Novel Therapeutics in Chondrosarcoma · Overview of bone chondrosarcomas Type % Characteristics Chemo Responsea Conventional chondrosarcoma ~ 70% IDH-1 or -2 mutation, may arise from

Novel Therapeutics in Chondrosarcoma

Tom Wei-Wu Chen, MD

Department of Oncology,

National Taiwan University Hospital

5th Singapore Sarcoma Symposium Oct 7th, 2017

Photo by Dr. Ting-Hui Wu

Overview of bone chondrosarcomas

Type % Characteristics Chemo Responsea

Conventional chondrosarcoma

~ 70% IDH-1 or -2 mutation, may arise from enchondroma or Ollier’s disease

11.5%

Dedifferentiated chondrosarcoma

~20% IDH-1 or 2 mutation (~ 50%), arise from conventional chondrosarcoma;

20.5%

Mesenchymal chondrosarcoma

~ 5% HEY1-NCOA2 translocation; Younger individuals, round cell component

31%

Clear cell chondrosarcoma

< 2% Chemo-resistant 0%

a based on study by Italiano A, et al. Ann Oncol 2013; 24: 2916-22 (n = 180)

Ifosfamide may provide survival benefit in dedifferentiated chondrosarcoma

Prognostic factor

p value HR (95% CI)

Ifosfamide 0.030 0.40 (0.17–0.92)

Pathologic fracture

0.063 2.52 (0.95–6.69)

Metastasis at diagnosis

0.179 2.00 (0.73–5.47)

N= 41

Clin Orthop Relat Res. 2014 Mar;472(3):983-9

32Yr female with rib mesenchymal chondrosarcoma and lung metastases treated with doxorubicin-ifosfamide

Contents of the next 20 min…….

•Molecular targets that are commonly seen in other cancer treatments PI3k/mTOR and IGF-1 pathways

•Molecular targets that are more specific to chondrosarcoma biology Hedgehog pathways Isocitrate dehydrogenase (IDH) mutations

• Immunotherapy

Activated IGF-1/PI3K/mTOR pathway in chondrosarcoma Phosphorylated S6 staining in CS

Clin Cancer Res. 2013 Jul 15;19(14):3796-807; BoneKEY Reports 2013; (2) Article number 437

IGF-1

mTORC1

Total Positive for pS6 (%)

Enchondroma 7 5 (71)

Osteochondroma 6 5 (83)

Conventional chondrosarcoma

106 73 (69)

Central chondrosarcoma

80 58 (73)

Grade 1 37 27 (73)

Grade 2 30 20 (67)

Grade 3 13 11 (85)

Peripheral chondrosarcoma

26 15 (58)

Grade 1 14 9 (64)

Grade 2 9 5 (56)

Grade 3 3 1 (33)


25 11 (44)

pS6K

PI3K

Modest activity of single agent mTOR inhibitor ridaforolimus in sarcomas (n = 212; 25% bone sarcomas)

Chawla S et al. J Clin Oncol 2012; 30:78-84

ORR by RECIST 1.9% Clinical benefit rate 28.8%

Median PFS 15.3 wks

Modest activity of single agent mTOR inhibitor ridaforolimus in bone and soft tissue sarcomas as maintenance therapy

Demetri GD et al. J Clin Oncol 2013; 31:2485-92

Median PFS 17.7 vs 14.6 weeks

Median OS 90.6 vs 85.3 weeks

HR 0.72, p < 0.001

HR 0.93, p = 0.456

Cixutumumab (IGF-1R inhibitor) and temsirolimus for patients with bone and soft-tissue sarcoma: Phase II Study

Schwartz GK et al. Lancet Oncol 2013; 14:371-82

Total IGF-1R positive

IGF-1R negative

CS 38 20 (53%) 18 (47%)

ES 61 33 (54%) 28 (46%)

LMS 45 26 (58%) 19 (42%)

LPS 11 5 (45%) 6 (55%)

MPNST 11 9 (82%) 2 (18%)

MFS 6 1 (17%) 5 (83%)

OGS 52 33 (63%) 19 (37%)

UPS 19 9 (47%) 10 (53%)

RMS 10 7 (70%) 3 (30%)

SFT 19 11 (58%) 8 (42%)

SS 18 14 (78%) 4 (22%)

IGF1+ vs IGF-1 - chondrosarcoma

FDA Approval: vismodegib to treat metastatic or recurrent locally advanced basal cell carcinoma (Jan 2012)

Nat Rev Drug Discov 2006; 1026–33

Hedgehog pathway is involved in many cancer and also cancer stem cell property

GLI factors

Indian Hedgehog pathway and parathyroid-related peptide (PTHrP) is involved in chondrocyte physiology

Tiet TD et al. Am J Pathol 2006; 168:321-30

Growth plate

cartilage growth cycle

% Patients with High expression of Indian Hedgehog and downstream GLIs

Growth plate

Cortical bone

Osteo-chondroma

Enchondroma Chondrosarcoma

4/4 (100%)

2/11 (18%)

0/4 (0%)

4/4 (100%)

23/23 (100%)

Hedgehog inhibitors showed some preclinical efficacy in chondrosarcoma xenograft models

Am J Pathol 2006; 168:321-30; Mol Cancer Ther 2014;13:1259-1269

Single agent GDC-0449 in advanced chondrosarcoma: single arm phase II study

Italiano A et al. Ann Oncol 2013; 24: 2922-26

Patient characteristics (n = 45) N (%)

Male: Female 31 :14 (69:31)

Median age (range) 58.0 (27.0-85.5)

Histological subtype

Conventional CS 39 (86.7)

Dedifferentiated CS 5 (11.1)

Clear cell CS 1 (2.2)

Prior lines of chemotherapy

0 25 (55.6)

1 12 (26.7)

> = 2 8 (17.8)

Single agent GDC-0449 in advanced chondrosarcoma: single arm phase II study (n=45)

The CBR (no progression at 6 months): 25.6% (95% CI 13.0–42.1) [Hypothesis CBR 6-month > 40%]

Median PFS 3.5 months (95% CI 1.8-3.9 months)

Median OS 12.4 months (95% CI 8.4 – not reached months)


Some hints of clinical efficacy signal of hedgehog inhibitor • Improved growth modulation index (GMI)

• the ratio of their PFS on GDC-0449 to their PFS on first-line therapy

• 9 patients (45%) had a GMI > 1; 6 of them (30%) had a GMI ≥ 1.3.

• Target validation • Hh overexpression was observed for all patients with SD

≥ 6 months for whom data were available (n = 4, 100%, all grade 1 or grade 2)

• Only 9 out of 16 patients with progressive disease (n = 16, 56%) had Hh overexpression

• In combination with chemotherapy to reverse drug resistance?


Targeting the metabolic pathway

• Fumarate hydratase – renal cell carcinoma, hereditary leiomyomatosis

• Succinate dehydrogenase – GIST, paraganglioma

Isocitrate dehydrogenase (IDH)

Semin Cell Dev Biol. 2012 Jun; 23(4): 370–380.

The role of IDH in normal physiology

The role of mutant IDH in carcinogenesis (neomorphism)

“Oncometabolite” Cancer Discov 2013; 3:730-41

IDH mutations are commonly found in gliomas, AML, and other specific solid tumors

Cancer type IDH1 /2 mutation %

AML 15-20%

Angioimmunoblastic lymphoma

20%

Cholangiocarcinoma 15-20% NEJM 2009; 360; 765-773

• All tumors with IDH1 or IDH2 mutations are heterozygous

• Nearly all IDH1 or IDH2 mutations cause a single amino acid substitution

• IDH1 and IDH2 mainly occurs in mutually exclusive manner

IDH mutation characteristics and hotspot mutations

Clin Cancer Res 2012; 18: 5562-71; Trend Mol Med 2010; 16:387-97

• 199 AML patients with IDH2 mutation were treated with single agent IDH2 inhibitor enasidenib

• 23% of patients experienced CR or CR with partial hematologic recovery lasted a median of 8.2 months

Blood. 2017 Aug 10;130(6):722-731

IDH1/2 somatic mutations is common among cartilaginous tumors

Tumor type % with IDH1/2

mutation Ref

Enchondroma in Ollier/Maffucci

87% Amary et al. 2011

Pansuriya et al. 2011

Primary central chondrosarcoma

38-70% Amary et al. 2011

Secondary central chondrosarcoma



Periosteal chondrosarcoma



54% Meijer et al. 2012 Amary et al. 2011

Adv Anat Pathol 2013;20:32–38

IDH1/2 somatic mutations is common among cartilaginous tumors

Tumor type % with IDH1/2

mutation Ref

Enchondroma in Ollier/Maffucci



Primary central chondrosarcoma

38-70% Amary et al. 2011

Secondary central chondrosarcoma



Periosteal chondrosarcoma



54% Meijer et al. 2012 Amary et al. 2011

Adv Anat Pathol 2013;20:32–38

• Early Event Mutation • High prevalence in

chondrosarcomas

Oncogenic driver?

Induction of sarcomas by mutant IDH2

IDH2 mut tumor

Parental 10T cell

IDH2 mutant 10T cell Chao Lu et al. Genes Dev. 2013;27:1986-1998

Decreased 2-HG by IDHi did not lead to decrease in cell viability in solid tumor cell lines

Cancer Cell 2015; 28:773-84; Oncotarget 2015; 6:12505-19

In glioma and AML, IDH1 or IDH2 often noted accompanying other oncogenic mutations

Clin Cancer Res; 2016; 22; 1837–42

Ongoing Clinical Trials in IDH1/2 Mutant Tumors

Study ID

Agent Mechanism of action

Study design

Study population Status

NCT02273739 AG-221

Oral IDH2 inhibitor

Phase I/II

Advanced solid tumors, including chondrosarcoma, and angioimmunoblastic T-cell lymphoma, with an IDH2 mutation

Ongoing, but not recruiting participants

NCT02481154

AG-881

Oral IDH inhibitor

Phase I

Advanced solid tumors, including chondrosarcoma, with an IDH1 and/or IDH2 mutation

Recruiting

NCT02073994

AG-120 Oral IDH inhibitor

Phase I

Advanced solid tumors, including chondrosarcoma, with an IDH1 mutation

Recruiting

NCT02496741

Metformin+ chloro-

quine

Oral antidiabetic and oral antimalarial

Phase Ib

IDH1/2 mutated patients with a glioma, intrahepatic cholangiocarcinoma or chondrosarcoma

Recruiting

2014

Discovery of immune checkpoint molecules

PD-1 CTLA-4 James P. Allison Tasuku Honjo

Immune Checkpoint Blockade

Tissue cell

Cytotoxic T-cell

PD1 × MHC Ag TCR

+

PDL1

Pardoll, Nature Rev Cancer 2012; 12: 252-26

Antigen presenting

cell

Cytotoxic T-cell

B7

+ MHC Ag TCR

CTLA4 ×

Effector phase

Priming phase Anti-CTLA4

Anti-PD1

+

Safety and Efficacy of PD-1 Blockade Using Pembrolizumab in Patients with <br />Advanced Soft Tissue and Bone Sarcomas: <br />Results of SARC028, a Multicenter Phase II Study

Slide 9

Slide 21 1 osteosarcoma 1 dedifferentiated chondrosarcoma (1/6 of chondrosarcoma)

Slide 24

Presented By Hussein Tawbi at 2016 ASCO Annual Meeting

Histology n PDL1+ Conventional TMA 157 Osteochondroma 11 0/8 (0%) Peripheral chondrosarcoma

Grade I 31 0/25 (0%) Grade II 11 0/10 (0%) Grade III 3 0/3 (0%) Enchondroma 9 0/8 (0%) Central chondrosarcoma

Grade I 42 0/40 (0%) Grade II 36 0/28 (0%) Grade III 14 0/13 (0%)

Histology n PDL1+ Rare subtypes TMA 66 Clear cell 20 0/20 (0%) Mesenchymal 21 0/19 (0%) Dedifferentiated 25 WD component 17 0/17 (0%) DD component 23 9/22 (41%) Validation cohort 22 Dedifferentiated 22 WD component 15 0/15 (0%)

DD component 22 11/21 (52%)

PD-L1 is only expressed in dedifferentiated chondrosarcoma but not in other chondrosarcoma subtypes or benign chondroid tumors

Kostine M et al. Modern Pathol 2016; 29:1028-37

PD-L1 expression limited in dedifferentiated CS part and is associated with TILs


DD PD-L1

WD PD-L1

CD3 PD-L1

• Dedifferentiated part with PD-L1 expression also showed high infiltration of M2 macrophages

Metastatic site and PD-L1 is associated with more immunosuppressive microenvironment

• CD8+ T cell (light gray) around 60% of all T cells

• Metastatic tumors had higher % Tregs


Areas to Improve in the Systemic Therapy for Chondrosarcoma

• Better method to evaluate treatment efficacy RECIST may not be the best method

Degree of differentiation after treatment

Growth modulation index

• The role of cancer immunology in bone sarcomas PD-1/PD-L1 is not the answer

• What is the sweet spot for chondrosarcoma with IDH mutations Single agent may not be the answer in solid

tumors

Summary • Chemotherapy may provide some benefits in

specific subtypes of chondrosarcoma (CS).

• Molecular targeted agents although provided preclinical anti-tumor activity, clinical studies results were inconsistent or still pending. The best way to reach clinical benefit through drug combinations remains to be eluted.

• How to accurately assess treatment efficacy and identify molecular or immune targets is crucial in the development of new therapeutics in CS.

Special thanks to Dr. Richard Quek and Dr. Mark Puhaindran, Wei Lin Goh The NCCS Team and the ASC Members

Documents

Novel Therapeutics in Chondrosarcoma · Overview of bone chondrosarcomas Type % Characteristics Chemo Responsea Conventional chondrosarcoma ~ 70% IDH-1 or -2 mutation, may arise from