1 FINAL - Loong Sarcoma JSOF 29JUN19

Current Updates in the Systemic Management of
Soft-Tissue Sarcomas
Dr. Herbert Loong
MBBS, PDipMDPath, MRCP(UK), FRCP Edin, FHKCP, FHKAM(Medicine)
Clinical Assistant Professor, Department of Clinical Oncology

Deputy Medical Director, Phase 1 Clinical Trials Centre
Convenor, Adult Sarcoma Multidisciplinary Team
The Chinese University of Hong Kong
Email: h_loong@clo.cuhk.edu.hk | @herbloong |#CUHKSarcoma
Copyright © 2017. All Rights Reserved. Faculty of Medicine, The Chinese University of Hong Kong
Disclosures
Advisory: Boehringer-Ingelheim, Celgene, Eli-Lilly, Novartis, Merck

Sereno
Speakers’ Bureau: AbbVie, Bayer, Eisai, Eli-Lilly, Guardant Health, Novartis
Travel Support: Bayer, MSD, Novartis, Pfizer
Research Funding: MSD, Mundipharma, Novartis
Challenges of drug development in sarcomas
• Rare and heterogeneous
with over 50 subtypes
• Diagnosis can be
challenging even to the
experienced pathologist
• Lack of interest and

advocacy amongst the
oncology community
Brennan et al. Management of soft tissue
sarcoma: Springer 2013
• Common belief of “If not
operable then prognosis
is dismal” Taylor et al. Nat. Rev. Cancer 2011
Agenda
• Pitfalls of earlier and more recent sarcoma trials
• 2nd line trials making an impact to patients’ survival
• Immunotherapy and checkpoint inhibition in sarcomas – all

“hype” or is there some truth?
1. Pitfalls of earlier and
more recent sarcoma trials
1. Using a ‘Targeted Therapy’ in a non-targeted
manner
PALETTE: Pazopanib for Treating Metastatic Soft
Tissue Sarcoma
• International, randomized, double-blind, placebo-controlled phase III trial

Stratified by number
of previous lines of
therapy, WHO PS Treatment
continued until
Pts aged 18 yrs or older with Pazopanib 800 mg PO QD PD,
angiogenesis inhibitor-naive, (n = 246) unacceptable
metastatic STS and PD despite toxicity,
≤ 4 prior systemic therapies; withdrawal of
WHO PS = 0-1 Placebo PO QD consent, or
(N = 369) (n = 123) death; no
• Primary endpoint: PFS crossover
allowed
• Secondary endpoints: OS, RR, safety, QoL
van der Graaf WT, et al. Lancet. 2012;379:1879-1886.

100
Median PFS, Mos (95% CI)
80 PAZO 4.6 (3.7-4.8)
PBO 1.6 (0.9-1.8)
PFS (%)
60
HR: 0.31 (95% CI: 0.24-
40 0.40; P < .0001)
20
0
0 3 6 9 12 15 18 21 24
Mos
100
Median OS, Mos (95% CI)
80 PAZO 12.5 (10.6-14.8)
PBO 10.7 (8.7-12.8)
60
OS (%)
40
20 HR: 0.86 (95% CI: 0.67-

1.11; P = .2514)
0
0 3 6 9
12 15 18 21 24
Mos
van der Graaf WTA, et al. Lancet. 2012;379:1879-1886.
Teasing out the responders
• Potentially more promising results are still being diluted by ‘less-responding’

histologies Van der Graaf et al. Lancet 2012
Mir et al. Lancet Oncol 2016
Leiomyosarcoma
Liposarcoma
Synovial sarcoma

The same mistakes were still being made …
Courtesy of William Tap – as presented at ASCO 2019

Olaratumab

Doxorubicin +/- Olaratumab
Olaratumab in Soft Tissue Sarcoma

Progression-free Survival: tSTS and LMS Populations

Notable Difference Between the Phase 1b/2 and 3 Studies

Note:
Stratification ≠
individual
cohorts
No control on
number of
individual
histologies
Statistical and
trial setup only
has adequate
power to look at
Need to recognize that even LMS is Total STS and
heterogenous – uLMS vs. non uLMS also LMS

2019
ANNOUNCE
dox vs.
dox+Olaratumab
mOS 19.7 vs. 20.4 mo.
• Better supportive
care
• More 2nd line and

beyond options
• Recognition that
The OS of patients treated with doxorubicin have increased dramatically sarcomas are
throughout the years heterogenous
• Specialist centres &

MDT approach
2. Effective 2nd line
Therapies for sarcomas
Case 1 – Mr. CCM
Case 1: Mr. CCM – M/56
• Known history of severe aortic regurgitation
• Presented with haematuria to a private hospital in 6/2015.
• CT urogram: R distal ureteric stone. Multiple enhancing nodules in R side of mesentery, R
paracolic gutter and alongside R iliacus muscle
• MRI pelvis: multiple enhancing lesions seen over RLQ, in close relationship with caecum,
proximal distending colon, adjacent mesentery.
• Biopsy: high grade sarcoma, favours dedifferentiated LPS; CDK4 amplification+ve;
MDM2 amplification+ve
• MDT discussion  operable
• Wide resection done 9/2015 – margins clear
• Reassessment CT 12/2015 – multiple intra-abdominal recurrences, with largest in R

psoas region near tumour bed
Eribulin vs Dacarbazine for Advanced
Leiomyosarcoma and Liposarcoma
• Randomized, open-label, multicenter, active-controlled, phase III trial
Pts aged 18 yrs or

older with locally Eribulin 1.4 mg/m2 IV Day 1, 8 Q3W
recurrent/advanced (n = 228) Treatment
or metastatic LMS or continued
LPS and ≥ 2 prior until PD
Dacarbazine 850-1200 mg/m2 IV Day 1 Q3W
systemic therapies;
(n = 224)
ECOG PS 0-2
(N = 452)
• Primary endpoint: OS
• Secondary endpoints: PFS, PFS rate at Wk 12, safety
Schöffski P, et al. Lancet. 2016
Eribulin vs Dacarbazine: Key Results
Outcomes, Mos Eribulin Dacarbazine HR P Value

(n = 228) (n = 224) (95% CI)
0.77
Median OS 13.5 11.5 (0.62-0.95) .0169
0.88
Median PFS 2.6 2.6 .2287
(0.71-1.09)
 Subgroup analysis showed activity of eribulin in liposarcoma
Median OS by Histologic
Eribulin Dacarbazine HR (95% CI)
Subgroup, Mos (Events/Pts)
Liposarcoma 15.6 (52/71) 8.4 (63/72) 0.51 (0.35-0.75)
Leiomyosarcoma 12.7 (124/157) 13 (118/152) 0.93 (0.71-1.20)
 Rate of grade ≥ 3 TEAEs higher with eribulin vs dacarbazine (67% vs 56%)
Schöffski P, et al. Lancet. 2016

Planned LPS Subgroup Analysis
Demetri et al. JCO 2017

CCM – M/56 – Metastatic Dedifferentiated LPS
12 cycles of eribulin with good tolerance
CCM – M/56 – Metastatic Dedifferentiated LPS
Returned last week for Cycle 43 …
12 cycles of eribulin with good tolerance
Case 2 – Mr. LKW
Case 2: Mr. LKW
• M/39
• Myxoid liposarcoma (with 5% round-cell component) of R thigh with WLE and vascular
reconstruction in 11/2011
• Post-op adjuvant RT and doxorubicin+ifosfamide completed 6/2012
• Lung, chest wall and pericardial metastases in 5/2014
• L VATS + excision of pericardiac and chest wall mass done 5/2014
– Path – myxoid LPS
– Chest wall margins clear
– Pericardiac masses no margins to speak of (piecemeal resection)
• “Pseudo-adjuvant” chemo with gemcitabine+docetaxel x 6 cycles
• PET-CT 2/2015 – No uptake
• PET-CT 9/2015 - Developed R abdominal wall deposit, recurrent chest wall masses and
progressive lesions in pericardium  3DRT to chest and abdominal wall, followed by L
thoracotomy and debulking surgery 3/2016
PET-CT 6/2016
CXR 6/2016 CXR 9/2016 CXR 12/2016
Serial CXR whilst on eribulin
CXR 12/2016 CXR 7/2017
Continued Eribulin for 17 cycles … but latest CXR
CXR 7/2017 What is the drug X CXR 9/2017
that was given?
Trabectedin vs Dacarbazine for Advanced
Liposarcoma or Leiomyosarcoma
 International, randomized, open-label, active-controlled,
parallel-group phase III trial
Pts aged 15 yrs or older
with unresectable locally
advanced or metastatic Trabectedin* 1.5 mg/m2 IV Day 1 Treatment
liposarcoma or (n = 345) repeated Q3W
leiomyosarcoma despite until PD or
prior anthracycline Dacarbazine 1.0 g/m2 IV Day 1 unacceptable
therapy; ECOG PS 0-1 (n = 173) toxicity
(N = 518)
*Administered after premedication with dexamethasone 20 mg IV.
 Primary endpoint: OS
 Secondary endpoints: PFS, TTP, ORR, DoR, safety
Demetri GD, et al. J Clin Oncol. 2016;34:786-793.
Trabectedin vs Dacarbazine: Efficacy
Trabectedi Dacarbazin
Endpoint n e HR (95% CI) P Value
(n = 345) (n = 173)
Median
12.4 12.9 0.87 .37
OS, mos*
Median 0.55
PFS, mos 4.2 1.5 (0.44-0.70) < .001
0.52
TTP, mos 4.2 1.5 < .001
(0.41-0.66)
ORR, n (%) 34 (10) 12 (7) 1.47 .33

(0.72-3.2)
DoR, mos 6.5 4.2 0.47 .14

(0.17-1.32)
*Interim analysis, 64% censored.
Trabectedin vs Dacarbazine: PFS by Histologic
Subtype
Histologic Subtype Trabectedin, Dacarbazine, HR (95% CI)
Median PFS, Mos Median PFS,
(Events/Pts) Mos (Events/Pts)
Leiomyosarcoma 4.3 (154/252) 1.6 (85/126) 0.55 (0.42-0.73)

 Nonuterine 4.9 (70/118) 1.6 (28/48) 0.58 (0.37-0.92)
 Uterine 4.0 (84/134) 1.5 (57/78) 0.58 (0.41-0.81)
Liposarcoma 3.0 (63/93) 1.5 (27/47) 0.55 (0.34-0.87)
 Dedifferentiated 2.2 (35/45) 1.9 (16/25) 0.68 (0.37-1.25)
 Myxoid ± round cell 5.6 (21/38) 1.5 (8/19) 0.41 (0.17-0.98)
 Pleomorphic 1.5 (7/10) 1.4 (3/3) 0.33 (0.07-1.64)
Trabectedin vs Dacarbazine: Safety
Trabectedin (n = 340) Dacarbazine (n = 155)
Adverse Event, %
Grade 3 Grade 4 Grade 3 Grade 4
Nausea 5 0 2 0
Fatigue 6 0 1 1
Neutropenia 21 16 11 10
ALT increase 25 1 1 0
AST increase 12 1 0 0
Vomiting 5 0 1 0
Anemia 14 0 11 1
Thrombocytopenia 8 9 10 8
Grade 3/4 adverse events occurring with ≥ 5% frequency.
Dosing of Trabectedin in Asians?
• Traditional 3+3 design, n=15

• MTD was determined at
1.5mg/m2 Q3W
• RP2D was 1.2mg/m2 Q3W
• Current dose in Japan is
1.2mg/m2 Q3W
3. Immunotherapy & Checkpoint
Inhibition in STS – “hype” or “truth”
Recent immunotherapy trials in sarcomas
1. Single-agent
Checkpoint
Pembrolizumab
Adapted from Immunity 2013 39, 1-10DOI: (10.1016/j.immuni.2013.07.012)

SARC028 – Single-agent pembrolizumab
• Soft tissue sarcomas (n=40)*

– Leiomyosarcoma (n=10)
– Undifferentiated pleomorphic sarcoma
(n=10)
– Liposarcoma (n=10)
– Synovial sarcoma (n=10)
• Bone sarcomas (n=40)
– Chondrosarcoma (n=5)
– Ewing’s sarcoma (n=13)
– Osteosarcoma (n=22)
*STS cohorts of the 4 histologies were capped at 10 each
Copyright © 2017. All Rights Reserved. Faculty of Medicine, The Chinese University of Hong Kong Tawbi et al. Lancet Oncol 2017
SARC028 – Response (Soft-tissue sarcomas)
• Sustained objective responses in 7/40 STS pts (18%)

• 12 wk PFS = 55%
• 6 / 7 objective responses were seen in pts with UPS or liposarcoma
Copyright © 2017. All Rights Reserved. Faculty of Medicine, The Chinese University of Hong Kong Tawbi et al. Lancet Oncol 2017
Recent immunotherapy trials in sarcomas
1. Single-agent
Checkpoint
e.g.
Pembrolizumab
2. Dual
Checkpoint
inhibition
e.g. Nivolumab &

Ipilimumab
Adapted from Immunity 2013 39, 1-10DOI: (10.1016/j.immuni.2013.07.012)

Dual Checkpoint Inhibition in metastatic sarcomas
D’Angelo et al. Lancet Oncol 2018

More durable responders on dual inhibition
Nivolumab Ipilmumab + nivolumab

Ipilimumab + Nivolumab – PFS 4.1months, OS
Nivolumab – PFS 2.1months, OS 10.7months
14.3months

“Million-dollar question” – Who are these
responders?
Do we have effective predictive markers of response to CPI?

Are there any potential risks of giving CPIs indiscriminately?
“Real-World”
Retrospective Series
• Retrospective review of >6000

sarcoma cases sent to
Foundation Medicine
• TMB-high (>/= 10 mutations/mb)

• MSI-High
• Genomic amplification of PDL1
Trabucco … Gounder et al. ASCO 2018

“Real-World”

Foundation Medicine

• MSI-High
• Genomic amplification
Huge variations of PDL1
between
different sarcoma histologies!

“Real-World”

Foundation Medicine

• MSI-High
• Genomic amplification of PDL1 No obvious concordance between
high TMB and PDL1 amplification and
MSI status

Do not be fooled though!

Even the histology with the highest number of

TMB >/= 10 mutations/mb
“Angiosarcoma – n=169”
= ~ only 15% of samples!

All TMB highs are

OUTLIERS in their group
of histologies!

Hyper-progressors on single-agent CPI?
• Hyper-progressors defined as1:
– “time-to-treatment failure” < 2
months
– > 50% increase in tumour burden
compared with pre-IO imaging
– >2-fold increase in progression pace
• MDM2 / MDM4 amplifications
and EGFR aberrations appear to
be associated with this
phenomenon
1. Kato … Kurzrock Clin Cancer Res 2017

The bottom line …
We need effective
biomarkers!
Without which we will just hit a
http://protomag.com/articles/problem-with-biomarkers
Do you have anything positive to say
about checkpoint inhibition for
sarcomas?
ASPS – A unique histology with exquisite sensitivity
to checkpoint inhibition?
• Accounts for 0.1% of all sarcomas (1% of all cancers – i.e. 0.001% of all cancers)
• Characteristic chromosome X and 17 translocation creating novel ASPL-TFE3

fusion protein
• Distinctively chemo- and radio-resistant
• Natural tempo maybe relatively indolent on presentation, followed by rapid growth
• Propensity for lung and CNS metastases
• Surgery as mainstay of treatment in localized disease
• Metastatic disease  VEGFR inhibitors

http://www.histopathology-india.net/AlveolarSoftPartSarcoma.htm
CTOS 2018 | Slides courtesy of O’Sullivan Coyne et al
Efficacy Endpoints of Atezolizumab in ASPS
Best Response Time on Treatment
CR 0 01
04
PR 02
confirmed 8 06
unconfirmed 1 05
07
11
SD 9
Patient Number
09
PD 1 16
15
Too Early to Assess 3 17

12
Best response:
• Observed response rate: 42% (8/19)
08
*
18 PR
• 95% confidence that the true 19
SD
response rate is >23% 03
20
PD
• Median time to first response: 14
* ǂ
5 cycles (range, 4-19 cycles) 10
• Median time on treatment: 0 2 4 6 8 10 12 14 16 18 20

Months
11 cycles (range, 1-25 cycles)
* Patient chose to withdraw from study.
CTOS 2018 | Slides courtesy of O’Sullivan Coyne et al
ǂ
Unconfirmed PR.
Conclusions
• Sarcomas are a heterogenous group of diseases requiring specialist care for optimal treatment
outcome
• Cytotoxic chemotherapy remains the backbone of advanced sarcoma treatment
• Effective 2nd line and beyond therapies are contributing to improving outcomes
• Recognition of individual behaviours of distinct types of sarcomas and their responses to

different treatments is of paramount importance
• The role of checkpoint inhibition in sarcomas is not confirmed, except for specific subgroups
(e.g. ASPS)
• Discovery of predictive biomarkers to systemic treatments (cytotoxics and IOs) is a matter of top
research priority!
Public & Professional Sarcoma Education
@ CUHK
#cuhksarcoma

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Current Updates in the Systemic Management of

Clinical Assistant Professor, Department of Clinical Oncology

Email: h_loong@clo.cuhk.edu.hk | @herbloong |#CUHKSarcoma

Advisory: Boehringer-Ingelheim, Celgene, Eli-Lilly, Novartis, Merck

Speakers’ Bureau: AbbVie, Bayer, Eisai, Eli-Lilly, Guardant Health, Novartis

Travel Support: Bayer, MSD, Novartis, Pfizer

Research Funding: MSD, Mundipharma, Novartis

• Lack of interest and

• 2nd line trials making an impact to patients’ survival

• Immunotherapy and checkpoint inhibition in sarcomas – all

• International, randomized, double-blind, placebo-controlled phase III trial

van der Graaf WT, et al. Lancet. 2012;379:1879-1886.

20 HR: 0.86 (95% CI: 0.67-

• Potentially more promising results are still being diluted by ‘less-responding’

Mir et al. Lancet Oncol 2016

Courtesy of William Tap – as presented at ASCO 2019

Courtesy of William Tap – as presented at ASCO 2019

Courtesy of William Tap – as presented at ASCO 2019

Courtesy of William Tap – as presented at ASCO 2019

Courtesy of William Tap – as presented at ASCO 2019

Courtesy of William Tap – as presented at ASCO 2019

• More 2nd line and

• Specialist centres &

• Reassessment CT 12/2015 – multiple intra-abdominal recurrences, with largest in R

Pts aged 18 yrs or

Outcomes, Mos Eribulin Dacarbazine HR P Value

Schöffski P, et al. Lancet. 2016

Demetri et al. JCO 2017

12 cycles of eribulin with good tolerance

Returned last week for Cycle 43 …

12 cycles of eribulin with good tolerance

Serial CXR whilst on eribulin

*Administered after premedication with dexamethasone 20 mg IV.

ORR, n (%) 34 (10) 12 (7) 1.47 .33

DoR, mos 6.5 4.2 0.47 .14

Leiomyosarcoma 4.3 (154/252) 1.6 (85/126) 0.55 (0.42-0.73)

Demetri GD, et al. J Clin Oncol. 2016;34:786-793.

• Traditional 3+3 design, n=15

Adapted from Immunity 2013 39, 1-10DOI: (10.1016/j.immuni.2013.07.012)

• Soft tissue sarcomas (n=40)*

*STS cohorts of the 4 histologies were capped at 10 each

• Sustained objective responses in 7/40 STS pts (18%)

e.g. Nivolumab &

Adapted from Immunity 2013 39, 1-10DOI: (10.1016/j.immuni.2013.07.012)

D’Angelo et al. Lancet Oncol 2018

D’Angelo et al. Lancet Oncol 2018

D’Angelo et al. Lancet Oncol 2018

Do we have effective predictive markers of response to CPI?

• Retrospective review of >6000

• TMB-high (>/= 10 mutations/mb)

Trabucco … Gounder et al. ASCO 2018

• Retrospective review of >6000

• TMB-high (>/= 20 mutations/mb)

Trabucco … Gounder et al. ASCO 2018

• Retrospective review of >6000

• TMB-high (>/= 10 mutations/mb)

Trabucco … Gounder et al. ASCO 2018

Trabucco … Gounder et al. ASCO 2018

Even the histology with the highest number of

= ~ only 15% of samples!

Trabucco … Gounder et al. ASCO 2018

All TMB highs are

Trabucco … Gounder et al. ASCO 2018