Changing AML Outcomes via Personalized Medicine: Transforming Cancer Management with Genetic Insight Co-Moderators: • Rick Winneker, PhD, Senior Vice President, Research, Leukemia & __Lymphoma Society • Mike Rice, Senior Consultant, Defined Health Panelists: • Brian J. Druker, MD, Director, OHSU Knight Cancer Institute, JELD-WEN __Chair of Leukemia Research, Oregon Health & Science University, __Investigator, Howard Hughes Medical Institute • Eric Hedrick, MD, Chief Medical Officer, Epizyme, Inc. • Omar Abdel-Wahab, MD, Assistant Member, Memorial Sloan Kettering __Cancer Center • Nicholas J. Sarlis, MD, PhD, Vice President & Head, Medical Affairs, __Incyte Corporation • Scott Biller, PhD, Chief Scientific Officer, Agios Pharmaceuticals
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Changing AML Outcomes via Personalized …...Changing AML Outcomes via Personalized Medicine: Transforming Cancer Management with Genetic Insight Co-Moderators: • Rick Winneker,
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Changing AML Outcomes via Personalized Medicine: Transforming Cancer Management with Genetic Insight Co-Moderators: • Rick Winneker, PhD, Senior Vice President, Research, Leukemia & __Lymphoma Society • Mike Rice, Senior Consultant, Defined Health Panelists: • Brian J. Druker, MD, Director, OHSU Knight Cancer Institute, JELD-WEN __Chair of Leukemia Research, Oregon Health & Science University, __Investigator, Howard Hughes Medical Institute • Eric Hedrick, MD, Chief Medical Officer, Epizyme, Inc. • Omar Abdel-Wahab, MD, Assistant Member, Memorial Sloan Kettering __Cancer Center • Nicholas J. Sarlis, MD, PhD, Vice President & Head, Medical Affairs, __Incyte Corporation • Scott Biller, PhD, Chief Scientific Officer, Agios Pharmaceuticals
AML Remains Among Highest Unmet Need Across Blood Cancers (and solid tumors)
♦ Acute myeloid leukemia (AML) is a life-threatening disease in which hematopoietic progenitor cells committed to the myeloid lineage become cancerous.
♦ This year, nearly 15,000 people will be diagnosed with AML in the US – causing >10,000 deaths. ♦ 90% of new cases in adults with an average age at diagnosis >65 yrs
AML Prognosis Involves Characteristics of The Patient and The Disease
American Cancer Society, www.cdc.gov
Historically the most important prognostic indicators to base treatment decision include: ♦ AML subclassification:
• FAB divides AML into subtypes, M0 through M7, based on the type of cell from which the leukemia developed and maturity based on microscopy after routine staining.
• Morphology, immunophenotype, cytogenetics and clinical features. • Leukemias that express the progenitor cell antigen CD34 and/or the P-glycoprotein (MDR1 gene product).
♦ Age and general health of Patient: • Increasing age is an adverse factor because older patients more frequently have a prior AHD and also co-morbid
medical conditions that compromise the ability to give full doses of chemotherapy. • Clinicians consider age 55-65 a general cut-off when considering aggressive, high-dose chemotherapeutic
Initial Treatment • Remission Induction • Clinical Trial • Best Supportive care
Post Remission Therapy •Consolidation
Salvage Therapy Long Term Remission / Cure
♦ The treatment of patients with AML ranges from standard therapy, to investigational approaches, to palliative care.
♦ The three stages of standard treatment for AML are:
1. Remission Induction therapy: Treatment should be sufficiently aggressive to achieve complete remission (CR= <5% blasts in bone marrow) because partial remission offers no substantial survival benefit.
2. Post-remission therapy: Post-remission therapy primarily consists of consolidative treatment with high dose chemotherapy.
3. Salvage Therapy: Following initial induction and consolidation treatment, patients are then treated with salvage therapy if they fail to achieve initial CR (primary refractory) of after disease recurrence (relapse) .
SOC Provides Meager Benefit to Majority Affected by AML: The Old
♦ ~75% of adult AML patients fit enough for chemotherapy (“7+3” regimen comprised of cytarabine with an anthracycline) achieve complete remission (CR); however, only 20 – 30% of patients achieve long-term disease-free survival.
♦ Disease tends to be more treatment resistant in older patients, (de novo, antecedent MDS, sAML) with dramatically worse outcomes than in younger adults.
♦ Many studies have compared the option of best supportive care with that of a standard “3 + 7” induction regimen for older patients with AML which show trends toward improved survival when patients received chemotherapy.
♦ However, it is important to be reminded of a sobering statistic—older patients with AML, usually defined in clinical trials as above 55 or 60 years of age, have a median time from treatment with 3 + 7 regimens to death of only 5-10 months.
Patient Age (median CR)
% of patients
Cytogenetics BMT? Relapse rate
<60 (60-80%)
40% good No (consolidative chemo) 30%
40% Int/poor Yes 20%
20% Int/poor No (no donors, patient refusal, commorbidities)
• FDA rejected submission, requested RCT Ph 3 trial
Phas
e 3
Oblimersen Genta
Bcl-2 inhibitor RCT: Dauno +
AraC +/- agent • Failed to meet OS endpoint
Lintuzumab Seattle Genetics
CD33 antigen inhibitor RCT: LoDAc +/-
agent • Failed to meet OS endpoint • Ph2b registration study
Troxacitabine SGX/Eli Lilly
DNA synthesis inhibitor
Historical: Single-arm, monotherapy
• Poor efficacy – Response rates
Amonafide Antisoma
DNA topo-isomerase inhibitor
RCT: AraC + agent vs. Dauno + AraC
• Failed to meet CR endpoint • Secondary AML patients
Sources: 1) Adis; 2) IDDB ; Note: Analysis limited to studies post-2005 in Phase 2b or higher, for which discontinuation in AML was discernibly related to trial outcomes in AML
Accordingly, AML Drug Market is Almost Nonexistent: Near-term Advancement in Treatment is Likely to be Incremental
EvaluatePharma
WW AML Revenue ($US Millions) ♦ Several other products designed to improve upon chemotherapy have progressed to late stage development for which physicians are optimistic to have access to in the near future. • Sunesis’ Vosaroxin, currently in phase 3 for primary refractor
and relapsed AML, is designed to avoid resistance mechanisms and broaden the therapeutic index of anthracyclines.
• Clavis’ elacytarabine is designed to increase import of the toxic nucleoside into the nucleus in phase 3 for second salvage.
• Cyclacel’s Sapacitabine is being tested in phase 3 trials (SEAMLESS trials) for treatment-naïve and relapsed elderly AML patients, in 2012 Cyclacel announced a CR rate of 25% at the highest dosing schedule (400 mg sapacitabine bid for 3 consecutive days per week every 3 to 4 weeks).
♦ Dacogen (decitabine) first new approval in AML in over a decade. Although FDA did not grant Eisai/Astex approval earlier this year, J&J/Astex recently received EMA approval based on Phase 3 DACO-016 trial results showing 7.7 months median overall survival in patients taking decitabine compared to 5.0 months for standard treatment.
AML Leads Sequencing Efforts – Although Translation is Needed, Early Data is Redefining Understanding of Cancer Progression
♦ In 2008, a team led by Dr. Timothy Ley became the first to sequence an entire cancer genome using a patient’s own cancerous cells. The cancer they chose to sequence first was AML.
♦ Today hundreds of AML genomes have been sequenced (between TGI and other WGS initiatives) that are mapping genetic mutations impacting the etiology, prognosis, responsiveness to therapy and progression of AML.
Genomics is Improving AML Prognostication and Treatment Strategies
♦ Seminal publications on findings from AML and MDS whole genome sequencing efforts provide context for applying data toward improving patient management:
“Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia”
♦ Investigated the prognostic value of recently identified somatic mutations in the context of a phase 3 trial comparing outcomes for patients treated with standard dose and high dose daunorubicin.
♦ Results demonstrated that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML.
Translating Genomic Analyses Into Drug Programs: Academics and Industry, with Support from Government and Philanthropy
Mutated Gene Development Projects
Mutated Gene Development Projects
FLT3 (ITD, TKD) 42 PHF6 0
NPM1 0 KRAS 3
DNMT3A 1 PTEN 1
NRAS 11 TP53 21
CEBPA 0 HRAS 1
TET2 0 EZH2 5
WT1 11 CDH23 0
IDH2 4 PTPN11 0
IDH1 3 SMC3 0
KIT 41 STAG2 0
RUNX1 0 U2AF1 0
MLL-PTD 7 UMODL1 0
ASXL1 0 ZSWIM4 0
Recent genome-wide analyses in patients with a variety of myeloid malignancies not only validated known markers, but has led to the rapid discovery of a series of recurrent genetic alterations, leading to: • New programs pursuing the
prognostic and therapeutic potential of novel epigenetic targets (e.g., DNMT3A, IDH1/2, MLL, EZH2 and RAS).
• Renewed interest in kinase inhibitors, given recent clinical responses with next generation inhibitors (FLT3, KIT, RAS).
However, Observed Mutations Need to be Vetted to Differentiate Drivers vs. Passengers in Disease Progression and Potential Therapeutic Targets
Model for evolution of genetic changes in acute myeloid leukemia ♦ A hypothetical model in which nonpathogenic somatic mutations (1–3) acquired over the
lifespan of a stem cell are propagated in the malignant clone after it acquires a critical initiating mutation (4). Mutation 5 is a progression mutation that cooperates with the AML-initiating mutation 4 to contribute to AML development. Other mutations (represented by 6 and 7) do not cooperate with the AML-initiating mutation 4, and do not contribute to AML development. These subclones are lost, or fail to expand to the limit of detection by sequencing studies.
From: Walter MJ, Graubert TA, DiPersio JF, Mardis ER, Wilson RK, Ley TJ Next-generation sequencing of cancer genomes: back to the future. Per Med 2009 Nov 1;6(6):653
Histone methyltransferases (HMTs) are enzymes that catalyze the addition of methyl marks to histone proteins. These types of chemical modifications to histones impact chromatin architecture and the regulation of gene expression. Aberrant activity of HMTs is implicated in a host of human diseases, including oncology, inflammation, infection, metabolism, and neurology.
The discovery of the first histone demethylase (HDM) fundamentally changed the understanding of the reversibility of histone methylation. There are two families of HDMs – amine oxidases and hydroxylases – and both are implicated in human diseases, including cancer, inflammation, and metabolic disease.
Readers are proteins that bind to specific recognition domains, typically methyl or acetyl marks, on chromatin in a highly regulated manner. These chromatin-binding events result in the modulation of chromatin architecture, which impacts gene expression and are ultimately implicated in key cellular processes such as cell cycle progression, cytokine signaling, and viral integration
Progress For Epigenetic Inhibitors as Cancer Therapies
Epigenetic Inhibitors as Cancer Therapies
Discussion Points • Why is AML a good model to employ personalized cancer care? What lessons have been
learned? What obstacles need to be overcome? What are the short term goals and the long term goals?
• What is the state of the art in changing AML outcomes via genetic evidence? – What progress is being made on functional analysis to get beyond AML “genomics” and
move towards useful information that can be applied in the clinic? • What new information has come out from AML whole genome sequencing and genetic
association studies? Preclinical models? Epigenetic modifiers (TET2, IDH1/2, ASXL1, etc.) – What implications does it have on the use of currently utilized AML therapies? How it
impacting care? • What are the specific implications of HMT alterations (DOT1L) to different subsets of AML?
– What does it take to translate this new science into clinically useful diagnostics and therapies?
• How do you develop a drug in these small niche malignancies and also provide a commercially viable product? What are the regulatory and commercial challenges?
• What are the specific implications of cancer metabolism IDH1/2 gain of function mutations? – Patient selection at the molecular level for clinical trials
• What might the future of AML management look like? How we get beyond the dogma of “7+3” after 35 years even if the target is molecularly defined?
• How can innovation be encouraged and how is collaboration between academics and industry being used to address these barriers?