Soft-tissue Sarcomas

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

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Vital Status
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Disease status among patients who are alive
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Cause of death
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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
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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
RT
SURG
EI x 3
RT
SURG
R
Biopsy
RT
SURG
EI x 3
EI x 2
RT
SURG
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
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Multivariate analysis - Bone Marrow toxicity
OR 95 CI P value
WBC G4 Age gt65 3.363 1.048-10.791 0.041
41-65 1.226 0.706-2.129 0.47
40 1
Sex F 2.513 1.454 -4.435 0.001
M 1
PLT G 3-4 Age gt65 4.124 1.541-11.042 0.005
41-65 2.923 1.479-5.778 0.002
40 1
RT Yes 1.868 1.060-3.292 0.03
No 1
Hgb G3-4 Sex F 2.365 1.328-4.210 0.003
M 1
Logistic Regregression-Logistic backward method
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Chemotherapy-related bone marrow toxicity and
protocol compliance
Multivariate analysis
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.
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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. Demetri11
• 1Sarcoma Oncology Center, Santa Monica, CA
  2HELIOS Klinikum Bad Saarow, Sarcoma Center
  Berlin-Brandenburg, Bad Saarow, Germany 3Centre
  Léon Bérard, Lyon, France 4Institut Gustave
  Roussy, Villejuif, France 5University of
  Pennsylvania, Philadelphia, PA 6University of
  Iowa, Iowa City, IA 7Centre Oscar Lambret,
  Lille, France 8Institut Bergonié, Bordeaux,
  France 9Merck, Whitehouse Station, NJ 10ARIAD
  Pharmaceuticals, Cambridge, MA 11Dana-Farber
  Cancer Institute, Boston, MA
• Abstract 1432489

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

• ATU Compassionate use program in France

3.6 mos.
16.1 mos.
N181, Median Follow up 6 years
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TrabectedineImportance of maintenance treatment?
p0,009
p0,001
33.4 vs 13.9 mos.
10.5 vs 5.3 mos.
N56, interruption vs continuation after 6
courses Explored in the randomized T-DIS trial
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Rechallenge with trabectedine
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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

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The design

• Stratification
• Age (lt50 vs 50)
• PS (0 vs 1)
• Liver metastases (0 vs )
• Histological grade (2 vs 3)

Doxorubicin 75 mg/m2 d 1 or as a 72 hour
continous i.v. infusion
R
New Treatment B
Doxorubicin 25 mg/m2 d 1-3 Ifosfamide 2.5 g/m2
d 1-4 Neulasta 6mg s.c. d5
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Best overall response
  Treatment Treatment Total(n455)
  Doxo(n228) Doxo-Ifos(n227) Total(n455)
  n () n () n ()

Complete Response 1 (0.4) 4 (1.8) 5 (1.1)
Partial Response 30 (13.2) 56 (24.7) 86 (18.9)
ORR 13.6 26.5
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 lt
0.001
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Reason for discontinuation of treatment
  Treatment Treatment Total(n230)
  Doxo(n121) Doxo-ifos(n109) Total(n230)
  n () n () 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 death 5 2
Patients 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)
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Progression free survival
HR 0.74 (95 CI 0.60 0.90) Stratified
logrank test, p 0.003
Median PFS dox-ifos 7.4 months Median PFS SA
dox 4.6 months
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Overall survival
HR 0.83 (95.5 CI 0.67 1.03) Stratified
logrank test, p 0.076
Median Survival dox-ifos 14.3 months Median
Survival SA dox 12.8 months
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Post protocol treatment
Treatment Treatment
Doxo(N215) DxIf(N210)
N () 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)
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Overall survival
HR 0.83 (95.5 CI 0.67 1.03) Stratified
logrank test, p 0.076
1-year Survival dox-ifos 60 1-year Survival SA
dox 51
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End-points of the study

• 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

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Statistical Assumption

• 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 0.737 or less. Two-sided logrank
  test (alpha0.05, beta 0.2).

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Rationale of the study

• 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?

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Overall survival
HR 0.83 (95.5 CI 0.67 1.03) Stratified
logrank test, p 0.076
Median Survival dox-ifos 14.3 months Median
Survival SA dox 12.8 months
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AI Chemotherapyfor Metastatic STSTime to
Progression and Survival
Survival Median 21 Months

Time to Progression Median 10 Months
Months
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PFS and OS analysis in 1L versus 2/3L subgroups
Patients enrolled after 1L of therapy
Patients enrolled after 2/3L of therapy
4.1 vs 3.5 mos.
3.8 vs 2.3 mos.
Progression-free survival
21.3 vs 21.4 mos.
19.7 vs 15.6 mos.
Overall survival
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TrabectedineImportance of maintenance treatment

• ATU Compassionate use program in France

3.6 mos.
16.1 mos.
N181, Median Follow up 6 years
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Conclusions

• 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.

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What now in daily practice?

• 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 pros and cons should as always- be
  discussed with the patient
• .and this is easier now, since we have the
  results of this study !

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• 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.

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