Melinda Yushak, MD, MPH, a medical oncologist at Winship Cancer Institute of Emory University presents How to Approach Systemic Treatment for Metastatic Disease (Ocular Melanoma) at the 2016 CURE OM Patient & Caregiver Symposium.

1. Winship Cancer Institute of Emory University
How to Approach Systemic
Treatment for Metastatic Disease
Melinda L. Yushak, MD, MPH
Winship Cancer Institute
Emory University

2. Outline
• Background
– Metastatic disease
– Clinical Trials
• Treatment of Metastatic
Disease
– Targeted Therapy
– Immunotherapy

3. Metastatic Disease
• Stage IV
• Outside of the eye
• Discovered through
surveillance or after
symptoms
• Biopsy
https://en.wikipedia.org/wiki/Melanoma

4. 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

5. Why Participate in a Clinical Trial?
• Ocular melanoma is rare
• Ocular melanoma is unique
• More options
• Help people in the future

6. 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

7. 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

8. 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

9. 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

10. Treatment of metastatic disease
- Liver Directed Therapies
- Targeted Therapies
- Immunotherapy

11. Treatment Options
• Individualized
• Standard of Care
• Clinical Trials
– Availability
– Eligibility
– Additional options
– Only presenting ocular trials

12. Treatment of metastatic disease
- Liver Directed Therapies
- Targeted Therapies
- Immunotherapy

13. 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

14. 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

15. Treatment of metastatic disease
- Liver Directed Therapies
- Targeted Therapies
- Immunotherapy

16. 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

17. 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

18. Targeted Therapy

19. Targeted Therapy

20. Targeted Therapy

21. 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

22. Cabozantinib
• Tyrosine kinase inhibitor
• RET, MET, VEGFR2

23. 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

24. LXS196
• Oral drug
• Phase I
– Increasing doses of medications

25. LXS196
• Protein kinase C (PKC) inhibitor

26. Combining Targeted Therapy
• Phase Ib
• AEB071 and BYL719
• Oral drug
• Twice a day and once a day
• Increasing dose of medications

27. Combining Targeted Therapy
• PKC Inhibitor
• PI3Kα Inhibitor

28. Vorinostat
• Phase II
• Oral drug
• Twice a day for three days every week
• GNAQ/GNA11 Mutation

29. Vorinostat
• HDAC inhibitor
• HDAC involved in expression of DNA
http://www.farydak.com/globalassets/farydak2/images/1.3-img_1.png

30. Vorinostat
• Fatigue
• Diarrhea
• Nausea
• Taste changes
• Increased blood sugar
• Increased creatinine
• Low platelet count

31. Treatment of metastatic disease
- Liver Directed Therapies
- Targeted Therapies
- Immunotherapy

32. Immune System
• Recognizes Threats
• Defends your body

33. How the Immune System Works

34. Cells of the Immune System

35. Antibodies
• Protein produced by body
• Identify and help neutralize threats
http://www.nwfsc.noaa.gov/hab/habs_toxins/marine_biotox
ins/detection/images/AntibodyMolecule.jpg

36. Immunotherapy
• Ipilimumab
• Anti-PD1
Nature Reviews Clinical Oncology Volume: 11, Pages:24–37 Year published:(2014)

37. Immunotherapy

38. Balance of the Immune System
• Autoimmunity
– Type 1 diabetes, rheumatoid arthritis,
inflammatory bowel disease
• Illness
– Bacterial infections
– Cancer

39. 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

40. The Immune System and Cancer
• Cancer cells use immune checkpoint proteins
to stop immune activity
– The immune system does not fight cancer
effectively

41. Immunotherapy
• Unlike traditional chemotherapy
– Is not cytotoxic
• Uses the power of the immune system to
control cancer
• Works through different ways
– Vaccines
– Injectable Medications

42. Immunotherapy for Melanoma
• Ipilimumab
– FDA approved in 2011
• Nivolumab
– FDA approved in 2014
• Pembrolizumab
– FDA approved in 2014

43. Immunotherapy for Melanoma
J Clin Oncol 31, 2013 (suppl; abstr 3003^)

44. Immunotherapy for Melanoma

45. Immunotherapy for Melanoma
“prevents the immune system for applying the
brakes”

46. Ipilimumab
• IV Treatment
• Given once every 3 weeks
• A total of 4 doses
• Anti-CTLA4

47. Nivolumab
• IV Treatment
• Given once every 2-3 weeks
• Continues for up to two years
• Anti-PD1

48. 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

49. Pembrolizumab
• IV Treatment
• Given once every 3 weeks
• Continues for up to two years
• Anti-PD1

50. 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

51. Availability
• Approved by the FDA
• Clinical trials available specifically for uveal
melanoma
– Ipi and nivo
– Pembro

52. Glembatumumab Vedotin
• Phase II Trial
• IV treatment every 3 weeks
• Antibody-drug conjugate

53. Tumor Infiltrating Lymphocytes (TIL)
• Phase II Trial at NIH
• Chemotherapy followed by TIL
• May receive aldesleukin (IL-2)
• Hospital stay for about 4 weeks

54. 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

55. Vaccine and IDO inhibitor
• IDO promotes suppression and tolerance
• Some cancers overexpress IDO
• Vaccine has several antigens found in
melanoma

56. Vaccine and IDO inhibitor
• Oral pills twice a day
• 6 injections over a 98 day period

57. 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

58. 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

59. Thank you
• Melanoma Research Foundation
• Ragi Kudchadkar, MD
• David Lawson, MD
• Melanoma Team at Emory

60. Questions ?