Changing AML Outcomes via Personalized Medicine: Transforming Cancer Management with Genetic Insight

Transcription

1 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

2 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 Page 2

3 AML Prognosis Involves Characteristics of The Patient and The Disease 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 a general cut-off when considering aggressive, high-dose chemotherapeutic treatment. Prior antecedent hematologic disorder (AHD): An AHD such as myelodysplastic syndrome (MDS) is associated with a poor outcome to therapy. Prior Treatment: High-doses of anthracyclines, in particular, is important when assessing risk of cumulative dosing toxicities. Treatment-induced secondary AML. Genetics: The WHO classification incorporates more recent discoveries regarding the genetics and clinical features of AML in an attempt to define entities that are biologically homogeneous and that have prognostic and therapeutic relevance. Each criterion has prognostic and treatment implications but, for practical purposes, antileukemic therapy is similar for all subtypes. American Cancer Society, Page 3

4 Heterogeneity of AML Translating Into Useful Prognostic Information Heterogeneity of Cytogenetically Normal AML BLOOD, 21 JANUARY 2010 VOLUME 115, NUMBE, March 22, 2012; n engl j med 366;12, p 1079 R 3 Page 4

5 However, AML Treatment Has Not Changed Much In Over 30 Years 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). Diagnosis / Workup (Morphology, Immunophenotype, Cytogenetics, molecular markers, Clinical Presentation (age, PS) Initial Treatment Remission Induction Clinical Trial Best Supportive care Long Term Remission / Cure Post Remission Therapy Consolidation Salvage Therapy Page 5

6 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 longterm 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 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 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) 60% >60yr (50-60%) >70yr (<10%) 20% Int/poor Yes (non-myeloablative) 30% 80% All types No 80% 100% All types No N/A (BSC) Page 6

7 However, Despite the Seemingly Low Benchmark, Many Agents Have Failed in AML Across Multiple Subsets Pre Reg Product MOA 1 st Line Laromustine Vion Clofarabine Genzyme Oblimersen Genta Relapsed / Refractory Trial Design Alkylating Agent Nucleoside Analog Bcl-2 inhibitor Elderly Comparator Commentary on Discontinuation Historical: Single-arm, monotherapy Historical: Single-arm, monotherapy RCT: Dauno + AraC +/- agent FDA rejected NDA, requesting RCT Ph 3 trial demonstrating survival benefit FDA rejected submission, requested RCT Ph 3 trial Failed to meet OS endpoint Phase 3 Lintuzumab Seattle Genetics Troxacitabine SGX/Eli Lilly CD33 antigen inhibitor DNA synthesis inhibitor RCT: LoDAc +/- agent Historical: Single-arm, monotherapy Failed to meet OS endpoint Ph2b registration study Poor efficacy Response rates Amonafide Antisoma DNA topoisomerase 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 Page 7

8 Accordingly, AML Drug Market is Almost Nonexistent: Near-term Advancement in Treatment is Likely to be Incremental 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. $700 $600 $500 $400 $300 WW AML Revenue ($US Millions) 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. $200 $100 $ Mylotarg PKC412 Quizartinib Rubida Tamibarotene Trisenox Vosaroxin Dacogen EvaluatePharma Page 8

9 Therapies in Development for AML Represent Nearly 1/5 of the Pipeline for Heme Cancers Number of Agents In Clinical Development (P1-Reg) For Hematological Malignancies HL 3% AML 18% CML 5% ALL 6% NHL 26% CLL 13% MM 19% (Total= 400) OTHER MYELOID 10% ADIS R&D Insight, Thomson Pharma Partnering Page 9

10 Novel clinical stage agents pursuing different MoAs and AML patient settings Chemotherapy Epigenetic Phase 1 RG 7536 AT 9283 MDX 1338 Rigosertib Phase 2 Crenolanib Quizartinib Phase 3 Vosaroxin Elacytarabine Kinase Inhibitor Proapoptotic Immuno-therapy Other Relapsed / Refractory SL 401 ALT 801 DCPrime Vac CNDO 109 AVE 9633 Lintuzumab Ac-225 PLX 3397 DFP Triciribine PR 104 Ponatinib Idelalisib ENMD 2076 AZ 1208 MK 8242 CWP BP CA1P Elesclomol Selumetinib Tosedostat LOR 2040 Non-Candidates for Induction CT BI KX2 391 RG 7112 Birinapant PF PRI 724 Lintuzumab Bi-213 Belinostat Volasertib Lestaurtinib SGI-110 Temozolomide Ganetespib Omacetaxine Liriilimumab Lenalidomide Treosulfan Sapacitabine CPX-351 Vidaza Arsenic trioxide Induction CT or Consolidation OCV 501 WT1-A10+AS01B ASCI 131-I-anti-CD45 GVAX (posthsct) Imatinib Sorafenib AEG Midostaurin GRNVAC1 Trials in Multiple (or undefined) Settings AKN 028 Rebastinib Plerixafor BL 8040 Pracinostat p.dom-wt1-126 VAL-1000 Vorinostat Panobinostat rhh1.3 Sources: 1) ADIS; 2) IDDB; 3) ClinicalTrials.gov; 4) DH analysis Page 10

11 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. Page 11

12 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 highdose induction chemotherapy in patients with AML. March 22, 2012; n engl j med 366;12, p 1079 Page 12

13 Translating Genomic Analyses Into Drug Programs: Academics and Industry, with Support from Government and Philanthropy 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). 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 Page 13

14 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. AML: Acute myeloid leukemia; HSC: Hematopoietic stem cell. 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 Page 14

15 Large number of variants in myeloid malignancies appear to be in genes whose function is involved in epigenetic regulation of gene transcription 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 Page 15

16 Progress For Epigenetic Inhibitors as Cancer Therapies Epigenetic Inhibitors as Cancer Therapies Page 16

17 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?