Medical Department

Oncology Business Unit

Targeted Therapy for

Advanced Soft Tissue
Sarcoma
dr Albertus Agung Mahode
Medical Advisor – Solid Tumor
Disclaimers

• This scientific material includes data on an indication that has not

been approved or cleared for use by regulatory authority. This
information is not intended to be promoting or recommending any
indication, dosage or other claim not covered in the licensed
product information.
• Novartis does not support the promotion of its products in a
manner inconsistent with its approved labeling.

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2
 Joglosemar Breast Cancer Oncology Summit 2017, Jogjakarta

Pazopanib Treatment for

Advanced Soft Tissue Sarcoma
 Pazopanib in advanced STS

• Strong rationale for targeting Endothelial Cell/

Blood Vessel2
VEGFR and PDGFR pathways
in STS Pazopanib PDGFR-b

• Inhibiting both VEGF and PDGF

pathways simultaneously may be VEGFR
more effective at inhibiting tumor VEGF, PDGF Ras
angiogenesis than targeting either production
Raf
pathway alone Tumor Cell
MEK
• Pazopanib is a selective oral
ERK
inhibitor of VEGFR-1, -2 and -3, VEGF, PDGF
production
PDGFR-α and -β, and c-Kit Vascular cell growth,
angiogenesis,
Nucleus migration

1. Votrient (pazopanib) [summary of product characteristics]. Brentford, United Kingdom: GlaxoSmithKline Pharmaceuticals; 2014.
2. Li L, Kaelin WG Jr. New insights into the biology of renal cell carcinoma. Hematol Oncol Clin North Am. 2011;25(4):667-686.

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 Phase 2 Trial of Pazopanib in Advanced STS
Four Patient Cohorts Were Included

Treatment phase Follow-up

Futility
Stage 1 Analysis Stage 2
EORTC 62043
Leiomyosarcoma Leiomyosarcoma

progression-free at Week 12
NCT00297258

Stop if ≤ 3 of 17 subjects in
(n=17) (additional n≈20) Follow-up
• ≥18 years old for PD

stage 1 are alive and

• Advanced STS Adipocytic tumors Adipocytic tumors
incurable by (n=17) (additional n≈20)
surgery or Follow-up
radiotherapy Synovial sarcoma Synovial sarcoma for survival
• Ineligible for
(n=17) (additional n≈20)
chemotherapy
or received ≤2 Other STS Other STS
prior cytotoxic
agents (n=17) (additional n≈20)
• WHO PS ≤1
WD due to AE

Treatment discontinued Experience PD

in either stage when
patients. . . Death on treatment
End of study
• Pazopanib 800 mg was administered orally, once daily WD consent
• Primary endpoint was progression-free rate at 12 weeks
AE, adverse event; EORTC, European Organisation for Research and Treatment of Cancer; PD, progressive disease; PFR, progression-free rate; PS, performance status;
STS, soft tissue sarcoma; WD, withdrawal; WHO, World Health Organization.
Sleijfer S, et al. J Clin Oncol. 2009;27:3126-3132.
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 Treatment Success Was Defined as Patients
Alive at 12 Weeks Without Disease Progression

Synovial
Leiomyosarcoma Liposarcoma Sarcoma Other Sarcoma
(n = 41) (n = 19) (n = 37) (n = 41)
PFR at 12 weeks, n (%) 18 (44) 5 (26) 18 (49) 16 (39)

Best overall response, n

PR 1 0 4 1
SD 17 5 14 15
PD 21 13 14 23

Early death, n 1 1 3 2

Not evaluable, n 1 0 1 0

Clinical progressive disease, 0 0 1 0

n

PD, progressive disease; LPS, liposarcoma; PFR, progression-free rate; PR, partial response; SD, stable disease.
Adapted from Sleijfer S, et al. J Clin Oncol. 2009;27:3126-3132.

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 Phase 3 Trial of Pazopanib in Advanced STS
(PALETTE)

EORTC 62072 Pazopanib

NCT00753688 800 mg PO QD Primary Endpoint
Phase 3, N=369 (n = 246) • PFS
• ≥18 years old R Secondary Endpoints
• Metastatic STSa and 2:1 • OS
progressive disease • Response rate
within 6 months Placebo
before start of study • QoL
(n = 123)
• WHO PS ≤1
• Prior treatment with
≤4 lines of systemic
therapy for metastatic
• Stratification
disease including at  Previous lines of therapy (0 or 1 vs 2+)
least 1 anthracycline  WHO PS (0 vs 1)

EORTC, European Organisation for Research and Treatment of Cancer; OS, overall survival; PFS, progression-free survival; PO, orally; PS, performance status; QD, once
daily; QoL, quality of life; STS, soft tissue sarcoma; WHO, World Health Organization.
a The most common histologic types of STS were allowed; excluded subtypes included all types of liposarcoma, embryonal rhabdomyosarcoma, chondrosarcoma,

osteosarcoma, Ewing tumors, primitive neuroectodermal tumor, gastrointestinal tumor, dermatofibrosarcoma protuberans, inflammatory myofibroblastic sarcoma, malignant
mesothelioma, and mixed mesodermal tumors of the uterus.
1. van der Graaf WTA, et al. Lancet. 2012;379:1879-1886.

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 Pazopanib Significantly Improved PFS by
3 Months Compared With Placebo

100 Median progression-free survival, months (95% CI) 100 Median overall survival, months (95% CI)
Progression-Free Survival, %

90 90
Pazopanib 4.6 (3.7-4.8) Pazopanib 12.5 (10.6-14.8)
80 1.6 (0.9-1.8) 80 10.7 (8.7-12.8)

Overall Survival, %
Placebo Placebo
70 70
HR=0.31 (95% CI: 0.24-0.40) HR=0.86 (95% CI: 0.67-1.11)
60 P<0.0001 60 P=0.2514
50 50
40 40
30 30
20 20
10 10
0 0
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
Time, months Time, months
Number at risk Number at risk
Placebo 123 15 6 1 0 0 0 0 Placebo 123 103 87 70 55 40 37 24
Pazopanib 246 103 63 30 12 4 1 1 Pazopanib 246 216 185 149 119 103 87 57

CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.
Reprinted from van der Graaf WTA, et al. Lancet. 2012;379:1879-1886.

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 PALETTE: Summary of best confirmed
response by independent review
PLACEBO PAZOPANIB
(n=123) (n=246)
Response rate (complete
0 (0%) 11 (4%)
response + partial response)
Partial response 0 (0%) 11 (4%)

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

Progression 76 (62%) 66 (27%)

• 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
* 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 first
GlaxoSmithKline. Data on File. Study VEG110727. 2011. Available at: http://www.gsk-clinicalstudyregister.com
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 Most Common AEs With Pazopanib Were Fatigue,
Diarrhea, Nausea, Weight Loss, and Hypertension

Adverse Events (AEs) Occurring in ≥ 10% of Patients

Pazopanib (n = 239) Placebo (n = 123)
Adverse Event, n (%) All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
Fatigue 155 (65) 30 (13) 1 (<1) 60 (49) 6 (5) 1 (1)
Diarrhea 138 (58) 11 (5) 0 20 (16) 1 (1) 0
Nausea 129 (54) 8 (3) 0 34 (28) 2 (2) 0
Weight loss 115 (48) 0 0 25 (20) 0 0
Hypertension 99 (41) 16 (7) 0 8 (7) 4 (3) 0
Anorexia 95 (40) 14 (6) 0 24 (20) 0 0
Hair hypopigmentation 92 (38) 0 0 3 (2) 0 0
Vomiting 80 (33) 8 (3) 0 14 (11) 1 (1) 0
Dysgeusia 64 (27) 0 0 5 (4) 0 0
Rash or desquamation 43 (18) 1 (<1) 0 13 (11) 0 0
Mucositis 29 (12) 3 (1) 0 4 (3) 0 0

• The most relevant laboratory abnormalities for pazopanib were increased

concentrations of liver enzymes
Reprinted from van der Graaf WTA, et al. Lancet. 2012;379:1879-1886.

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 Subgroup analysis: 22.1% (76/344) of Patients
Were Both Long-Term Responders and Survivors
100 100
90 90
Progression-Free Survival, %

Combined median PFS: Combined median OS:

80 80
4.4 months (95% CI, 3.5-4.7) 11.7 months (95% CI, 10.6-13.6)

Overall Survival, %
70 70
60 60
50 50
40 Cut-off for long-term response 40 Cut-off for long-term survival
30 30
20 20
10 10
0 0
0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Time, months Time, months
Number 344 124 46 24 12 5 2 1 Number 344 265 163 116 61 24 9 4
at risk at risk

• 124 patients (36%) had PFS ≥6 months and were defined as long-term
responders (CR, PR, and SD)
• 116 patients (34%) had OS ≥18 months and were defined as long-term survivors
CI, confidence interval; CR, complete response; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease.
Adapted from Kasper B, et al. Ann Oncol. 2014;25:719-724.

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 PFS Benefit Was Associated With Maintained
HRQoL

• Assessed using the 30-item EORTC QoL questionnaire (EORTC

QLC-C30) at baseline and at weeks 4, 8, and 12
Change in Mean Global Health Status Score

100
90
80
70
60
50
40
30
20
10 Treatment arm Placebo Pazopanib
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Time, weeks

EORTC, European Organisation for Research and Treatment of Cancer; HRQoL, health-related quality of life; PFS, progression-free survival; QoL, quality of life.
Reprinted from Coens C, et al. Cancer. 2015;121:2933-2941.

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 Efficacy and Safety of Pazopanib in Japanese
Patients Is Consistent With Clinical Trial Data
Histologic subtype n Median PFS
1.0 All 446 3.5
Leiomyosarcoma
Synovial sarcoma
140
30
3.3
4.9
• Median duration
0.8
of treatment:
Progression-Free Survival

Liposarcoma
r 80 3.0
Other 196 3.5
0.6
3.4 months
• Average daily
0.4
All
pazopanib dose:
Leiomyosarcoma 562.1 mg
0.2 Synovial sarcoma
Liposarcoma
r
Other
0.0
0 3 6 9 12
Time, months

• Treatment-related AEs were reported in 444 of 539 patients (82.4%), with

no differences between histologic subtypes
AE, adverse event; PFS, progression-free survival.
Reprinted from Kawai A, et al. ESMO 2015. Abstract 3438 [poster].

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Safety and Efficacy of Pazopanib (PAZ) in Advanced Soft Tissue Sarcoma (aSTS) by
Prior Lines of Therapy, Age, and Dose Modifications: PALETTE Subgroup Analyses
Le Cesne (Abstract # 1501P) ESMO 2017. Poster
Objectives
• To evaluate the safety and efficacy of PAZ in the subgroups of age, prior lines of therapy, dose intensity, and dose modifications
Methods
• Phase 3 trial of PAZ vs placebo in pts with aSTS (progressed during or following prior chemotherapy)

Phase 3 (N=369) PAZ

(800 mg PO QD) Primary Endpoint
 18 years old
(n = 246) • PFS
 Metastatic STS and PD within 6 mo before start of study R

 WHO PS ≤ 1
2:1 Secondary Endpoints
Placebo • OS, RR, QoL
 Prior Tx with ≤4 lines of systemic therapy including at (n = 123)
least 1 anthracycline

Pazopanib, mPFS, Pazopanib, mOS,

Results Subgroups N
weeks (95% CI) months (95% CI)
• A total of 246 pts received PAZ during the study, and
majority of the pts received PAZ in the range of 600 to Lines of therapy
1 prior line 110 24.7 (19.6-27.4) 13.7 (95% CI, 9.2-17.1)
800 mg daily
11.3 (95% CI, 10.3-
• mPFS was highest in the 4 pts in the lower dose range of 2+ prior lines 136 18.9 (11.9-20.1)
14.5)
400 to 600 mg daily Age
• mPFS was higher in pts who received dose reductions or <65 y (range: 18-64) 184 20.0 (17.9-22.0) -
≥65 y (range: 65-83) 62 20.1 (11.7-31.6) -
dose interruptions to manage toxicities
Dose reduction
• Patients sub grouped by age has reported similar AEs No dose reduction 154 11.9 (8.9-19.3) -
and SAEs ≥1 dose reduction 92 27.7 (21.1-35.7) -
- AEs leading to study discontinuation were higher in Dose interruption
No dose interruption 107 11.0 (8.1-19.3) -
≥65-yrs versus the < 65-yrs age group (30% vs 17%,
≥1 dose interruption 139 21.3 (20.1-27.7) -
respectively)
Author’s Conclusions
• Patients receiving PAZ following only 1 line of therapy had longer mPFS compared with 2+ lines of prior therapy
• mPFS with PAZ was maintained irrespective of age or dose modification
• There was no evidence that dose modification to manage toxicity negatively impacted mPFS
AE, adverse events; aSTS, advanced soft tissue carcinoma; CI, confidence interval; mo, month; mPFS, median progression-free survival; OS, overall survival; PAZ, pazopanib;
PS, performance status; pts, patients; QoL, quality of life; RCC, renal cell carcinoma; RR, response rate; Tx, treatment; y, years

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 15

Medical Department | Oncology Business Unit

 Joglosemar Breast Cancer Oncology Summit 2017, Jogjakarta

Imatinib Treatment for

Unresectable or Metastatic GIST
 GIST: KIT Mutations

• Mutant forms of KIT are constitutively active3

• Knock-in mice studies with KIT mutations showed4:
– Constitutive KIT signaling is sufficient to induce GIST
– Parallel pathology is seen with familial KIT mutations (eg, mastocytosis)
• Microscopic GIST are thought to be common in the general
population5–7
– Some micro-GIST harbor mutations in KIT or PDGFRα genes
– Genetic events that transform these micro-GIST into clinically important
disease are not well understood

The most common genetic abnormality in

GIST is mutation of the tyrosine kinase KIT
1. Corless CL et al. Annu Rev Pathol. 2008;3:557-586. 5. Agaimy A et al. Am J Surg Pathol. 2007;31:113-120.
2. Heinrich CM et al. J Clin Oncol. In press. 6. Kawanowa K et al. Hum Pathol. 2006;37:1527-1535.
3. Hirota S et al. Science. 1998;279:577-580. 7. Abraham SC et al. Am J Surg Pathol. 2007;31:1629-1635.
4. Sommer G et al. Proc Natl Acad Sci U S A.2003;100:6706-6711.
Medical Department | Oncology Business Unit
 Normal KIT Signaling

A substrate protein
(e.g. PI3 kinase) is
phosphorylated by
Substrate
KIT kinase1,2

Effector
Kinase
domains
Activation of the substrate P
initiates a signaling cascade,
ADP
culminating in cell PPP
proliferation and survival1,2 ATP
PPP
ADP, adenosine diphosphate; ATP, adenosine triphosphate.
1. Savage DG et al. N Engl J Med. 2002;346:683-693.
2. Scheijen B et al. Oncogene. 2002;21:3314-3333. SIGNALING
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 Inhibition of KIT Signaling by Imatinib

The ATP binding pocket of

the KIT kinase domain
is occupied by
imatinib1
Substrate phosphorylation
is prevented and
signaling is inhibited1 Kinase
With signaling inhibited, domains
proliferation and
survival are
interrupted1,2 P
ATP
PPP
Imatinib
1. Savage DG et al. N Engl J Med. 2002;346:683-693. mesylate SIGNALING
2. Scheijen B et al. Oncogene. 2002;21:3314-3333.

Medical Department | Oncology Business Unit

 20

Medical Department | Oncology Business Unit

 Key Studies of Imatinib in Metastatic or
Unresectable GIST: Overview
• All 3 randomized, open-label, multicenter trials evaluated efficacy and safety of continuous
imatinib in patients with metastatic or unresectable KIT+ GIST
Studies Study Design Primary Secondary
Endpoint Endpoint
Phase II

B2222 400 mg/d (n=73) vs Response Time to treatment

(N=147)1 600 mg/d (n=74) rates failure, survival, PK,
(CR/PR) and safety
EORTC 62005 400 mg/d (n=473) vs PFS OS, response to
(N=946)2
Phase III

800 mg/d (n=473) treatment, and

toxicity
Intergroup S0033 400 mg/d (n=345) vs PFS and OS Response rates and
(N=694)3,4 800 mg/d (n=349) toxicity
CR, complete response; PFS, progression-free survival; PK, pharmacokinetics; PR, partial response; OS, overall survival.

• The Phase II B2222 trial was the pivotal study, leading to accelerated approval in
2002
• Data from the confirmatory Phase III studies (EORTC 62005 and S0033) were pooled
(called the MetaGIST analysis) and added to the label in 2008
1. Demetri GD et al. N Engl J Med. 2002;347:472–480.
2. Verweij J et al. Lancet. 2004;364:1127–1134.
3. Blanke CD et al. J Clin Oncol. 2008;26:626–632.
4. Blanke C et al. Eur J Cancer. 2011;47(suppl 1):abstr 9404.
Medical Department | Oncology Business Unit
 Pivotal Multicenter US-Finland
Study B2222: Study Design
• Imaging was performed with CT scanning or MRI
• PET imaging was performed at the discretion of the investigator

Glivec
Histologic criteria of (400 mg/d)
GIST with KIT+
staining Continue to treat as long
Metastatic and/or as patient benefits and
unresectable PD
drug-related safety
disease
No concomitant concerns are absent
therapy
(N=147) Glivec
(600 mg/d)

• Primary Endpoint: Response rate with Glivec in patients with GIST

• Secondary Endpoints
– Pharmacokinetic profile; time to treatment failure; survival; safety
Medical Department | Oncology Business Unit
CT, computed tomography; MRI, magnetic resonance imaging.
Demetri GD et al. N Engl J Med. 2002;347:472-480.
 Pivotal Phase II (B2222) Trial: Partial Response
Was the Most Common Best Observed Tumor
Response
(Primary Endpoint)
400 mg/d 600 mg/d
(n=73) (n=74)
70 69 65
60
50
Patients, %

40
30
18
20 14
10 3
0
0
CR PR SD CR PR SD
63 Months’ Median Follow-up

Approximately two-thirds of patients

achieved PR or better in both dose groups
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Blanke CD et al. J Clin Oncol. 2008;26:620–625.
 Pivotal Phase II (B2222) Trial: High Rates of OS
Were Observed With Both Doses of Glivec

400 mg
600 mg
Pooled

63 Months Median Follow-up

Median OS for the total population was 57 months

No significant difference between the two study arms was observed (P=.5506)

Medical Department | Oncology Business Unit

Adapted with permission of Blanke CD et al. J Clin Oncol. 2008;26:620-625.
 Pivotal Phase II (B2222) Trial: OS Was
Equivalent in Patients Who Achieved PR or SD
PR
SD
PD

63 Months Median Follow-up

Estimated 5-year survival was higher for patients with

PR or SD (55%) than patients with PD on Glivec (9%)

Medical Department | Oncology Business Unit

CI, confidence interval; LL, lower limit; N/A, not available; UL, upper limit.
Adapted with permission of Blanke CD et al. J Clin Oncol. 2008;26:620-625.
 Pivotal Phase II (B2222) Trial: Safety and
Overall Summary
Most common drug-related AEs (occurring Glivec 400 mg Glivec 600 mg
in ≥10% of patients in either group) (n=73) (n=74)
Grade  Any 3/4 Any 3/4
Any AE, n (%) 71 (97.3) 15 (20.5) 73 (98.6) 16 (21.6)
Edema or fluid retention 52 (71.2) 1 (1.4) 57 (77.0) 1 (1.4)
Nausea 37 (50.7) 1 (1.4) 40 (54.1) 1 (1.4)
Diarrhea 29 (39.7) 1 (1.4) 37 (50.0) 2 (2.7)
Myalgia or musculoskeletal pain 27 (37.0) 0 31 (41.9) 0
Fatigue 22 (30.1) 0 29 (39.2) 0
Abdominal pain 19 (26.0) 1 (1.4) 19 (25.7) 0
Dermatitis or rash 18 (24.7) 2 (2.7) 27 (36.5) 2 (2.7)
Headache 14 (19.2) 0 24 (32.4) 0
Flatulence 14 (19.2) 0 18 (24.3) 0

B2222 results show Glivec (400 mg or 600 mg daily) is highly active resulting in
durable responses in KIT+ unresectable and/or metastatic GIST
Confirmatory trials (EORTC 62005 and Intergroup S0033) evaluated long-term
outcomes of Glivec (400 mg or 800 mg daily) in this patient population

Medical Department | Oncology Business Unit

Demetri GD et al. N Engl J Med. 2002;347:472-480.
Thank you