yes vs. No Primary site involved Yes vs. No <0.001 Better survival for Synovial patients: with WHO PS 0 vs. PS 1 & 2 with metastatic site not involved the role of primary site involved is less clear as it is correlated with metastatic site involved and it is not statistical significant in the univariate analysis No significant effect of chemotherapy regimen in first line treatment observed for OS

PFS univariate analysis 16

PFS by Performance status 17 (months) ONNumber of patients at risk : Performance status PS 0 PS 1 PS 2+ Overall Score test: p=0.000 (df=2) Performance status Median (95% CI) (year) % at 1 Year (95% CI) PS (0.5, 0.7)24.7 (18.2, 31.7) PS (0.3, 0.5)13.7 (8.5, 20.2) PS >=2 0.3 (0.2, 0.4)0

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19 PFS multivariate analysis Factor Hazard Ratio 95% Lower CL for Hazard Ratio 95% Upper CL for Hazard Ratio P Performance status PS 1 vs. PS PS 2+ vs. PS Metastatic site involved Yes vs No <.001 Better PFS for Synovial patients: with WHO PS 0 vs. PS 1 & 2 with metastatic site not involved Treatment was borderline not-significant (p=0.051) when adjusting for the different potential prognostic factors for OS

Response to chemotherapy 20 RR to chemotherapy overall:28%; no change 46%

Conclusions 21 Prognostic impact of performance status and metastatic site involved on OS an PFS  A better outcome for patients with PS 0 compared to PS ≥ 1 and with metastatic site not involved  Variable primary site involved seems to be significant for OS but this variable is correlated with metastatic site involved There was no significant effect of treatment regimen observed neither for PFS nor OS 28% responders to chemotherapy among the SyS pts.

What next? Given the fact that the prognosis of locally advanced and metastatatic SyS pts is still poor, we should consider cooperative groups for new clinical studies in this not so rare STS WORK IN PROGRESS!! 22

Acknowledgements Patients who participated in these studies All investigators of EORTC STBSG EORTC Headquarters

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Patients and Methods 25 Categorical variables were summarized by frequencies and percentages, continuous variables were summarized by median, range, interquartile range (IQR). Comparisons between factors was done using chi-square or Kruskal- Wallis tests. Survival was estimated by Kaplan Meier method Univariate and multivariate analyses (using backward selection to reduce the multivariate model) were done using  Cox regression for PFS and OS  Logistic regression for RR