Targeting Sarcomas The Advancement of Molecularly Driven Therapies

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1 Targeting Sarcomas The Advancement of Molecularly Driven Therapies Victor M. Villalobos, M.D., Ph.D. Assistant Professor Director, Sarcoma Medical Oncology Director, T3 (Target-based Therapeutics Team) Division of Medical Oncology Disclosures Advisory board: Lilly Janssen Consultant Novartis Learning Objectives Learn the high genetic variability within mesenchymal tumors. Discuss how to best target these lesions with drugs using novel mechanisms. Learn about the newest advances in the field of sarcoma. Discuss multidisciplinary approach to GIST treatment

2 Sarcoma background Sarcoma is derived from the Greek σάρξ (sarx), meaning flesh Defined as as tumors that arise from mesenchymal origin Hematolymphoid (hematopoietic origin) Carcinoma (epithelial cells) Sarcoma (mesenchymal cells) As of 2013, there are over 170 different subtypes of bone and soft tissue tumors classified by the WHO 40% (75+) of those types being classified as malignant or potentially malignant 4 Epidemiology Annual incidence 50 per million <1% of all malignancies Benign mesenchymal tumors about 100 x more common than malignant sarcoma Location of tumors 75% in extremities 25% in trunk and peritoneum. 5 Etiology In most cases etiology is unknown Risk factors: Genetic susceptibility p53 [Li-Fraumeni], RB1, NF1, FAP Prior radiation Risk increases with dose Peak from time to exposure is 10 years Significantly increased risk if germline mutation present Viral infection in immunodeficiency Kaposi sarcoma (HHV8) High exposure to certain chemicals (not entirely clear) Phenoxyacetic herbicides, Chlorophenols, Dioxin Sometimes linked to prior local trauma Lymphedema (Stewart-Treves syndrome) risk of angiosarcoma 6

3 Diversity of soft tissue Sarcomas Taylor, B. S. et al. Nat Rev Cancer 11, (2011). 7 Genomic alterations in sarcomas Driver Mutations Activating mutations Deactivating mutations Simple translocations TET fusions Tyrosine kinase fusions Chromatin remodeling fusions Others Copy number variation Amplification/Overexpression Deletion/Suppression Complex karyotype/genomics nuclear bombs. Patient case Patient is a 50 yo male with history of HTN presents to ED with abdominal fullness and pain. CT scan done showing 3 liver masses and large gastric mass. EGD shows fungating tumor. Biopsy shows a spindle cell neoplasm (CD117+, DOG1+)

4 Patient started on imatinib 400 mg daily Symptoms improve however on first scan there are several new lesions Q: How would you proceed at this point? Baseline 1) No change in treatment 2) Increase dose of imatinib to 800 mg daily 3) Change therapy to sunitinib 4) Consider radiation to new lesions 3 month scan Variability in Genetic Drivers Driver Mutations GIST (Ckit) Simple translocations myxoid liposarcoma (FUS-DDIT3) Copy number alteration Well Diff/Dediff liposarcoma (MDM2 & CDK4) Complex karyotype Leiomyosarcoma (PDGFRα) UPS/Pleomorphic liposarcoma Driver mutations: Gastrointestinal Stromal Tumor (GIST) Originates from the interstitial cell of Cajal (gut pacemaker cell) Chemotherapy and radiation insensitive. Prior management surgical Risk stratification based on: location of primary (gastric vs. other) Grade (cut off of 5 mits / 5 mm 2 ) Size (5 cm) Mutation status 12

5 Driver mutations: Gastrointestinal Stromal Tumor (GIST) Prior to TKI therapies, 2 yr survivals of 40% and < 25% overall survival in fully resected cases Many GISTs found to have activating mutations in CKIT (CD117) This is targetable with the tyrosine kinase inhibitor - imatinib Verweij, et al. Lancet, 364(9440), Patient on therapy for 1 year. New scan shows oligoprogression in his stomach with new onset melena. Next steps: 1) Increase dose to imatinib 800 mg 2) Proceed to surgical resection of mass and proceed with same dose of imatinib 3) Radiate stomach 4) Change therapy to Sunitinib Genotype of GIST B Progression free survival Associated mutations in GIST are many CKIT mutations most common (84% of all tumors) CKIT Exon 11 associated with better prognosis start imatinib at 400mg. Minimal benefit with increase to 800mg CKIT Exon 9 Mutation associated with poor prognosis clear benefit with 800mg imatinib HR = 0.392, p=0.001 Wild Type or other mutations (except PDGF) are almost as bad as exon 9 Treat with 400 mg imatinib Tended to do worse with higher dose of imatinib Overall Survival PFS Debiec-Rychter, et al. European Journal of Cancer 2006, 42(8), C O N Number of patients at risk: Wild Kit-ex9 Kit-ex O N Number of patients at risk: Exon 9 Overall survival Exon 9 Exon Exon 11 Wild Kit-ex9 Kit-ex11 (years) (years) 15

6 Genotype of GIST B Progression free survival Associated mutations in GIST are many CKIT mutations most common (84% of all tumors) CKIT Exon 11 associated with better prognosis start imatinib at 400mg. Minimal benefit with increase to 800mg CKIT Exon 9 Mutation associated with poor prognosis clear benefit with 800mg imatinib HR = 0.392, p=0.001 Wild Type or other mutations (except PDGF) are almost as bad as exon 9 Treat with 400 mg imatinib Tended to do worse with higher dose of imatinib Overall Survival PFS Debiec-Rychter, et al. European Journal of Cancer 2006, 42(8), C O N Number of patients at risk: Wild Kit-ex9 Kit-ex O N Number of patients at risk: Overall survival DOX IMATINIB Wild Kit-ex9 Kit-ex11 (years) (years) 16 Genotype of GIST Blay et. al. Discovery Medicine GIST CASE Patient stomach mass is resected and shows mutation in Exon 11 that makes imatinib resistant. Initial tumor is classic Exon 11 mutation Maintained on 400 mg imatinib for another 12 months Follow up scan shows 2 liver lesion have grown substantially. All other lesions stable What next? 1) Increase imatinib dose to 800 mg daily 2) Change to sunitinib 3) Radiate this lesion and continue imatinib 400mg 4) Perform radioembolization to right lobe of liver and continue imatinib 400 mg 5) Resect lesion and continue imatinib 400mg

7 Continuation of imatinib in metastatic setting When patients taken off imatinib while still having response, tumors grew quickly and often would not respond as well after restarting. This study treated patients for 3 years after initiation of imatinib and randomized discontinuation Le Cesne, A., The Lancet Oncology, 11(10), Adjuvant therapy Thus far, extended therapy in adjuvant setting leads to longer RFS and OS. Ongoing studies are looking at 5 years of treatment and beyond. 20 Joensuu, H., et al. JAMA, 307(12), Adjuvant therapy Thus far, extended therapy in adjuvant setting leads to longer RFS and OS. Ongoing studies are looking at 5 years of treatment and beyond. 21 Joensuu, H., et al. JAMA, 307(12),

8 Adjuvant therapy 1 yr 2.5 yrs Thus far, extended therapy in adjuvant setting leads to longer RFS and OS. Ongoing studies are looking at 5 years of treatment and beyond. 22 Joensuu, H., et al. JAMA, 307(12), Variability in Genetic Drivers Driver Mutations GIST (Ckit) Desmoid tumors (B-Catenin of APC mutations) Simple translocations myxoid liposarcoma (FUS-DDIT3) Copy number alteration Well Diff/Dediff liposarcoma (MDM2 & CDK4) Complex karyotype Leiomyosarcoma (PDGFRα) UPS/Pleomorphic liposarcoma Genomic patterns in liposarcoma

9 Variability in Genetic Drivers Driver Mutations GIST (Ckit) Desmoid tumors (B-Catenin of APC mutations) Simple translocations myxoid liposarcoma (FUS-DDIT3) Copy number alteration Well Diff/Dediff liposarcoma (MDM2 & CDK4) Complex karyotype Leiomyosarcoma (PDGFRα) UPS/Pleomorphic liposarcoma Myxoid liposarcoma EWSR1/FUS DDIT3 translocation blocks vital adipogenic transcription factors PPARγ C/EBPα PPARγ regulates the maturation of progenitor cells into mature adipocytes PPARγ agonist can overcome the block in maturation and induce terminal differentiation Perez-Mancera, P. A. et al Carcinogenesis 28, (2007). Pérez-Mancera, P. A. et al. PLoS ONE 3, e (2008). Myxoid liposarcoma PPAR-γ (peroxisome proliferator activated receptor gamma) Can be activated by thiazolidinediones 1999 study used troglitazone Induced terminal differentiation of round cells into adipocytes Ongoing clinical trial through ALLIANCE using efatutazone Prior to dosing Rebiopsy 6 weeks post Rx Demetri, G. D. et al. Proceedings of the National Academy of Sciences 96, (1999).

10 Variability in Genetic Drivers Driver Mutations GIST (Ckit) Desmoid tumors (B-Catenin of APC mutations) Simple translocations myxoid liposarcoma (FUS-DDIT3) Copy number alteration Well Diff/Dediff liposarcoma (MDM2 & CDK4) Complex karyotype Leiomyosarcoma (PDGFRα) UPS/Pleomorphic liposarcoma Targets in Dedifferentiated liposarcoma Barretina, J. et al. Nat Genet 42, (2010). MDM2 P53 is a tumor suppressor mutated in >50% of cancers MDM2 is an E3 ligase that suppresses p53 activity Well Diff and Dediff liposarcoma almost all have wild-type p53 with MDM2 amplification No published Phase II studies yet with this drug Nalepa et al. Nature Reviews Drug Discovery 5, (July 2006)

11 Liposarcoma patient treated with MDM2 inhibitor Dec 2014 Jul 2015 Started MDM2 inhibitor Mar months 7 months Well diff lipo: 14 to 22 cm = 8 cm 22 to 24 cm = 2 cm Dediff: 1 to 4.4 cm = 3.4 cm 4.4 to 4.5 cm = 0.1 cm Variability in Genetic Drivers Driver Mutations GIST (Ckit) Desmoid tumors (B-Catenin of APC mutations) Simple translocations myxoid liposarcoma (FUS-DDIT3) Copy number alteration Well Diff/Dediff liposarcoma (MDM2 & CDK4) Complex karyotype Leiomyosarcoma (PDGFRα) UPS/Pleomorphic liposarcoma Complex genomic sarcomas 50% of all sarcomas have complex genomics with complex karyotype Often catastrophic genomic variation Most develop de novo Aggressive clinical course Examples: Leiomyosarcoma (LMS) Undifferentiated pleomorphic sarcomas (UPS) Pleomorphic liposarcoma Barretina, J. et al.. Nat Genet 42, (2010).

12 Pleomorphic liposarcoma Highly malignant and aggressive Accounts for 5% of liposarcoma Occurs more frequently in older patients Behaves more like an undifferentiated pleomorphic sarcoma than a liposarcoma Almost exclusively metastasizes to lung 34 PDGFRα: Platelet derived growth factor alpha Activation of RTK leads to activation of : RAS/MAPK pathway PI3K pathway JAK/STAT pathway Aberrant expression leads to Increased metastatic potential Increased angiogenesis Alteration and stimulation of tumor microenvironment. PDGFRα - Olaratumab Results of Phase II clinical randomized clinical trial Doxorubicin vs Doxorubicin + olaratumab 2.5 month PFS benefit PFS benefit met predefined endpoint > 11.8 month overall survival benefit in combination arm p< Phase III ongoing Olaratumab recently given conditional FDA approval in STS Tap, W. et. al. Abstract Number: ASCO Annual Meeting

13 Diversity of soft tissue Sarcomas Taylor, B. S. et al. Nat Rev Cancer 11, (2011). 37 Sarcoma at CU-Denver High volume of sarcoma cases (~ new sarcoma patients/year) Multidisciplinary clinic: surgery, radiation and medical oncology, sarcoma pathologist and MSK radiologist all in one day. Our time from first telephone contact to start of therapy can be short, typically 2-3 week range, depending on the therapy. Orthopedic oncology, surgical oncology, thoracic oncology, ENT, plastic surgery, neurosurgery. 13 ongoing sarcoma clinical trials specifically for sarcoma and over 40 trials in phase 1 or T3 for which sarcoma patients may be eligible, 7 more in pipeline. Members of SWOG, SARC, NCCN bone and STS committees and CTOS Active research collaborations with our basic science departments Sarcoma Team Medical Oncology Victor Villalobos MD, PhD, Director Anthony Elias, MD Brianna Hoffner, NP Surgical Oncology Martin McCarter, MD Ana Gleisner, MD, PhD Orthopedic Oncology Bennie Lindeque, MD Nate Donaldson, DO Andrew Park, MD Pathology Jeff Schowinsky MD Radiation Oncology Tracey Schefter, MD Ryan Lanning, MD, PhD Thoracic Surgery Rob Meguid, MD, MPH Mike Weyant, MD John Mitchell, MD Plastics Tae Chong, MD ENT/Neurosurgery/IR/MSK radiology/gyn ONC

14 LET ME KNOW HOW WE CAN HELP Victor Villalobos MD, PhD Director Sarcoma Oncology Sarcoma Clinic