Novel Therapeutics in Chondrosarcoma · Overview of bone chondrosarcomas Type % Characteristics...
Transcript of Novel Therapeutics in Chondrosarcoma · Overview of bone chondrosarcomas Type % Characteristics...
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)
Dedifferentiated chondrosarcoma
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)
Italiano A et al. Ann Oncol 2013; 24: 2922-26
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?
Italiano A et al. Ann Oncol 2013; 24: 2922-26
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
86% Amary et al. 2011
Pansuriya et al. 2011
Periosteal chondrosarcoma
100% Amary et al. 2011
Dedifferentiated 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
87% Amary et al. 2011
Pansuriya et al. 2011
Primary central chondrosarcoma
38-70% Amary et al. 2011
Secondary central chondrosarcoma
86% Amary et al. 2011
Pansuriya et al. 2011
Periosteal chondrosarcoma
100% Amary et al. 2011
Dedifferentiated 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
Kostine M et al. Modern Pathol 2016; 29:1028-37
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
Kostine M et al. Modern Pathol 2016; 29:1028-37
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