Dr. Marlana Orloff gives an update on targeted therapies currently being studied in clinical trials.

1. Marlana Orloff, MD
Assistant Professor
Thomas Jefferson University
Department of Medical Oncology
Clinical Trial Update
Targeted Therapies
Eyes on A Cure
Patient & Caregiver Symposium
4.6.19

2. Disclosures
• BMS: Speaker, consultant, advisory board, research funding
• Immunocore: Consultant, advisory board

3. Targeted Therapy
• What is “targeted therapy”
• Can think of it as drugs that interfere with specific molecules or
targets that are involved in the growth, progression, or spread of
cancer
• Typically we think of it differently than other types:
• Immunotherapy* (i.e. ipilimumab, nivolumab, pembrolizumab)
• Cytotoxic chemotherapy (i.e. carboplatin, paclitaxel, dacarbazine)
• Hormonal therapy (i.e. tamoxifen, leuprolide)
National Cancer Institute: Targeted Therapies

4. https://www.qiagen.com/ch/shop/genes-and-pathways/pathway-details/?pwid=301
• MANY MANY MANY
molecular targets
• GNAQ and GNA11
mutations found in
about 85% of cases
of UM
• BAP1 mutations
• Other mutations
SF3B1 and EIFAX

5. What Makes it a Good Target?
• Present in a decent amount of tumors
• Can be a mutation or overexpression
• Plays a key role in growth and survival
• Present in cancer cells but not normal cells
• Can target it safely without too much toxicity
National Cancer Institute: Targeted Therapies

6. Why Should We Get Excited About Targeted Therapy?
• Success in other cancers when the right target / right drug
has been discovered
• Imatinib for BCR-ABL mutations in AML
• Vemurafenib, dabrafenib, encorafenib for BRAF mutations in
cutaneous melanoma
• Traztuzumab for HER-2 overexpression in breast cancer
• Gefitinib and erlotinib for EGFR mutations in lung cancer

7. Wagle et al 2011

8. Targeted Attempts in Uveal Melanoma
Krantz et al 2017
Yang et al 2018
PKC Inhibition
AEB071
ORR: 3%
PFS: 15.2 weeks
MEK Inhibition
Selumetinib Phase 2
ORR: 14%
PFS: 15.9 weeks
Selumetinib Phase 3
ORR:
PFS:
Trametinib
ORR: 0%
PFS: 7.8 weeks
MEK + AKT
Trametinib + GSK795
ORR: 5%
PFS: 15.7 weeks
MEK + PI3K
AEB071 + BYL719
ORR: 0%
PFS: 7.6 weeks
RAF
Sorafenib
ORR: 0%
24 Week PFS: 31%
Mouriax et al 2016

10. Ardisia Crenata
• AKA Coral Berry, Christmas Berry, Australian Holly
• Primrose family of plants
• Compound FR900359 extracted from this plant
• In cell culture (NOT HUMANS) has been shown to inhibit the
GNAQ/GNA11 mutations
• Ways away from in human clinical trials
• Don’t eat this plant

11. Epigenetics … The Indirect Target
• What is epigenetics?
• “If DNA is like the hard drive that contains the information to
guide every cellular function, then epigenetic modulation acts as
software that regulates the packaging of DNA to guide potential
for gene expression patterns.” (Ahuja et al 2016)
• Pros of manipulating the epigenome (the stuff that regulates
the genes)
• Can indirectly target the un-targetable
• Reverse, re-program, silence, unsilence …

12. Cancer Research Product
Guide Edition 3, 2015.

13. Currently Available Clinical Trials
Drug Target Phase Disease State
LXS196 PKC Phase 1 Metastatic
BDV-523 ERK Phase 2 Metastatic
Selumetinib MEK Phase 1b Metastatic
PLX2853 BET Phase 1 Metastatic
Neraparib DNA MM Phase 2 Metastatic
Sunitinib KIT/VEGF Phase 2 Adjuvant
Vorinostat HDAC POC Adjuvant

14. THANK YOU