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 ?