Commentary: Old and New Drugs Robert S. Benjamin, M.D. Department of Sarcoma Medical Oncology The SARCOMA Center

Long-term Outcomes of Metastatic Sarcoma: Is Metastatic Sarcoma Curable? Vinod Ravi MD, Wei-Lien Wang MD, Sarah H. Taylor, Shreyaskumar Patel MD, Laurence Baker DO, Robert S. Benjamin MD. Departments of Sarcoma Medical Oncology, Pathology, and Tumor Registry, UT MD Anderson Cancer Center, Houston Texas. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

Vital Status

Disease status among patients who are alive

Cause of death

PRIMARY CHEMOTHERAPY (CT) TOXICITY AND PREOPERATIVE RADIATION THERAPY (RT) IN HIGH-RISK ADULT SOFT TISSUE SARCOMAS: A REPORT FROM THE ITALIAN SARCOMA GROUP AND THE SPANISH SARCOMA GROUP TRIAL Stefano Ferrari, Elena Palassini, Antonino DePaoli, Isabel Sevilla*, Javier Martinez Trufero*, Enza Barbieri, Sergio Frustaci, Alexia Bertuzzi, Annalisa Nobile, Emanuela Palmerini, Silvia Stacchiotti, Xavier Martin Broto*, Paolo Casali, Piero Picci Alessandro Gronchi. ISG - *GEIS PRIMARY CHEMOTHERAPY (CT) TOXICITY AND PREOPERATIVE RADIATION THERAPY (RT) IN HIGH-RISK ADULT SOFT TISSUE SARCOMAS: A REPORT FROM THE ITALIAN SARCOMA GROUP AND THE SPANISH SARCOMA GROUP TRIAL Stefano Ferrari, Elena Palassini, Antonino DePaoli, Isabel Sevilla*, Javier Martinez Trufero*, Enza Barbieri, Sergio Frustaci, Alexia Bertuzzi, Annalisa Nobile, Emanuela Palmerini, Silvia Stacchiotti, Xavier Martin Broto*, Paolo Casali, Piero Picci Alessandro Gronchi. ISG - *GEIS

Biopsy EI x 3 RT EI x 2 SURG RTSURG R R EI x 3 RTSURG RTSURG EI = epiDOX 120 mg/sqm + IFX 9,000 mg/sqm + GCSF q 21 days RT ( total dose of 44 to 50.4 Gy) was given preoperatively at the discretion of the treating physician Objective: To evaluate the chemotherapy-related toxicity and protocol compliance in patients with high-risk extremity soft tissue sarcoma preoperatively treated with combined chemotherapy and radiotherapy

Logistic Regregression-Logistic backward method OR95% CIP value WBC G4 Age> ≤401 SexF M1 PLT G 3-4 Age> ≤401 RTYes No1 Hgb G3-4 SexF M1 Multivariate analysis - Bone Marrow toxicity

Preoperative RT prolonged TTS and increased the incidence of PLT G3-4 toxicity. The female sex and older age significantly increased the incidence of haematological toxicity. Preoperative RT prolonged TTS and increased the incidence of PLT G3-4 toxicity. The female sex and older age significantly increased the incidence of haematological toxicity. Chemotherapy-related bone marrow toxicity and protocol compliance Multivariate analysis

Phase 3, placebo-controlled trial (SUCCEED) evaluating ridaforolimus as maintenance therapy in advanced sarcoma patients following clinical benefit from prior standard cytotoxic chemotherapy: subgroup analysis of patients after second- and third-line therapy S. P. Chawla, 1 P. Reichardt, 2 I. L. Ray-Coquard, 3 A. Le Cesne, 4 A. P. Staddon, 5 M. M. Milhem, 6 N. Penel, 7 R. B. Bui Nguyen, 8 P. Y. Song, 9 S. Ebbinghaus, 9 F. G. Haluska, 10 P. F. Dodion, 10 J-Y. Blay, 3 G. D. Demetri 11 1 Sarcoma Oncology Center, Santa Monica, CA; 2 HELIOS Klinikum Bad Saarow, Sarcoma Center Berlin- Brandenburg, Bad Saarow, Germany; 3 Centre Léon Bérard, Lyon, France; 4 Institut Gustave Roussy, Villejuif, France; 5 University of Pennsylvania, Philadelphia, PA; 6 University of Iowa, Iowa City, IA; 7 Centre Oscar Lambret, Lille, France; 8 Institut Bergonié, Bordeaux, France; 9 Merck, Whitehouse Station, NJ; 10 ARIAD Pharmaceuticals, Cambridge, MA; 11 Dana-Farber Cancer Institute, Boston, MA Abstract #

PFS and OS analysis in 1L versus 2/3L subgroups 11 Patients enrolled after 1L of therapyPatients enrolled after 2/3L of therapy Progression-free survival Overall survival 21.3 vs 21.4 mos. 4.1 vs 3.5 mos vs 15.6 mos. 3.8 vs 2.3 mos.

Trabectedine Importance of maintenance treatment ATU Compassionate use program in France N=181, Median Follow up 6 years 16.1 mos. 3.6 mos.

Trabectedine Importance of maintenance treatment? N=56, interruption vs continuation after 6 courses Explored in the randomized T-DIS trial p=0,001 p=0, vs 5.3 mos vs 13.9 mos.

Rechallenge with trabectedine

Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced, high grade soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group. Ian Judson, Jaap Verweij, Hans Gelderblom, Jorg- Thomas Hartmann, Patrick Schöffski, Jean-Yves Blay, Angelo Paolo dei Tos, Sandrine Marreaud, Saskia Litiere, Winette van der Graaf

The design Stratification: Age (<50 vs ≥50) PS (0 vs 1) Liver metastases (0 vs +) Histological grade (2 vs 3) R Doxorubicin 75 mg/m 2 d 1 or as a 72 hour continous i.v. infusion New Treatment: B Doxorubicin 25 mg/m 2 d Ifosfamide 2.5 g/m 2 d Neulasta 6mg s.c. d5

Best overall response 17 Treatment Total (n=455) Doxo (n=228) Doxo-Ifos (n=227) n (%) Complete Response 1 (0.4) 4 (1.8) 5 (1.1) Partial Response 30 (13.2) 56 (24.7) 86 (18.9) ORR No Change 105 (46.1) 114 (50.2) 219 (48.1) Progressive Disease 74 (32.5) 30 (13.2) 104 (22.9) Early Death - Progression 4 (1.8) 5 (2.2) 9 (2.0) Early Death – Other cause 3 (1.3) 2 (0.9) 5 (1.1) Not evaluable 11 (4.8) 16 (7.0) 27 (5.9) Significant difference between the two arms: p < 0.001

Reason for discontinuation of treatment 18 Treatment Total (n=230) Doxo (n=121) Doxo-ifos (n=109) n (%) Progression of Disease/death due to PD 95 (41.7) 47 (20.7) 142 (31.2) Toxicity (incl toxic death) 6 (2.6) 40 (17.6) 46 (10.1) Toxic death52 Patient’s refusal (not related to toxicity) 4 (1.8) 10 (4.4) 14 (3.1) Intercurrent death (not related to malignant disease or toxicity) 4 (1.8) 1 (0.4) 5 (1.1) Other 12 (5.3) 11 (4.8) 23 (5.1)

Progression free survival 19 HR = 0.74 (95% CI 0.60 – 0.90) Stratified logrank test, p = Median PFS dox-ifos: 7.4 months Median PFS SA dox: 4.6 months

Overall survival 20 HR = 0.83 (95.5% CI 0.67 – 1.03) Stratified logrank test, p = Median Survival dox-ifos: 14.3 months Median Survival SA dox: 12.8 months

Treatment Doxo (N=215) DxIf (N=210) N (%) Surgery 44 (20.5) 43 (20.5) Chemotherapy 136 (63.3) 134 (63.8) Doxorubicin 12 (5.6) 27 (12.9) Analog 3 (1.4) 1 (0.5) Ifosfamide 99 (46.0) 32 (15.2) Analog 6 (2.8) 13 (6.2) Trabectedin 33 (15.3) 37 (17.6) Docetaxel 25 (11.6) 34 (16.2) Analog 5 (2.3) 6 (2.9) Gemcitabine 32 (14.9) 40 (19.0) Dacarbazine 7 (3.3) 18 (8.6) Analog 0 (0.0) 1 (0.5) Pazopanib 14 (6.5) 14 (6.7) Eribulin 7 (3.3) 11 (5.2) Etoposide 8 (3.7) 11 (5.2) Post protocol treatment 21

Overall survival 22 HR = 0.83 (95.5% CI 0.67 – 1.03) Stratified logrank test, p = year Survival dox-ifos: 60% 1-year Survival SA dox: 51%

The primary end point: overall-survival The secondary end points: response (RECIST) toxicity (CTC 2.0) treatment related mortality Early stopping rule: as PFS was used as surrogate for OS a failure to produce a significant improvement in PFS (at least 50% increase) would predict a likely failure End-points of the study 23

Improvement of survival is clinically significant if 1yr survival is at least 10% higher in the combination arm (60 versus 50%), corresponding with a HR of or less. Two- sided logrank test (alpha=0.05, beta 0.2). Statistical Assumption 24

The outcome of patients with soft tissue sarcomas with locally advanced unresectable primary tumors and/or metastatic disease is poor. Systemic treatment is usually given with a palliative intent, but has toxicity. There is (transatlantic and/or cultural) debate about the best first-line treatment in this situation: single agent doxorubicin or a combination of doxorubicin and ifosfamide Which situation justifies which treatment, especially the more toxic combination treatment? And in comparing new treatments: what will be the standard treatment arm to compare with? Rationale of the study 25

Overall survival 26 HR = 0.83 (95.5% CI 0.67 – 1.03) Stratified logrank test, p = Median Survival dox-ifos: 14.3 months Median Survival SA dox: 12.8 months

% Months AI Chemotherapy for Metastatic STS Time to Progression and Survival Time to Progression Median = 10 Months Survival Median = 21 Months

PFS and OS analysis in 1L versus 2/3L subgroups 28 Patients enrolled after 1L of therapyPatients enrolled after 2/3L of therapy Progression-free survival Overall survival 21.3 vs 21.4 mos. 4.1 vs 3.5 mos vs 15.6 mos. 3.8 vs 2.3 mos.

Trabectedine Importance of maintenance treatment ATU Compassionate use program in France N=181, Median Follow up 6 years 16.1 mos. 3.6 mos.

The combination of doxorubicin and ifosfamide doubled the response rate improved PFS significantly it did not significantly improve survival (using the frequentist statistical assumptions behind this study) It was considerably more toxic than doxorubicin alone. Conclusions 30

The standard treatment remains single agent doxorubicin – Why? If surgery for unresectable tumors or (curative) metastasectomy is foreseen, combination therapy can be considered In highly symptomatic disease in patients without co- morbidity combination treatment is optional and pro’s and cons should – as always- be discussed with the patient… ….and this is easier now, since we have the results of this study ! What now in daily practice? 31

I have always been impressed by the fantastically high regard that clinical scientists and statisticians hold for the 5% level of significance.... It seems clear to me that a drug which has a 90% probability of being better would be my personal treatment choice.

Commentary: Old and New Drugs Robert S. Benjamin, M.D. Department of Sarcoma Medical Oncology The SARCOMA Center