Targeted Therapy in Acute Myeloid Leukemia

1. Targeted Therapy in Acute Myeloid Leukemia Ross L. Levine M.D. Human Oncology and Pathogenesis Program Leukemia Service, Department of Medicine Memorial Sloan Kettering Cancer Center Weill Cornell School of Medicine

2. Acute Myeloid Leukemia Remains Associated with Poor Overall Survival Even with intensive induction chemotherapy/transplantation most patients die of their disease new insights are needed Issa, Kantarjian et al, Cancer 2008

3. Mutational Analysis of AMLHas Identified Many New Classes of Mutations DNA Methylation Chromatin State TCGA AML NEJM 2013

4. IDH1 Mutations in AML* Whole genome sequencing identified somatic IDH1 mutation->seen in 8% of 187 additional samples *Mardiset al NEJM 2009

5. IDH1 mutations acquire a novel enzymatic function • Metabolomic profiling found that IDH1 mutant allele expression resulted in production of 2-hydroxyglutarate, an aberrant metabolite • IDH1 mutant cancers produce a vast excess of 2HG • Leukemias • Brain Tumors • Pancreatic Cancer • Sarcomas • Many others Dang et al. Nature 2009

6. IDH2 mutations in AML • Elevated 2-HG levels in IDH1-wildtype patients led to discovery of IDH2 mutations in AML in patients from ECOG and Alliance Cooperative Group Trials • The overall incidence of IDH1/2 mutations is 15-30%, most common in older patients, normal karyotype • However, it was not known HOW these mutations contribute to AML or other cancers Ward et al. Cancer Cell 2010 Marcucci et al JCO 2010 Gross et al. J Ex Med 2010

7. Human genetics is always right: using mutational studies to elucidate AML pathogenesis • By profiling primary patient samples we can improve our understanding of AML biology • We hypothesized that we could elucidate the function of IDH mutations in AML by identifying mutations exclusive of IDH mutations of AML

8. ECOG 1900 Cohort: IDH1/2 mutations mutually exclusive of TET2 mutations Figueroa, Abdel-Wahab, Lu et al,Cancer Cell 2010

9. Mutations in IDH1/2 and TET2 lead to impaired DNA Hydroxymethylation and Increased DNA Methylation Can these mutations be therapeutically targeted? Figueroa, Abdel-Wahab, Lu et al,Cancer Cell 2010

10. Development of Specific inhibitors of IDH1/2* • Small molecule inhibitors of IDH2 and IDH1 have been developed with potent, specific on target effects • In vitro and in vivo assays in mouse models and patient samples show significant efficacy alone and in combination with other AML therapies • Led to first-in-man clinical trials of AG-221, IDH2-specific inhibitor in relapsed/refractory IDH2-mutant AML (Eytan Stein, PI) *Kate Yen/Agios, Alan Shih

11. Efficacy of IDH2 Inhibitor AG-221 in Relapsed/Refractory AML C7 C1 C2 C3 C4 C5 C6 CR Transplant Bone Fracture, Death Unrelated 30 mg BID CRp CR PR On Study CR* Off Study CR Response 50 mg BID PR Bone Marrow CRi CR** • Significant clinical activity in AML patients with IDH2 mutations (required for enrollment) • PD studies show target inhibition at doses which show efficacy • Evidence of differentiation in vivo with neutrophil expansion followed by clinical response 75 mg BID PR 100 mg QD CR CRp 100 mg BID PR 150 mg QD PR Stein et al. AACR, 2014; Agresta et al. EHA, Milan, 2014

12. Conclusions • Genome sequencing of AML patients can identify novel, clinically important mutations • Can use these data to improve our understanding of AML biology • Can lead to the development of novel, molecularly targeted therapies

13. Acknowledgements • NYU • IannisAifantis • Levine Lab • Alan Shih • Kaitlyn Shank • Jay Patel • MSKCC • Craig Thompson • Eytan Stein • Kristina Knapp • Omar Abdel-Wahab • Scott Armstrong • Marty Tallman • Scott Lowe • Chicago • Chuan He • Lucy Godley • Einstein • UliSteidl • Laura Barreyo • Ileana-Antony Debre • ECOG • Elisabeth Paietta • Robert Comis • Cornell • Ari Melnick • Chris Mason • Agios • Kate Yen • Sam Agresta • David Scheikein • Michigan • Ken Figueroa • Funded by National Cancer Institute