Novel Therapeutics in Chondrosarcoma Tom Wei-Wu Chen, MD Department of Oncology, National Taiwan University Hospital 5 th Singapore Sarcoma Symposium Oct 7 th, 2017 Photo by Dr. Ting-Hui Wu
Overview of bone chondrosarcomas Type % Characteristics Chemo Response a Conventional chondrosarcoma Dedifferentiated chondrosarcoma Mesenchymal chondrosarcoma Clear cell chondrosarcoma ~ 70% IDH-1 or -2 mutation, may arise from enchondroma or Ollier s disease ~20% IDH-1 or 2 mutation (~ 50%), arise from conventional chondrosarcoma; ~ 5% HEY1-NCOA2 translocation; Younger individuals, round cell component 11.5% 20.5% 31% < 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 Metastasis at diagnosis 0.063 2.52 (0.95 6.69) 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 IGF-1 PI3K mtorc1 ps6k Clin Cancer Res. 2013 Jul 15;19(14):3796-807; BoneKEY Reports 2013; (2) Article number 437 Total Positive for ps6 (%) Enchondroma 7 5 (71) Osteochondroma 6 5 (83) Conventional chondrosarcoma Central chondrosarcoma 106 73 (69) 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)
Modest activity of single agent mtor inhibitor ridaforolimus in sarcomas (n = 212; 25% bone sarcomas) Median PFS 15.3 wks ORR by RECIST 1.9% Clinical benefit rate 28.8% Chawla S et al. J Clin Oncol 2012; 30:78-84
Modest activity of single agent mtor inhibitor ridaforolimus in bone and soft tissue sarcomas as maintenance therapy 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 Demetri GD et al. J Clin Oncol 2013; 31:2485-92
Cixutumumab (IGF-1R inhibitor) and temsirolimus for patients with bone and soft-tissue sarcoma: Phase II Study 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%) IGF1+ vs IGF-1 - chondrosarcoma 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%) Schwartz GK et al. Lancet Oncol 2013; 14:371-82
Hedgehog pathway is involved in many cancer and also cancer stem cell property Nat Rev Drug Discov 2006; 1026 33 GLI factors FDA Approval: vismodegib to treat metastatic or recurrent locally advanced basal cell carcinoma (Jan 2012)
Indian Hedgehog pathway and parathyroid-related peptide (PTHrP) is involved in chondrocyte physiology Growth plate cartilage growth cycle % Patients with High expression of Indian Hedgehog and downstream GLIs Growth plate 4/4 (100%) Cortical bone 2/11 (18%) Osteochondroma 0/4 (0%) Enchondroma 4/4 (100%) Chondrosarcoma 23/23 (100%) Tiet TD et al. Am J Pathol 2006; 168:321-30
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 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) Italiano A et al. Ann Oncol 2013; 24: 2922-26
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) Italiano A et al. Ann Oncol 2013; 24: 2922-26 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 firstline 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) Cancer Discov 2013; 3:730-41 Oncometabolite
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
IDH mutation characteristics and hotspot mutations 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 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 Enchondroma in Ollier/Maffucci Primary central chondrosarcoma Secondary central chondrosarcoma Periosteal chondrosarcoma Dedifferentiated chondrosarcoma % with IDH1/2 mutation 87% Ref Amary et al. 2011 Pansuriya et al. 2011 38-70% Amary et al. 2011 86% Amary et al. 2011 Pansuriya et al. 2011 100% Amary et al. 2011 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 Enchondroma in Ollier/Maffucci Primary central Early chondrosarcoma Event Mutation High Secondary prevalence central in chondrosarcomas Periosteal chondrosarcoma Dedifferentiated chondrosarcoma % with IDH1/2 mutation 87% Ref Amary et al. 2011 Pansuriya et al. 2011 38-70% Amary et al. 2011 86% Amary et al. 2011 Pansuriya et al. 2011 100% Amary et al. 2011 54% Oncogenic driver? Meijer et al. 2012 Amary et al. 2011 Adv Anat Pathol 2013;20:32 38
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 Agent ID NCT0 2273 739 AG-221 NCT0 2481 154 NCT0 2073 994 NCT0 2496 741 AG-881 AG-120 Metformin + chloroquine Mechanism of action Oral IDH2 inhibitor Oral IDH inhibitor Oral IDH inhibitor Oral antidiabetic and oral antimalarial Study design Phase I/II Phase I Phase I Phase Ib Study population Advanced solid tumors, including chondrosarcoma, and angioimmunoblastic T- cell lymphoma, with an IDH2 mutation Advanced solid tumors, including chondrosarcoma, with an IDH1 and/or IDH2 mutation Advanced solid tumors, including chondrosarcoma, with an IDH1 mutation IDH1/2 mutated patients with a glioma, intrahepatic cholangiocarcinoma or chondrosarcoma Status Ongoing, but not recruiting participants Recruiting Recruiting Recruiting
2014 PD-1 Tasuku Honjo CTLA-4 James P. Allison Discovery of immune checkpoint molecules
Immune Checkpoint Blockade Antigen presenting cell MHC Ag B7 TCR CTLA4 + Cytotoxic T-cell Priming phase + Anti-CTLA4 Tissue cell MHC Ag TCR PDL1 PD1 + Cytotoxic T-cell Effector phase Anti-PD1 Pardoll, Nature Rev Cancer 2012; 12: 252-26
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
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Slide 21 1 osteosarcoma 1 dedifferentiated chondrosarcoma (1/6 of chondrosarcoma)
Slide 24 Presented By Hussein Tawbi at 2016 ASCO Annual Meeting
PD-L1 is only expressed in dedifferentiated chondrosarcoma but not in other chondrosarcoma subtypes or benign chondroid tumors 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%) 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 PD-L1 CD3 Kostine M et al. Modern Pathol 2016; 29:1028-37
Metastatic site and PD-L1 is associated with more immunosuppressive microenvironment Kostine M et al. Modern Pathol 2016; 29:1028-37 CD8+ T cell (light gray) around 60% of all T cells Metastatic tumors had higher % Tregs Dedifferentiated part with PD-L1 expression also showed high infiltration of M2 macrophages
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