YONDELIS 5TH ANNIVERSARY SYMPOSIUM Current questions in STS YONDELIS 5TH ANNIVERSARY SYMPOSIUM Current questions in STS. Further steps with Yondelis Peter Reichardt HELIOS Klinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg

Systemic therapy More recent agents: Unregistered agents: Classical active agents: Anthracyclines, ifosfamide, DTIC More recent agents: Trabectedin, pazopanib Unregistered agents: Gemcitabine, docetaxel, trofosfamide, temozolomide HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Combination chemotherapy in first line Combination of doxorubicin or epirubicin with ifosfamide + DTIC results in response rates of up to 50 % (appr. 10% CR). Significantly higher response rate and progression-free survival compared to single agent therapy. Significantly higher toxicity. No significant improvement of overall survival in first-line therapy so far. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

EORTC 62012 randomized phase III trial (1) Patients with STS aged 60 years and less. Doxorubicin at 75 mg/m² or doxorubicin at the same dose plus ifosfamide given at 10 g/m² over four days. Randomization was stratified by performance status (0 or 1), patient age of less than 50 years or 50 years and older, the presence or absence of liver metastases and histological grade of 2 versus 3. A total of 455 patients from 38 centers were randomized, median follow-up is 56 months. Judson et al., Ann Oncol (2012) 23 (suppl 9): ixe28 HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

EORTC 62012 randomized phase III trial (2) Overall survival was 60% with ifosfamide/doxorubicin compared to 51% with sole doxorubicin, hazard ratio HR 0.82; p = 0.061. Median progression-free survival was significantly increased to 7.4 months in ifosfamide/doxorubicin patients compared to 4.6 months with doxorubicin, HR 0.72; p = 0.002. Complete response were seen in 4 versus 1 patients, partial response in 56 (24.7%) versus 30 (13.2%) and stable disease was achieved by 114 (50.2%) ifosfamide/doxorubicin patients versus 105 (46.1%) doxorubicin patients, respectively. Combination therapy was associated with increased adverse events; 45.9% versus 13.6% and 35.3% versus 4.6% of ifosfamide/doxorubicin patients compared to doxorubicin patients, respectively, reported neutropenia and anemia. Judson et al., Ann Oncol (2012) 23 (suppl 9): ixe28 HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Combination chemotherapy in first line Conclusion from EORTC 62012: Wrong treatment? Wrong STS subtypes? Wrong patients? Wrong endpoint? HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

First-line treatment of STS (1) Standard chemotherapy is based on anthracyclines as first line treatment. No formal demonstration that multiagent chemotherapy is superior to single-agent chemotherapy with doxorubicin alone in terms of OS. Higher response rate may be expected, in particular in a number of sensitive histological types. Multiagent chemotherapy with anthracyclines plus ifosfamide may be the treatment of choice, particularly when a tumour response is felt to be able to give an advantage and patient performance status is good. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de 9

First-line treatment of STS (2) In angiosarcoma, taxanes are an alternative option, given their high antitumour activity in this specific histological type. An alternative option is gemcitabine ± docetaxel. Doxorubicin plus dacarbazine is an option for multiagent first-line chemotherapy of leiomyosarcoma, where the activity of ifosfamide is far less convincing on available retrospective evidence. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de 9

Ongoing randomized phase III trials on combinations in first-line treatment Doxorubicin vs. doxorubicin plus palifosfamide (ClinicalTrials.gov Identifier: NCT01168791) Doxorubicin vs. doxorubicin plus TH-302 (ClinicalTrials.gov Identifier: NCT01440088) HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Single agent in refractory STS Trabectedin Evaluable patients q3wk 24-h qwk 3-h Stats. Independent review CR+PR (95% CI) 5.6% (2.3-11.2) 1.6% (0.2 – 5.8) p=0.1718 SD 53% 42% PD 56% CR+PR+SD 58% 44% High tumour control rate (58%). PFS at 6 months: 35.5% / Median OS: 13.9 months. Lack of cumulative toxicities and good tolerability: Prolonged number of cycles allowed. “15-20% of patients had long-term benefit from trabectedin treatment (20-30 cycles).” Morgan JA, et al. J Clin Oncol. 2007;25(Suppl18):abstract 10060. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Single agent in refractory STS Pazopanib van Der Graaf et al., Lancet 2012 HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Combination CT in refractory STS gemcitabine/docetaxel Maki RG et al., J Clin Oncol 2007 HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Combination CT in refractory STS gemcitabine/DTIC Garcia Del Muro et al., J Clin Oncol 2011 HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Current questions in refractory STS: Choosing the best treatment What is the PS of the patient? What is the specific STS subtype? What is the specific disease stage or the amount of disease? And the most important… What is the goal of treatment? HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Choosing the best treatment in refractory STS: Different agents for different goals Goal 1: Make an advanced tumour resectable Treatment with high probability of RECIST responses High toxicity acceptable Goal 2: Control symptomatic disease Treatment with high probability of RECIST responses Toxicity acceptable Goal 3: Stabilization of the tumour with a good QoL High tumour control rate RECIST response not necessary Long term benefit Well tolerated therapy HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Further steps with Yondelis HELIOS Klinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg 15

Further steps with Yondelis Trabectedin in first line therapy in STS Translocation related sarcomas TRUSTs GEIS-20 (Trabectedin + Doxorubicin) LMS-02 (Doxorubicin + Trabectedin) Planned: TR1US First line in unfitted to Doxo/Ifo Why trabectedin in first line?? Promising efficacy and safety results in chemo-naïve patients (Phase II). Already approved for doxo/ifo unsuited patients. Trabectedin + Doxo is a feasible combination with acceptable tolerability (phase I). Outstanding efficacy results in Myxoid liposarcoma (a TRS subtype) in metastatic disease and neoadjuvant setting. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Randomized phase III trial is comparing Yondelis vs Randomized phase III trial is comparing Yondelis vs. Doxorubicin based chemotherapy as first-line therapy in patients with TRS including the following STS subtypes (accrual completed) TRS Yondelis: 1.5 mg/m2 24h q3w ® Doxorubicin-based CT q3w N = 80 Front-line Sarcoma type Clear cell sarcoma Extraskeletal myxoid chondroS Myxoid liposarcoma Angiomatoid fibrous histiocytoma Alveolar rhabdomyosarcoma Desmoplastic small round cell tumour Synovial sarcoma Inflammatory myofibroblastic T Alveolar soft part sarcoma Endometrial stromal sarcoma Stratification: Myxoid liposarcoma vs. others Primary endpoint: PFS Other endpoints: 6PFS, OS, RR, CHOI, Safety HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

A phase IIb/III multicenter study comparing efficacy of trabectedin administered as a 3-hour or 24-hour infusion to doxorubicin in patients with advanced or metastatic untreated STS TRUSTs Primary endpoint: Secondary endpoints: Study Design: HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

A randomized, open, multicenter, prospective, phase II clinical trial of doxorubicin vs. trabectedin+doxorubicin in the first line treatment of patients with advanced non operable and/or metastatic STS GEIS-20 Primary endpoint: Secondary endpoints: HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Phase II multicenter study to determine the efficacy of doxorubicin +trabectedin as a first line treatment for patients with metastatic leiomyosarcoma (uterine or soft tissue) and/or inoperable relapse (accrual completed) Primary endpoint: Secondary endpoints: LMS-02 HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Safety and activity of trabectedin as 1st line in advanced STS patients unfit to receive standard chemotherapy: a prospective phase II study with clinical and molecular correlates TR1US Highlights An Italian, multicenter, non-randomized, two-stage study according to Bryant & Day phase II study. Metastatic and locally advanced STS patients unfit to receive standard chemotherapy (doxorubicin/epirubicin and/or ifosfamide). Tumour assessment by Choi and RECIST. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de 21

Further steps with Yondelis Trabectedin as Neoadjuvant treatment ISG-STS-01 HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Localized high-risk soft tissue sarcomas of the extremities and trunk wall in adults: an integrating approach comprising standard chemotherapy vs histotype-tailored neoadjuvant chemotherapy ISG-STS 10-01 Rationale Yondelis® (single-agent) is effective in neoadjuvant setting for STS. To test that Histotype-tailored chemotherapy is associated with a 30% reduction in the hazard of relapse in STS patients. Objective Disease-free survival. OS, probability of response, ORR (RECIST and Choi), pathological RR, feasibility of combining preoperative chemotherapy and local-regional treatments. Surrogacy objective: To validate the response (both radiological and pathological) to preoperative chemotherapy as a surrogate endpoint of DFS and OS. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Further steps with Yondelis Maintenance and Rechallenge T-DIS comparing Maintenance vs Interruption and Rechallenge Yondelis maintenance after stabilization with doxo Why in maintenance and rechallenge?? Safety profile allowing for long term treatment. Non cumulative toxicities. Good results for long term responders. Possible influence of trabectedin´s interaction with tumour microenvironment. Increasing evidence showing efficacy up to the third rechallenge. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Phase II randomized trial to evaluate two strategies: continuing vs Phase II randomized trial to evaluate two strategies: continuing vs. Intermittent (drug-holiday) trabectedin-regimen in patients with advanced STS experiencing response or SD after the sixth cycle T-DIS-1001 Primary endpoint: Secondary endpoints: HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Further steps with Yondelis Different ways of assessing response to trabectedin Trabectedin and tumour Microenvironment PROACTYON (Choi vs RECIST) Y – Image (Choi vs RECIST) Why studying different ways of assessing response?? It is questionable whether RECIST accurately measures the impact of trabectedin on STS. Choi criteria, integrating tumour volume and tumour density, could be a more appropriate method to assess trabectedin activity in STS patients. Target therapies have shown better accuracy of measurement using density- based criteria. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Trabectedin in soft tissue sarcomas pre-treated with conventional chemotherapy. Evaluation of “tumour microenviroment” Rationale The antitumour activity of trabectedin might not only arise from a direct effect on tumour cells, but also by the changes it induces on tumour microenvironment. Trabectedin may be associated with the number of macrophages in the tumour. Design Study evaluating the activity of trabectedin is STS through the quantitative variations of macrophages and monocytes in serum at pre- defined time, as a predictive index of efficacy in this patients population. End points Primary: disease control rate (DCR) according to both RECIST criteria and Choi criteria in STS patients, pre-treated with anthracyclines and / or ifosfamide, or unsuitable for these agents. Secondary: to determine the variation of circulating monocytes , TTP, PFS, OS, safety. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Further steps with Yondelis: Different ways of assessing response PROACTYON: Prognostic value of Choi criteria compared to RECIST for the activity assessment of trabectedin (Yondelis®) in patients with advanced STS. ET-D-020-12 / Y-IMAGE: Non-interventional multicenter, prospective study to evaluate treatment outcome assessment methods used in routine clinical practice on patients with advanced STS treated with trabectedin according to the SmPC practice. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Further steps with Yondelis New Combinations Trabectedin + Gemcitabine Planned: Trabectedin + PARP inhibitor Olaparib Planned: Trabectedin + mTOR inhibitor Why studying new combinations?? The complex mechanism of action of trabectedin allows for synergies with other compounds. Trabectedin has an effect on tumour microenvironment in addition to the well characterized cytotoxic effect. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Further steps with Yondelis Other clinical trials Trabectedin in Retroperitoneal Lipo/Leiomyosarcoma US trial for registration HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Dexamethasone pre-medication Randomized, open, phase III clinical trial of trabectedin vs. DTIC in patients with locally advanced, metastatic L-sarcoma (lipo/leiomyosarcoma) after previous treatment with anthracyclines and ifosfamide therapy SAR-3007 R A N D O M I Z T Primary endpoint: OS Need ~570 patients to observe 376 deaths 380 pts Trabectedin 1.5 mg/m2 24h q3wks Dexamethasone pre-medication Stratification: Performance Status (0 vs 1) Subtype L-sarcoma (liposarcoma vs LMS) Previous lines (1 vs 2 or more) 2:1 190 pts DTIC 1000mg/m2 20 min q3wks HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Continuous vs. intermittent treatment currently investigated. CONCLUSIONS For many patients, long term disease stabilization is a major goal of treatment. Trabectedin offers long term tumour control without cumulative toxicity. Continuous vs. intermittent treatment currently investigated. Numerous trials in different treatment lines and combinations are underway. HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

Paolo Giovanni Casali, Italy Jean-Yves Blay, France Axel Le Cesne, France Paolo Giovanni Casali, Italy Peter Reichardt, Germany All HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de

HELIOS KLinikum Berlin-Buch / Sarcoma Center Berlin-Brandenburg peter.reichardt@helios-kliniken.de