DISCLOSURES FOR CHARLES SAWYERS, M.D. Board of Directors of Novartis Co-founder of ORIC Pharmaceuticals Co-inventor of enzalutamide and apalutamide, entitled to royalties from UCLA Science advisor: Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra and PMV Co-founder of Seragon, purchased by Genentech/Roche in 2014 Non-profit activities: National Cancer Advisory Board; Science Trustee, CSHL RFP-luminal CK5 GFP-basal DAPI Overcoming resistance to molecularly targeted cancer therapy Charles L. Sawyers, M.D. Howard Hughes Medical Institute Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center The first gatekeeper mutation: T315I in chronic myeloid leukemia WILD-TYPE T315I MUTANT (MODEL) STI571 = imatinib (Gleevec) Gorre et al Science, 2001 Overcoming Resistance with Next Generation Kinase Inhibitors -longer response duration -reduced toxicity through selectivity for mutant allele Sequist et al Sci TM 2011; Chen et al J Med Chem 2018 A New Drug Resistance Challenge: Lineage Plasticity TP53WT, RB1WT TP53Alt, RB1Alt Normal Gland Fixed Lineage Lineage Plasticity (luminal) Antiandrogen (luminal/basal/NE) CRPC CRPC Tumor cells can change identity: -epithelial to mesenchymal (EMT) AR Dependent AR Independent -neuroendocrine (small cell, NEPC) (AR amplification/mutation (loss of luminal identity) GR bypass) Mu et al Science, 2017 Examples: lung cancer, prostate cancer, melanoma Can we solve these challenges with combination therapy? 1. Precedent from infectious disease (TB, HIV) 2. Emerging examples in targeted cancer therapy -RAF+MEK inhibitor is superior to RAF inhibitor alone -additional benefit of reduced side effects (squamous skin cancer, keratoacanthomas) -even more dramatic benefit in adjuvant setting -anti-CTLA4 + anti-PD1 in BRAF wild-type melanoma 3. Scientific rationale is compelling, but few examples have made it into practice. Why not? -combo toxicity is real (but manageable with new dose/schedule?) -heterogeneity may demand 3-4 drug combinations -treat early! Larkin et al NEJM 2014; Robert et al NEJM 2014; Long et al NEJM 2017.