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Winship Cancer Institute of Emory University
How to Approach Systemic Treatment for Metastatic Disease
Melinda L. Yushak, MD, MPHWinship Cancer Institute
Emory University
Outline• Background– Metastatic disease– Clinical Trials
• Treatment of Metastatic Disease– Targeted Therapy– Immunotherapy
Metastatic Disease• Stage IV• Outside of the eye• Discovered through
surveillance or after symptoms
• Biopsy
https://en.wikipedia.org/wiki/Melanoma
Where does ocular melanoma go?• Most common site is
liver• Lung, bone, skin, lymph
nodes• Any area of the body
.https://en.wikipedia.org/wiki/Melanoma
Why Participate in a Clinical Trial? • Ocular melanoma is rare
• Ocular melanoma is unique
• More options
• Help people in the future
What is involved in a Clinical Trial?
• Trials have rules– Only at certain sites– Must follow strict rules about giving treatments– Each trial has unique rules• Physician familiar with the site will be able to tell if you
are eligible
Do I have to be in a Clinical Trial? • There are treatment options outside of trials
• Standard of care may be a good option depending on your situation
What types of trials are there? • Phase I– Researchers test an experimental drug or
treatment in a small group of people for the first time. The researchers evaluate the treatment’s safety, determine a safe dosage range, and identify side effects.
http://www.fda.gov/ForPatients/ClinicalTrials/Types/ucm20041762.htm
What types of trials are there? • Phase 2– The experimental drug or treatment is given to a
larger group of people to see if it is effective and to further evaluate its safety.
• Phase 3– The experimental study drug or treatment is given
to large groups of people. Researchers confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely.http://www.fda.gov/ForPatients/ClinicalTrials/Types/ucm20041762.htm
Treatment of metastatic disease- Liver Directed Therapies- Targeted Therapies- Immunotherapy
Treatment Options• Individualized• Standard of Care• Clinical Trials– Availability– Eligibility– Additional options– Only presenting ocular trials
Treatment of metastatic disease
- Liver Directed Therapies- Targeted Therapies- Immunotherapy
Liver Directed Therapies• Local therapies to the liver– Surgery– Selective Internal Radiation Therapy (SIRT)– Transarterial Chemoembolization (TACE)– Hepatic Artery Infusion• Percutaneous Hepatic Perfusion (PHP)
TO BE DISCUSSED TOMORROW BY DRS. RUSSELL, KHAN, AND KIES
Liver Directed Therapies• Local therapies to the liver– May be a good option for some patients– Treats areas in the liver– Does not treat other sites of disease
TO BE DISCUSSED TOMORROW BY DRS. RUSSELL, KHAN, AND KIES
Treatment of metastatic disease
- Liver Directed Therapies
- Targeted Therapies- Immunotherapy
What is Targeted Therapy?• Targeted therapies act on specific molecular targets
that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells.
• Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells.
• Targeted therapies are often cytostatic (that is, they block tumor cell proliferation), whereas standard chemotherapy agents are cytotoxic (that is, they kill tumor cells).
http://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet
What is Targeted Therapy?• Molecular targeted drugs
• Molecularly targeted therapies
• Precision medicine
http://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet
Targeted Therapy
Targeted Therapy
Targeted Therapy
Targeted Therapy in Melanoma• Cutaneous melanoma can have a BRAF
mutation– Dabrafenib and Trematinib– Vemurafenib and Cobimetinib
• Ocular melanoma rarely has a BRAF mutation– GNAQ and GNA 11– Clinical trials
Cabozantinib• Tyrosine kinase inhibitor• RET, MET, VEGFR2
Cabozantinib• Oral drug• Phase II Randomized Trial• Comparing to Temozolomide or dacarbazine• Randomized
• Common side effects• Diarrhea, mouth sores, Palmar-plantar erythrodyesthesia,
fatigue, high blood pressure, decreased appetite, liver and blood count abnormalities
• Severe bleeding and clotting risks
LXS196• Oral drug • Phase I– Increasing doses of medications
LXS196• Protein kinase C (PKC) inhibitor
Combining Targeted Therapy• Phase Ib • AEB071 and BYL719• Oral drug• Twice a day and once a day• Increasing dose of medications
Combining Targeted Therapy• PKC Inhibitor• PI3Kα Inhibitor
Vorinostat• Phase II• Oral drug• Twice a day for three days every week• GNAQ/GNA11 Mutation
Vorinostat• HDAC inhibitor• HDAC involved in expression of DNA
http://www.farydak.com/globalassets/farydak2/images/1.3-img_1.png
Vorinostat• Fatigue• Diarrhea• Nausea• Taste changes• Increased blood sugar• Increased creatinine• Low platelet count
Treatment of metastatic disease
- Liver Directed Therapies- Targeted Therapies
- Immunotherapy
Immune System• Recognizes Threats• Defends your body
How the Immune System Works
Cells of the Immune System
Antibodies• Protein produced by body • Identify and help neutralize threats
http://www.nwfsc.noaa.gov/hab/habs_toxins/marine_biotoxins/detection/images/AntibodyMolecule.jpg
Immunotherapy• Ipilimumab• Anti-PD1
Nature Reviews Clinical Oncology Volume: 11, Pages:24–37 Year published:(2014)
Immunotherapy
Balance of the Immune System• Autoimmunity– Type 1 diabetes, rheumatoid arthritis,
inflammatory bowel disease
• Illness– Bacterial infections– Cancer
The Immune System and Cancer• Cancer cells look similar to normal body cells– Makes it difficult to recognize
http://vcvoices.org/wp-content/uploads/2015/09/wolf-in-sheeps-clothing.jpg
The Immune System and Cancer• Cancer cells use immune checkpoint proteins
to stop immune activity– The immune system does not fight cancer
effectively
Immunotherapy• Unlike traditional chemotherapy – Is not cytotoxic
• Uses the power of the immune system to control cancer
• Works through different ways– Vaccines– Injectable Medications
Immunotherapy for Melanoma• Ipilimumab– FDA approved in 2011
• Nivolumab– FDA approved in 2014
• Pembrolizumab– FDA approved in 2014
Immunotherapy for Melanoma
J Clin Oncol 31, 2013 (suppl; abstr 3003^)
Immunotherapy for Melanoma
Immunotherapy for Melanoma
“prevents the immune system for applying the brakes”
Ipilimumab• IV Treatment• Given once every 3 weeks• A total of 4 doses• Anti-CTLA4
Nivolumab• IV Treatment• Given once every 2-3 weeks• Continues for up to two years• Anti-PD1
Ipilimumab and Nivolumab• Can be combined
• Ipi and nivo given every 3 weeks for 4 doses
• Nivo continued every 2 weeks for up to 2 years
Pembrolizumab• IV Treatment• Given once every 3 weeks• Continues for up to two years• Anti-PD1
Side Effects• Not for people with autoimmune diseases• Different rates for combination and single
agents– Fatigue– Rash– Endocrinopathies– Diarrhea– Inflammation in the lung, liver, and kidneys
Availability• Approved by the FDA
• Clinical trials available specifically for uveal melanoma– Ipi and nivo– Pembro
Glembatumumab Vedotin• Phase II Trial• IV treatment every 3 weeks• Antibody-drug conjugate
Tumor Infiltrating Lymphocytes (TIL)
• Phase II Trial at NIH
• Chemotherapy followed by TIL
• May receive aldesleukin (IL-2)
• Hospital stay for about 4 weeks
Tumor Infiltrating Lymphocytes (TIL)
https://www.jax.org/news-and-insights/jax-blog/2015/august/five-terms-you-need-to-know-about-cell-therapies-for-cancer
Vaccine and IDO inhibitor• IDO promotes suppression and tolerance• Some cancers overexpress IDO• Vaccine has several antigens found in
melanoma
Vaccine and IDO inhibitor• Oral pills twice a day
• 6 injections over a 98 day period
Summary of Clinical Trials• NCT01585194 Phase II Study of Nivolumab in
Combination with Ipilimumab for Uveal Melanoma• NCT02363283 Glembatumumab Vedotin in Treating
Patients with Metastatic or Locally Recurrent Uveal Melanoma
• NCT02359851 Pembrolizumab in Treating Patients with Advanced Uveal Melanoma
• NCT01814046 Immunotherapy using Tumor Infiltrating Lymphocytes for Patients with Metastatic Ocular Melanoma
• NCT01961115 INCB024360 and Vaccine Therapy in Treating Patients with Stage III-IV Melanoma
Summary of Clinical Trials• NCT02273219 Trial of AEB071 in Combination
with BYL719 in Patients with Melanoma• NCT01587352 Vorinostat in Treating Patients
with Metastatic Melanoma of the Eye• NCT01835145 Cabozantinib-S-Malate
Compared with Temozolomide or Dacarbazine in Treating Patients with Melanoma of the Eye
• NCT02601378 A Phase I Study of LXS196 in Patients with Metastatic Uveal Melanoma
Thank you• Melanoma Research Foundation
• Ragi Kudchadkar, MD
• David Lawson, MD
• Melanoma Team at Emory
Questions ?