Soft Tissue Sarcoma, Can we refine the approach

Soft Tissue Sarcoma:Can We Refine The Approach?

Mohamed Abdulla M.D.Prof. of Clinical OncologyCairo University ACOD 2015 – Novartis Symposium

Helnan Palestine – 22/10/2015

Member of Advisory Board, Consultant, and Speaker for:● Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen

Cilag, Merck Serono, Novartis, Pfizer

Speaker Disclosures:

Fast Statistics & Challenges:

• 1% of all malignancies.• More than 50 histopathological subtypes.• Local Control is 75 – 80% after definitive surgery.• 5 Year OAS 50% (Death From Metastases).• 5 Year OAS (Isolated Operable Lung Deposits)

25%.• Median survival = 12 months for metastatic

disease.• Grouped as 1 disease for many decades.

Improvement of Disease Specific Survival: “DSS”

Proper Surgery

Radiation Therapy

Systemic Therapy

Improvement in Local Control Eradication of Micrometastases

?

Sensitivity of STS to Systemic Agents:

● Very Sensitive: Ewing/PNET, RMS, Desmoblastic Small Round Cell Tumor, GIST, DFSP, Angiosarcoma, Myxoid/Round Cell Sarcoma, Synovial, Leiomyosarcoma.

● Intermediately Sensitive:MFH, Fibrosarcoma, MPNT, Hemangiopericytoma, Solitary Fibrous Tumor, Heamgioendothelioma.

● Minimally Sensitive:Extraskeletal Myxoid Chondrosarcoma, Epithelioid Sarcoma, Dedifferentiated Liposarcoma, Perivascular Epithelioid Cell Sarcoma.

● Resistant Histologies:Alveolar Soft Part Sarcoma, Clear Cell Sarcoma, Melanoma of Soft Parts, Conventional Chondrosarcoma, GI Leiomyosarcoma

High Risk Patients:

• High Grade Lesions.• Large Tumors > 5 cm.• Deep Lesions.• Recurrent Tumors at Presentations.• Leiomyosarcoma & PNST.• Positive Margins.??

Van Glabbeke M, et al. J Clin Oncol. 1999;17:150

Histopathological Grading:

Classical Management for Non Metastatic Disease:• R0 Resection is the only curative management.• Adjuvant Radiation Therapy:

1. High Grade Lesions.2. Intermediate Grade with Positive Margins.3. Low Grade Lesions with Positive Margins.4. Recurrent Tumors.5. Retroperitoneal Disease.

Local Recurrence

10%

Amputation Rate 5%

75% of All Patients with Localized Extremity STS will not Relapse After Effective Local Treatment.

No Need For Further Therapy

• Neo-adjuvant + Surgery vs Surgery:No Survival Advantage.(Gortzak et al, Eur J Cancer; 2001)

• Neo-adjuvant vs Adjuvant:No Superiority(DeLaney et al, Int J Oncol Biol Phys; 2003).

Neo-Adjuvant Chemotherapy:

Results with Adjuvant Chemotherapy:

Endpoint HR Absolute Benefit P ValueLocal RFI .73 6% .016

Distant RFI .70 10% .0003

Overall RFS .75 10% .0001

OAS (All Sites) .89 4% .12

OAS (Extremities) .80 7% .029

Sarcoma Meta-Analysis Collaboration. Lancet. 1997;350:1647

Updated Results with Adjuvant Chemotherapy:

Therapy Local Recurrence

ARR (95%CI)

Distant Recurrence

ARR (95%CI)

Any Recurrence

ARR (95%CI)

SurvivalARR (95%CI)

A 3% 9% 9% 5%

AI 5% 10% 12% 11%

A or AI 4% 9% 10% 6%

Peraviz et al. Cancer. 2008;13:573

Treatment Related Toxicity

Primary Treatment of Non Metastatic STS:Guidelines

Trials of Doxorubicin + Ifosfamide in Metastatic Disease:

Dose (AI) Number RR %50/5000/m2(a) 258 25

60/7500/m2(b) 88 34

75/5000/m2(c) 104 45

75-90/10000/m2(d) 79 65

(a) Santoro et al. JCO. 1995;13:1537.(b) Edmonson et al. JCO. 1993;11:1269.(c) Steward et al. 1993. JCO.11.15.(d) Patel et al. Expert Opin Investig Drugs. 2000;9:1545.

• Growth Factor Support• Treatment Related Toxicity

Metastatic STS: Other Regimens:

Soft Tissue Sarcoma RegimenGeneral Doxorubicin Single Agent.

Doxorubicin, Ifosfamide, Mesna (AIM)Doxorubicin, Dacarbazine (AD)Mesna, Doxorubicin, Ifosfamide, Mesna (MAID)Gemcitabine, Docetaxel.Gemcitabine, Vinoralbine.

Leiomyosarcoma Doxorubicin, Gemcitabine, DacarbazineGemcitabine, Docetaxel

Myxoid Liposarcoma AnthracyclinesTrabectedinIfosfamide

G III Liposarcoma Ifosfamide

Angiosarcoma Paclitaxel or Docetaxel or Liposomal DoxorubicinDesmoid Tumor Doxorubicin based or Methotrexate or Vinblastine or

Tamoxifen.

Soft Tissue Sarcoma:Biological Key Players & Possible Targets

Characteristic Chromosomal Translocation

Complex Karyotypes

• Overexpression of Growth Factors• Upregulation of Biological Cascades

++ Angiogenesis

Mahaling et al. Targeting sar- comas: novel biological agents and future perspectives. Curr Drug Targets. 2009;10:937–49.

Soft Tissue Sarcoma

• High Grade• Advanced Disease• Metastases

Tyrosine Kinase Receptors

VEGFR - 1 VEGFR - 2 VEGFR - 3 NRP - 1 NRP - 2

VEGFs

VEGF - A VEGF - B VEGF - C VEGF - D PlGF


VE

GFR

PI3K AKT

Grb SOS

mTOR

Protein Synthesis

HIF-1@Metabolism

Growth

Angiogenesis

RAS

RAF

Mek

Erk

Cell Cycle Progression & Proliferation

PDG

FR

1. Avastin [package insert]. South San Francisco, CA: Genentech; 2009. 2. Escudier B et al; TARGET Study Group. N Engl J Med. 2007;356:125-134. 3. Escudier B et al. J Clin Oncol. 2009;27:3312-3318. 4. Nexavar [package insert]. Wayne, NJ: Bayer

Healthcare Pharmaceuticals; 2007.

Bevacizumab

EverolimusSorafinib



Pazopanib PDGFRα & β

VEGFR1,2,3

Kit

Kumar R et al. Mol Cancer Ther 2007;6:2012; Sonpavde G & Hutson TE. Curr Oncol Rep 2007;9:115; GlaxoSmithKline. VOTRIENT® (pazopanib) SPC. 2012; 4. Kumar R et al. Br J Cancer 2009;101:1717.

Significant Anti-Angiogenic Effect

Matching placebo(n=123)

Registration trial; PALETTE phase III: Study design

Disease assessment • At week 4, 8, 12, 20 and at 8-week intervals thereafter

VOTRIENT* (800 mg QD)(n=246)

Secondaryendpoints

Primary endpoint

OS ORR QoL SafetyTTRDoR

PFS by independent review(RECIST v 1.0)

2:1n=369

RANDOMI ZE

DoR, duration of response; ORR, overall response rate; PFS, progression-free survival; QoL, quality of life; QD, once daily; RECIST, Response Evaluation Criteria in Solid Tumors; TTR, time to response

*Until disease progression, unacceptable toxicity, withdrawal of consent for any reason or deathVan Der Graaf W et al. Lancet 2012;19:1879)

PALETTE: Included/excluded histological subtypes

Included:1,2 ● Fibroblastic● Fibrohistiocytic● Leiomyosarcoma● Synovial sarcoma● Malignant peripheral nerve sheath

tumours● Sarcoma not otherwise specified (NOS)● Vascular STS● Malignant glomus tumours

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References: 1. Van Der Graaf W et al. Lancet 2012;19:1879; 2. Van Der Graaf W et al. ASCO 2011; abstract LBA10002: oral presentation.

Excluded:1,2 • Adipocytic sarcoma

• Osteosarcoma

• Inflammatory myofibroblastic sarcoma

• Chondrosarcoma

• Dermatofibrosarcoma protuberans

• Mixed mesodermal uterine tumour

• GIST

• Mesothelioma

• Ewing’s sarcoma/PNET

• Non-alveolar and non-pleiomorphic rhabdomyosarcoma

PALETTE: Patient demographics

PLACEBO (n=123)

PAZOPANIB (n=246)

AgeMedian (years) 51 56

Range (years) (18–78) (20–83)

Performance status (WHO)

0 60 (49%) 118 (48%)

1 63 (51%) 128 (52%)

Histology (by central pathology or local if unavailable)

Leiomyosarcoma 49 (40%) 109 (44%)

Synovial sarcoma 13 (11%) 25 (10%)

Other type 61 (49%) 112 (46%)

Grade at initial diagnosis (local)

I / low 3 (2%) 24 (10%)

II / intermediate 30 (24%) 63 (26%)

III / high 90 (73%) 159 (65%)

GlaxoSmithKline. Data on File. Study VEG110727. 2011. Available at: http://www.gsk-clinicalstudyregister.com

PALETTE: Prior systemic therapies

PLACEBO (n=123) PAZOPANIB (n=246)

Prior (neo)adjuvant therapy 45 (37%) 74 (30%)

Prior systemic therapy for advanced disease

1st line 110 (89%) 232 (94%)

2nd line 67 (54%) 132 (54%)

3rd line 28 (23%) 51 (21%)

4th line 9 (7%) 16 (7%)

Including: Doxorubicin 121 (98%) 242 (98%)

Ifosfamide 93 (76%) 164 (67%)

Gemcitabine 42 (34%) 85 (35%)

Docetaxel 35 (28%) 69 (28%)

Trabectedin 22 (18%) 38 (15%)

mTOR inhibitor(s) 3 (2%) 11 (4%)

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PALETTE: Median PFS nearly 3 times greater than placebo at 20 weeks

REGULATORY ANALYSISPLACEBO

(n=123)VOTRIENT

(n=246)Median PFS (weeks) 7.0 20.0

Median PFS (months) 1.6 4.6

Hazard ratio (95% CI) 0.35 (0.26, 0.48); p<0.001CI, confidence interval; PFS, progression-free survival

1.0

PlaceboVOTRIENT

Time since randomization (weeks)

Estim

ated

sur

viva

l fun

ctio

n

0.8

0.6

0.4

0.2

0.0

0 20 40 60 80 100

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PALETTE: Progression-free survival according to subgroup

Hazard ratio (95% CI)Favours pazopanib

Favours placebo

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

Primary analysis (n=369)

Prior lines 0/1 (n=162)

Prior lines 2+ (n=207)

WHO PS 0 at baseline (n=178)

WHO PS 1 at baseline (n=191)

Recruited from US (n=43)

Recruited from Europe and Australia (n=245)

Recruited from Japan and Korea (n=81)

Leimoyosarcoma (n=158)

Other STS histology (n=173)

Synovial sarcoma (n=38)


PALETTE: Progression-free survival by prior lines of treatment

Number of prior lines of therapy

Median PFS (weeks), 95% CI

Hazard ratio, 95% CI p valuePlacebo Pazopanib

0/1 (n=162)

7.6 (4.3, 9.1)

24.7 (19.6, 27.4)

0.31 (0.19, 0.50) <0.001

2+ (n=207)

6.1 (4.3, 8.1)

18.9 (11.9, 20.1)

0.39(0.26, 0.57) <0.001

Stratified log rank test and Pike estimator, independent reviewer, adjusted for WHO PS


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PALETTE: Overall survival

REGULATORY ANALYSISPLACEBO

(n=123)PAZOPANIB

(n=246)

Median OS (weeks) 46.5 54.8

Hazard ratio (95% CI) 0.87 (0.67, 1.12); p=0.256

CI, confidence interval; OS, overall survival

Placebo

Pazopanib

1.0

0.0

0.2

0.4

0.6

0.8

Estim

ated

sur

viva

l fun

ctio

n

0 5 10 15 20 25 30 35

Time since randomization (months)

Reference: GlaxoSmithKline. VOTRIENT® (pazopanib) SPC. 2014; Sharma S et al. BMC Cancer 2013;13:385. Additional file 4.

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PALETTE: Summary of best confirmed response by independent review

● The median time to response* by independent review in the pazopanib arm was 8.4 weeks (95% CI 4.7, 19.1)

● Median duration of response was 38.9 weeks (95% CI 16.7, 40.0) for pazopanib in the responder population

PLACEBO (n=123)

PAZOPANIB (n=246)

Response rate (complete response + partial response) 0 (0%) 11 (4%)

Partial response 0 (0%) 11 (4%)

Stable disease 33 (27%) 134 (54%)

Progression 76 (62%) 66 (27%)

* Time to response was defined as the time from the start of treatment until the first documented evidence of complete response or partial response, whichever status was recorded firstGlaxoSmithKline. Data on File. Study VEG110727. 2011. Available at: http://www.gsk-clinicalstudyregister.com

PALETTE: Adverse event overview

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PLACEBO(n=123)

PAZOPANIB(n=240)*

On-therapy AEs by maximum gradeAll Grades 110 (89%) 237 (99%)

Grade 3 23 (19%) 118 (49%)

Grade 4 7 (6%) 23 (10%)

Grade 5 4 (3%) 8 (3%)

All SAEs† 29 (24%) 99 (41%)

Fatal SAEs† 6 (5%) 8 (3%)

Discontinuations due to AEs‡ 3 (2%) 41 (17%)

Discontinuations due to drug-related AEs 1 (<1%) 34 (14%)

On-therapy treatment-related AEs (all grades) 78 (63%) 219 (91%)

AE, adverse event; SAE, serious adverse event

* Six patients (pazopanib arm) were excluded from safety population as they did not begin investigational product.† Includes off therapy SAEs‡ Primary reason for discontinuation


PALETTE: Newly identified serious adverse events

ON-THERAPY AND POST-THERAPY ADVERSE EVENTS

PLACEBO (n=123)

PAZOPANIB (n=240)

Any grade Grade 3 Grade 4

Any grade Grade 3 Grade 4

Myocardial dysfunction* 6 (5%) – – 21 (9%) 3 (1%) 1 (<1%)

Venous thromboembolic events† 3 (2%) 1 (<1%) 2 (1%) 13 (5%) 5 (2%) 1 (<1%)

Pneumothorax – – – 8 (3%) – 1 (<1%)

SAEs with a higher incidence in the pazopanib-treated aSTS population than in the pazopanib-treated aRCC population

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* Grouping of MedDRA terms, including left ventricular dysfunction, cardiac failure, restrictive cardiomyopathy and pulmonary oedema

† Fatal pulmonary embolus occurred in two of 240 patients treated with pazopanibGlaxoSmithKline. Data on File. Study VEG110727. 2011. Available at: http://www.gsk-clinicalstudyregister.com

PALETTE*:Health-related quality of life (HRQoL)

Patients receiving treatment with Pazopanib did not experience a clinically meaningful or statistically significant deterioration in HRQoL compared with

placebo (p=0.291)1,3

Adapted from Sharma S et al. 2013 - Additional file 4.2 HRQoL was measured using the EORTC QLQ-C30 Global Health Status/HRQoL score†For EORTC QLQ-C30, data were collected at baseline, week 4, week 8 and week 12.4 MID: Minimally important difference, 5 to 10. SE: Standard error. ITT: Intention to treat

1. van der Graaf W et al. Lancet 2012; 379: 1879-1886; supplementary appendix published online; 2. Sharma S et al. BMC Cancer 2013; 13: 385. Additional file 4; 3. Sharma S et al. BMC Cancer 2013; 13: 385; 4. FDA Oncology Drug Advisory Committee Briefing Document, March 2012. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM296303.pdf(Accessed February 2015)

*Phase III study excluded selective STS subtypes such as GIST and adipocytic sarcoma

Pazopanib (n=246)Placebo (n=123)

Change from baseline in health-related quality of life (HRQoL, ITT population) 1,2†

Take Home Message:

● Soft-tissue sarcoma (STS) is a rare disease that encompasses over 50 separate histological subtypes with varying sensitivity to systemic treatment

● Although Ifosfamide and doxorubicin remain important treatment options in STS, therapy is increasingly tailored towards different histological subtypes

● In post-Imatinib era; Targeted therapies such as tyrosine kinase inhibitors will become increasingly important as we further define the molecular basis of sarcomagenesis.

● Pazopanib is a recently approved option for advanced refractory STS with significant prolongation of PFS and perfect compliance.

● Clinical trials remain a challenge due to the rarity and heterogeneity of STS and international collaboration is critical to achieve high quality clinical trials stratified by histological subtype.

Thank You

Soft Tissue Sarcoma, Can we refine the approach

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