6/22/2017 TARGETING THE TARGETS IN 2017 TARGETING THE TARGETS IN 2017

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Elijah Wilcox
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1 TARGETING THE TARGETS IN 2017 Primary Care Focus Symposium July 1, 2017 Grace Wang MD I do not have any relevant financial relationships to disclose at this time TARGETING THE TARGETS IN 2017 What are the targets for breast cancer? What about targets for other cancers-do they cross different primaries-lung, breast, etc.? What can the primary care physician do about the host environment? FEMALE CANCER DEATH RATES

BREAST CANCER MARKERS Estrogen Receptor Progesterone Receptor Her 2 Neu TRIPLE NEGATIVE No Targeted Agents Approved TRIPLE NEGATIVE BREAST

MUTATION-1990 LINKED TO BREAST CANCER TRIPLE NEGATIVE TARGETS PARP repairs single stranded DNA breaks 1/3 of BRCA patients are triple

2 BREAST CANCER MARKERS Estrogen Receptor Progesterone Receptor Her 2 Neu TRIPLE NEGATIVE No Targeted Agents Approved TRIPLE NEGATIVE BREAST CANCER BASAL LIKE 1 BASAL LIKE 2 IMMUNOMODULATORY MESENCHYMAL MESENCHYMAL LIKE LUMINAL ANDROGEN RECEPTOR Mary Claire King BRCA GENE MUTATION-1990 LINKED TO BREAST CANCER TRIPLE NEGATIVE TARGETS PARP repairs single stranded DNA breaks 1/3 of BRCA patients are triple negative Link between the BRCA mutation and basal like features of triple negative breast cancer. BRCA mutations inhibit repair of double stranded DNA breaks 2

VELIPARIB/CARBOPLATIN TREATMENT IN TRIPLE NEGATIVE BREAST CANCER OLYMPIAD:PHASE

8% Progression free survival 7 months vs 4.

Niriparib Telazoparib Rucaparib 2014 Ovarian Cancer-Olaparib 2016 Ovarian

ANDROGEN RECEPTOR BLOCKADE 12-55% AR positive Bicalutamide AR Antagonist 424

3 VELIPARIB/CARBOPLATIN TREATMENT IN TRIPLE NEGATIVE BREAST CANCER OLYMPIAD:PHASE III OLAPARIB VS CHEMOTHERAPY HER 2 NEG /BRCA POSITIVE Response 59.9% vs 28.8% Progression free survival 7 months vs 4.2 months ASCO 2017 PARP INHIBITORS PARP INHIBITORS Iniparib Olaparib Veliparib Niriparib Telazoparib Rucaparib 2014 Ovarian Cancer-Olaparib 2016 Ovarian Cancer-Rucaparib 2017 Ovarian Cancer Niriparib ANDROGEN RECEPTOR MODULATORS ANDROGEN RECEPTOR BLOCKADE 12-55% AR positive Bicalutamide AR Antagonist 424 Triple Negative Patients Androgen Receptor >10% 6 Month Clinical benefit rate 19% 1 patient stable for greater than 4 years TBCRC 011 3

ANDROGEN RECEPTOR BLOCKADE Enzalutamide 404 Triple negative patients 118 Androgen Receptor Positive 6 month clinical benefit 36% vs 6% AR negative ANDROGEN RECEPTOR MODULATORS Table 1.

gov identifier Phase Patient population Treatment NCT01889238 II Advanced AR+ TNBC Enza NCT02457910 I/II Postmenopausal AR+, metastatic TNBCEnza +/ taselisib NCT02348281 II Postmenopausal AR+,

4 ANDROGEN RECEPTOR BLOCKADE Enzalutamide 404 Triple negative patients 118 Androgen Receptor Positive 6 month clinical benefit 36% vs 6% AR negative ANDROGEN RECEPTOR MODULATORS Table 1. Clinical trials of AR therapies in breast cancer. ClinicalTrials.gov identifier Phase Patient population Treatment NCT II Advanced AR+ TNBC Enza NCT I/II Postmenopausal AR+, metastatic TNBCEnza +/ taselisib NCT II Postmenopausal AR+, metastatic TNBCBicalutamide NCT I Postmenopausal metastatic or locally advanced, endocrine responsive-her2- and TN-AR+ CR1447 (4-OH-testosterone) NCT II Postmenopausal pretreated metastatic, AR+ DHEA NCT II Postmenopausal pretreated metastatic, AR+ DHEA NCT II Advanced AR+ TNBC GTx-024 NCT I/II Advanced AR+ TNBC; ER+/Her2- BC VT-464 NCT II Advanced AR+ BC Bicalutamide + palbociclib NCT IIB Advanced AR+ BC Taxol+/ enzalutamide AR, androgen receptor; BC, breast cancer; DHEA; ER, estrogen receptors; Her2, human epidermal growth factor receptor 2; TNBC, triple-negative breast cancer; VT, ANDROGEN RECEPTOR MODULATORS PROGRAMMED DEATH INHIBITOR Bicalutamide- Prostate Cancer Enzalutamide Prostate Cancer Pembrolizumab PD-1 Inhibitor Checkpoint inhibitor PD-1 INHIBITOR-TRIPLE NEGATIVE ASCO 2017 Keynote 86 Response 4.6% Greater than or equal 1 chemotherapy not dependent on PDL1 expression ASC ISPY Complete response tripled from 20% to 60% in triple negative patients prior to surgery PEMBROLIZUMAB: MELANOMA, NONSMALL CELL LUNG CANCER, HEAD AND NECK, HODGKINS 2014 Melanoma 2016 NSCLC (nonsquamous)- PDL 1 greater than 50% first line monotherapy or if PDL-1 is greater than 1% with pemetrexed and carboplatin or second line 2016 Recurrent or metastatic head and neck 2017 Hodgkins after 3 or more lines therapy 4

5 PD-L1 INHIBITORS-BREAST CANCER Avelumab SABCS-2015 Triple negative 8.6% response Higher if PDL1 + response P Atezolizumab AACR 2017 First line therapy 25% response Median duration response responders 21 months PD-L1 INHIBITORS-OTHER TUMORS Avelumab 2017-Merkel Cell 2017-Bladder cancer-failed platinum Atezolizumab 2016-Nonsmall cell lung cancer-failed platinum therapy Bladder cancer HER 2 POSITIVE BREAST CANCER 20-25% HER 2 POSITIVE HER 2 POSITIVE THERAPIES Therapies Trastuzumab 1998 Lapatinib 2007 Pertuzumab 2012 Pertuzumab/Neoadjuvant 2013 Ado-trastuzumab Emtansine 2013 HER 2 DIRECTED THERAPIES TRASTUZUMAB-GASTRIC OR GE JUNCTION 2010-Gastric or GE Junction Her 2 neu positive-10-25% Overall survival months in trastuzumab arm compared with 11.1 months with chemotherapy alone 5

6 ONE OF THE FIRST TARGETS-ESTROGEN RECEPTOR ESTROGEN / PROGESTERONE RECEPTOR 1893 Oophorectomy- Dr. George Beatson 3 patients 1958 Dr. Elwood Jensen University of Chicago 75% ER positive SELECTED ESTROGEN RECEPTOR MODIFIERS(SERM) AROMATASE INHIBITORS 1977 AROMATASE INHIBITORS SELECTIVE ESTROGEN RECEPTOR DOWNREGULATORS 1995 Anastrozole 1998 Letrozole 1999 Exemestane 6

SELECTIVE ESTROGEN RECEPTOR DOWNREGULATORS FULVESTRANT 2002 Fulvestrant-competition for estrogen binding to ER and degradation of ER Non cross resistant to tamoxifen MTOR PATHWAY-EVEROLIMUS MTOR

Sorafenib 2011 Pancreatic Neuroendocrine tumor(pnet) 2012 Subependymal Giant Cell Astrocytoma (SEGA) with Tuberous Sclerosis Complex (TSC) 2016 Non-functional neuroendocrine tumors (NET) of

7 SELECTIVE ESTROGEN RECEPTOR DOWNREGULATORS FULVESTRANT 2002 Fulvestrant-competition for estrogen binding to ER and degradation of ER Non cross resistant to tamoxifen MTOR PATHWAY-EVEROLIMUS MTOR PATHWAY- EVEROLIMUS 2012-Everolimus-MTOR inhibitor resistant to nonsteroidal AIimprovement progression free survival 6 months with Exemestane 2009 Renal cell carcinoma after failure Sunitinib and Sorafenib 2011 Pancreatic Neuroendocrine tumor(pnet) 2012 Subependymal Giant Cell Astrocytoma (SEGA) with Tuberous Sclerosis Complex (TSC) 2016 Non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. CYCLIN D 4/6 KINASE INHIBITORS CYCLIN D 4/6 KINASE INHIBITORS CD4/6 K INHIBITOR 2015 Palbociclib +Letrozole Increased progression free survival from 14.5 months to 24.8 months 2017 Ribociclib +Aromatase inhibitor Progression free survival 63% 18 months vs 42% 2017-ASCO- Abemaciclib + Fulvestrant median progression free survival 16.4 vs 9.3 months 7

8 CHRONIC MYELOGENOUS LEUKEMIA PHILADELPHIA CHROMOSOME 1960 IMATINIB: CHRONIC MYELOGENOUS LEUKEMIA TARGETED AGENTS-CML 2001 CR 95% DASATINIB NILOTINIB BOSUTINIB SECOND LINE PONATINIB T3151 MUTATION IMATINIB-GIST-KIT PDGFRA NON SMALL CELL LUNG CANCER U.S. patients 53 % had a partial response 2008 Adjuvant- can lower recurrence rate 54% 8

EGFR IS HER 1 NONSMALL CELL LUNG CANCER 2003 GEFITINIB 2004 ERLOTINIB NSCLC T790M MUTATION

GEFITINIB EGFR-T790M 63% RESISTANT TO TKI OSIMERTINIB ALK 5% (10-15%) NONSMOKER CRIZOTINIB ROS

9 EGFR IS HER 1 NONSMALL CELL LUNG CANCER 2003 GEFITINIB 2004 ERLOTINIB NSCLC T790M MUTATION NONSMALL CELL T790M MUTATION 2016 Osimertinib Progression free survival increased from 4.4 months chemotherapy to 10.1 months. LIQUID BIOPSIES NON SMALL CELL LUNG CANCER-2017 TARGET % DRUG 10%(50% NON SMOKER) ERLOTINIB, GEFITINIB EGFR-T790M 63% RESISTANT TO TKI OSIMERTINIB ALK 5% (10-15%) NONSMOKER CRIZOTINIB ROS 1 2% CRIZOTINIB PDL-1 >50% 30% PEMBROLIZUMAB PDL-1 >1% FAILED FIRST LINE CHEMO FAILED FIRST LINE CHEMO FAILED FIRST LINE CHEMO 66% PEMBROLIZUMAB NIVOLUMAB ATEZOLUZIMAB 9

THERAPY IN THE GENOMIC ERA Salivary Cancer

PRIMARY CARE PHYSICIAN DO FOR OUR CANCER

10 NONSMALL CELL LUNG CANCER-KEYNOTE 24 PDL1>50% OVERALL SURVIVAL PEMBROLIZUMAB VS CHEMOTHERAPY UMBRELLA TRIAL Treatment A Colon cancer Molecular Profile Treatment B Treatment C NEJM RECK,MARTIN NOV BASKET TRIAL RETHINKING TARGETED THERAPY IN THE GENOMIC ERA Salivary Cancer Molecular Abnormality Targeted Drug Colon Cancer Mesothelioma RETHINKING TARGETED THERAPY IN THE GENOMIC ERA WHAT CAN A PRIMARY CARE PHYSICIAN DO FOR OUR CANCER PATIENTS? Routine Screening Improve the host environment Avoid hormone replacement especially if ER positive Exercise Limit alcohol Low fat diet Treat obesity 10

11 INSULIN GROWTH FACTOR RECEPTORS RETHINKING TARGETED THERAPY IN THE GENOMIC ERA Thank You! 11

CLINICAL TRIALS ACC. Jul 2016

CLINICAL TRIALS ACC. Jul 2016 CLINICAL TRIALS ACC Jul 2016 Glioblastoma BRAIN A071102 A Phase II/III Randomized Trial of Veliparib or Placebo in Combination With Temozolomide in Newly Diagnosed Glioblastoma With MGMT Promoter Hypermethylation