Presentation by Rich Carvajal, Memorial Sloan-Kettering (March 24, 2012, Santa Monica)

1. Patient
Education
Series
Systemic Treatment Options
for Uveal Melanoma
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without the express permission of the Richard D. Carvajal, MD
Ocular Melanoma Foundation (OMF).
Memorial Sloan-Kettering Cancer Center
These materials are for educational
use only. No information provided
herein constitutes a medical
diagnosis, advice, or treatment.
Please consult a healthcare
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herein.

2. Richard D. Carvajal, MD
Memorial Sloan-Kettering Cancer Center
Rich Carvajal is a medical oncologist with a special interest in the
treatment of melanoma and sarcoma. His research is focused on the
development of new targeted drugs and immunologic therapy against
these diseases, with the hope of attacking cancer cells while minimizing
damage caused to normal cells.
Education: MD, New York University School of Medicine
Residencies: University of Michigan Medical Center
Fellowships: Memorial Sloan-Kettering Cancer Center
Board Certifications: Internal Medicine, Medical Oncology, Hematology
Clinical Expertise: Melanoma; Sarcoma
Appointments for New Patients: 646-497-9067
Phone: 646-888-4161
Patient
Education
Series

3. Systemic Treatment Options
for Uveal Melanoma
Richard D. Carvajal, M.D.
Assistant Attending Physician
Melanoma/Sarcoma Service
Memorial Sloan‐Kettering Cancer Center

4. Who is a Cancer Survivor?
“An individual is considered a cancer survivor from the
time of diagnosis through the balance of his or her life.
Family members, friends, and caregivers are also
impacted by the survivorship experience and are
therefore included in this definition.”
-National Coalition for Cancer Survivorship
Consolidation
Initial Long-Term
Active Therapy Therapy/
Diagnosis Survivorship
Observation
Twombly R. J Natl Cancer Inst. 2004.
Mullan F. N Engl J Med. 1985.

5. Topics
1. What is uveal melanoma?
2. What FDA approved treatment options are available
for this disease?
3. What clinical trials are currently available specifically
for patients with uveal melanoma?
4. How do I find and participate in a clinical trial?

6. Ocular Melanoma
• Uveal Tract
– >95% of ocular
melanomas
• Conjunctiva
– <4% of ocular
melanomas
• Orbit/Eyelid
– <1% of ocular
melanomas

7. Uveal Melanoma
 The most common primary eye cancer in adults
 Represents 5% of all melanomas
 Biologically distinct from skin melanoma
 Plaque brachytherapy (radiation treatment) or enucleation
(surgery) is effective in eliminating the disease in the eye
 Once it has spread from the eye, treatment is challenging

8. Timeline for FDA Approved Drugs
for the Adjuvant Treatment of Melanoma
1994 2011
PEG IFN approved
for Stage II/III
Melanoma
HD IFN approved
for Stage II/III
Melanoma

9. Interferon-
• Approved in 1994 based on results of ECOG 1684
• Administered 20 MU/m2 IV, 5 days/week x 4 weeks, then 10 MU/m2 SC,
TIW x 11 months
• With a median f/u of 7 years,
ECOG 1684 demonstrated:
– 9% survival benefit at 5
years
– Prolongation in median
survival from 2.8 to 3.8
years
Relapse-free survival Overall survival

10. ECOG 1690: High Dose vs Low P = 0.05 for HD
P = 0.17 for LD
Dose vs Observation
Relapse-free survival
P = NS
Overall survival
Kirkwood et al. JCO 18:2444, 2000

11. Adjuvant Interferon in Uveal Melanoma
 Enrolled 121 patients with high risk ocular melanoma (118 PBI; 3 enucleation)
 Age > 65, tumor diameter > 15mm, ciliary body involvement, extrascleral
extension
 Treated with 3 MIU IFN-alfa-2a subq 3 times/week x 2 years
 Compared with historical controls matched for age, tumor diameter, gender,
survival time from primary tx to initiation of adjuvant tx
Lane et al. Ophthalmology. Volume 117, Issue 9, September 2010.

12. Adjuvant Uveal Melanoma Trials
(03/2012)
Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID
mRNA Transfected Dendritic Cell Radboud University,
II NCT00929019
Vaccination Netherlands
DTIC & Interferon Alfa‐2b II Cleveland Clinic NCT01100528
San Diego Pacific Onc &
Sunitinib, Tamoxifen, and Cisplatin II NCT00489944
Hematology
Challenges of developing effective adjuvant trials:
 What treatments should be tested?
 Which patients should be enrolled onto the study?
 What defines a “positive” study?
 How many patients are required to prove that a
treatment is effective?
www.clinicaltrials.gov

13. www.clinicaltrials.gov
• A service of the US National Institutes of Health
• Offers up-to-date information on federally and privately
supported clinical trials for a wide range of diseases and
conditions.
• Currently contains 116,889 trials* sponsored by the
National Institutes of Health, other federal agencies, and
private industry.
• Studies listed in the database are conducted in all 50
States and in 178 countries*
(* - as of November 2011)

14. Timeline for FDA Approved Drugs
for Melanoma
2011
1975 1994 1998 2011 2011
DTIC approved Aldesleukin (IL2) PEG IFN approved
for Stage IV approved for for Stage II/III
Melanoma Stage IV Melanoma Melanoma
HD IFN approved
for Stage II/III
Vemurafenib
Melanoma
Ipilimumab

15. Vemurafenib inhibits BRAFV600E Kinase
RTK
RAS
40-60% of melanomas BRAFV600E
RAF
ATP VEMURAFENIB
(PLX4032, RO5185426)
MEK
ATP
ERK
Cellular
Proliferation

16. Vemurafenib
Screening
960 mg po bid
(N=337)
BRAFV600E mutation
Randomization
Stratification
• Stage N=675
• ECOG PS (0 vs 1) Dacarbazine
• LDH level (↑ vs nl)
• Geographic region 1000 mg/m2 iv q3w
(N=338)
Courtesy of P Chapman

17. Maximal tumor shrinkage by individual patient
(RECIST 1.1)
>100
Vemurafenib
Percent change from baseline in sum of tumor diameters
CR: 0.9% PR: 47.5%
50 ORR: 48.4%
0
-50
-100
>100 Dacarbazine
CR: 0% PR: 5.5%
50
ORR: 5.5%
0
-50
-100
Courtesy of P Chapman

18. 0/276 BRAF 0/195 NRAS
Mutations Mutations

19. Differential Sensitivity of Uveal Melanoma Cell Lines
to PLX4720 by Mutational Status
Ambrosini et al. AACR 2010, abstr 5035.

20. Ipilimumab: Mechanism of Action
T-cell T-cell T-cell
activation inhibition potentiation
CTLA4
T cell T cell T cell
CD28 CD28 CTLA4
CTLA4
TCR TCR TCR
B7 IPILIMUMAB
MHC B7 MHC MHC B7 blocks
CTLA-4
APC APC APC

21. MDX010-20: Study Design
Ipilimumab + gp100 (N=403)
R
A
Pre-treated N
Metastatic D
Melanoma Ipilimumab + placebo (N=137)
(N=676)
O
M
I
Z
E gp100 + placebo (N=136)
Courtesy of S O’Day

22. Kaplan-Meier Analysis of Survival
Ipi + gp100 (A)
Ipi alone (B)
gp100 alone (C)
Ipilimumab Alone versus GP100 Alone
HR 0.66
Median OS 10.1 vs 6.4 months
P value 0.003
1 2 3 4
Years
Survival Rate Ipi + gp100 N=403 Ipi + pbo gp100 + pbo
N=137 N=136
1 year 44% 46% 25%
2 year 22% 24% 14%
Courtesy of Steven O’Day

23. Efficacy of Ipilimumab in Uveal Melanoma
Week 1: n = 13
Week 12: n = 9
2 SD; 7 POD
Week 24: n = 5
3 SD; 2 POD
Week 36: n = 3
1 SD; 2 POD
Danielli et al. Cancer Immunol Immunother. 2011.

24. Response to Systemic Therapy
Author Study n RR OS/PFS
Homsi et al, 2010 Phase 2 Docosahexaenoic 22 4% 9.8 mo OS
acid-Paclitaxel (1/22)
Penel et al, 2008 Phase 2 Imatinib 10 0% 10.8 mo OS
Schmittel et al, Phase 2 Gem/Treosulfan vs 48 2% 2-3 mo PFS
2006 Treosulfan (1/48)
Oneill et al, 2006 Phase 2 DTIC/Treosulfan 15 0% 3 mo PFS
Schmittel et al, Phase 2 17 0% 3 mo PFS
2005 Gem/Cis/Treosulfan
Schmidt-Hieber et Phase 2 Bendamustine 9 0% NR
al, 2004
Bedikian et al, Phase 2 Temozolomide 14 0% 1.8 mo TTP
2004
Kivelä et al, 2003 Phase 2 BOLD + IFN 22 0% 1.9 mo PFS
157 1.3%
2/157

25. More than one disease…
Gnaq/11
4%
"Wild-type"
28%
BRAF
45%
KIT Melanoma
3%
NRAS
20%

26. G Protein Biology
Gβ
Gα
Gγ
GDP
GTP

27. Gq/11 Mutations are Frequent
in Primary UM Samples
GNAQ Exon 5
Q209P
Onken et al, 2008 49% 33%
(33/67)
Q209L
Van Raamsdonk et al, 2008 46%
67%
(22/48)
GNAQ Ex 4 GNAQ Ex 5 GNA11 Ex 4 GNA11 Ex 5
Blue Nevi 1.0% 54.7% 1.0% 6.5%
(1/96) (76/139) (1/96) (9/139)
Primary UM 2.8% 44.8% 2.1% 31.9%
(4/145) (73/163) (3/145) (52/163)
Metastatic 5.9% 21.7% 5.9% 56.5%
UM (1/17) (5/23) (1/17) (13/23)
Onken et al. Investigative Ophthalmology and Visual Science, 2008.
Van Raamsdonk et al. Nature, 2008.
Van Raamsdonk et al. NEJM, 2010.

28. The Gα
Pathway
Gα Gα PLCβ
Gβγ
GTP
GDP
DAG
PIP2
GNAQ Q209L PKC
IP3
P Raf Raf
Akt
P MEK MEK
P ERK ERK
mTOR
Tumor growth
and proliferation

29. Differential Sensitivity of Uveal Melanoma Cell Lines
to AZD6244 by Mutational Status
Ambrosini et al. AACR 2010, abstr 5035.

30. A Randomized Phase II Trial of Temozolomide versus
AZD6244 in Patients with Metastatic Uveal Melanoma
(NCI#8443)
Part A Temozolomide Cross‐over to
AZD6244 Allowed
TMZ/DTIC Naïve (n = 60) at Progression
Metastatic Uveal
Melanoma Stratification by:
AZD6244 1. Mutation status
(n = 60) 2. M1a/b vs M1c
3. Prior therapy (0 vs ≥1)
TMZ (n) AZD6244 (n) TOTAL (n)
Gnaq/11 Mut At least 40 At least 40 At least 80
Gnaq/11 Wt Up to 20 Up to 20 Up to 40
Probability is 80% that this design will detect a treatment
difference at a one-sided 10% significance level if the
true PFS hazard ratio is 0.6 in the Gq/11 mutant only
population AND the overall population

31. Phase I Study of AEB071 in UM
• Includes a dose‐escalation portion and a 25 patient dose expansion
cohort at the MTD
– Starting dose 300 mg BID
– Dose escalation using an adaptive Bayesian logistical regression model
• Pre‐ and day 15 biopsies in all patients
• Primary Endpoint: Estimate the MTD, safety/tolerability
• Secondary Endpoints: Overall response rate, PFS, TTP, PK
• Exploratory Endpoints: pMARCKS, correlation of PK/PD
• Participating Centers: 1. MSKCC (PI: Gary K. Schwartz)
2. DFCI (PI: Stephen F. Hodi)
3. Institut Curie (Sophie Piperno‐Neumann)
4. Leiden Univ (H.W. Kapitejin)

32. Major Oncogenic Events in Uveal Melanoma
45% Gnaq mutations
30% Gna11 mutations
60% PTEN loss
70% IGF1R expression
80% MET expression
100% SSTR expression
85% KIT expression
85% ERK activation
Patel M et al. Clin Cancer Res 2011;17:2087-2100

33. Metastatic Uveal Melanoma Trials
(03/2012)
Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID
AEB071 I Novartis NCT01430416
Sorafenib (STREAM Trial) II Essen, Germany NCT01377025
Sunitinib vs DTIC II Clatterbridge Centre, UK NCT01551459
Alberta Health Sciences,
CP‐675,206 II NCT01034787
Canada
Liposomal vincristine (Marqibo) II Talon Therapeutics, Inc NCT00506142
Genasense, Carboplatin & Paclitaxel II MD Anderson NCT01200342
SOM230 & RAD001 II Memorial Sloan‐Kettering NCT01252251
Cixutumumab (A12) II MD Anderson NCT01413191
AZD6244 versus Temozolomide II Memorial Sloan‐Kettering NCT01143402
Paclitaxel Albumin‐Stabilized
II Ohio State NCT00738361
Nanoparticle Formulation
Temozolomide & Bevacizumab II Institut Curie, Paris, France NCT01217398
STA‐9090 II Dana‐Farber NCT01200238
SAHA II Memorial Sloan‐Kettering pending
www.clinicaltrials.gov

34. Uveal Melanoma Liver Targeted Trials
(03/2012)
Rational for Liver-Directed Therapy:
1. Liver is 1st site of metastasis in >60% of cases and may be the dominant
site of disease
2. Currently available systemic treatments have limited effectiveness
3. Regional tx allows dose escalation to the cancer-bearing organ while
minimizing systemic exposure/toxicity via separation of the regional and
systemic circulation
4. Based on its unique vascular anatomy, the liver is a favorable site for
regional therapy (established tumors in liver derive the majority of blood
flow from the arterial tree - tumors: 100% versus normal liver: 25%)
Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID
SIR‐Spheres® 90Y Microspheres II Thomas Jefferson NCT01473004
IV versus Hepatic Arterial Infusion of
III EORTC NCT00110123
Fotemustine
Liver Transplantation II Oslo University NCT01311466
www.clinicaltrials.gov

35. A Phase-III Random Assignment Trial Comparing Percutaneous Hepatic
Perfusion with Melphalan (PHP-mel) to Standard of Care for Patients with
Hepatic Metastases from Metastatic Ocular or Cutaneous Melanoma
H
E
P
A
PHP Arm T
R Follow-up
(n= 44) I
A
C
N
Melanoma D
Metastatic P
O Cross over to PHP
R
to Liver M (n=27, 55%)
O
(n = 93) I
G
Z
R
E
E
BAC Arm S Follow-up
1:1 (n = 49) S
I
Total Accrual: 93 patients O
(PHP: 44, BAC: 49, Crossover: 27) N

36. Results: Patient Demographics
Baseline
Characteristic Category PHP (N=44) BAC (N=49) P value*
Age (years) Mean 54.8 54.8 0.9866
Male 23 (52.3%) 22 (44.9%)
Gender 0.5362
Female 21 (47.7) 27 (55.1)
White 44 (100.0) 48 (98)
Race 1.0000
Non-White 0 (0.0) 1 (2.0)
Missing 3 (6.8) 4 (8.2)
ECOG 0 37 (84.1) 42 (85.7) 0.7044
1 4 (9.1) 3 (6.1)
Ocular 39 (88.6) 43 (87.8) 1.0000
Primary Tumor
Cutaneous 5 (11.4) 6 (12.2)
*Fisher’s Exact Test. Two-sided PR <= P

37. Results: Treatment Related Toxicities
(40 Patients, 116 Treatments)
Treatment Related Toxicity, Grade 3-4 and Grade 5 (n=116 treatments)
Hematologic Grade 3-4 (n,%) Grade 5 (n,%)
Neutropenia 71 (61.2%) 2 (1.7%)
Thrombocytopenia 86 (74.1%)
Anemia 54 (46.6%)
Hepatic
Elevated AST 14 (12.1%)
Elevated ALT 6 (5.2%)
Hyperbilirubinemia 8 (6.9%) 1 (0.86%)
Increase Alkaline Phosphatase 6 (5.2%)
Other GI
Acute Cholecystitis (Grade 3) 1
Gastric Ulcer/perforation 1/1
Vascular
Arterial Pseudoaneurysm with A-V fistula 1 (0.86%)
Mortality Rate:
3/40 patients (7.5%), 3/116 procedures (2.6%)
Treatment Related Deaths:
Neutropenic Sepsis (n=2), Hepatic Failure (n=1)

38. Results: Primary Endpoint
-Hepatic Progression Free Survival (ITT) -
Hazard Ratio: 0.301
(CI: 0.183-0.497)
P < .001
PHP
BAC

39. Results: Secondary Endpoint
-Overall Progression Free Survival (ITT)-
Hazard Ratio: 0.404
(CI: 0.252-0.648)
P < .001
PHP
BAC

40. Results: Secondary Endpoint
-Overall Survival (ITT)-
PHP Hazard Ratio: 0.920
(CI: 0.524-1.615)
BAC
p = .78

41. Results: Secondary Endpoint
-Overall Survival BAC Patients-
BAC  PHP
BAC Only
p = .01

42. Results: Secondary Endpoint
-Response (ITT)-
Best Alternative Care
PHP All Crossover Non-Cross
Overall Response: n (%) (N= 44) (n=49) (N= 27) (N= 22)
CR 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
PR 15 (34.1) 1 (2.0) 6 (22.2) 1 (4.5)
SD 23 (52.3) 13 (26.5) 11 (40.7) 6 (27.3)
PD 2 (4.5) 31 (63.3) 1 (3.7) 12 (54.5)
NE 4 (9.1) 4 (8.2) 9 (33.3) 3 (13.6)
Objective Response Rate (CR+PR) 15 (34.1) 1 (2.0) 6 (22.2) 1 (4.5)
P < 0.001

43. Outline
1. What is uveal melanoma?
2. What FDA approved treatment options are available
for this disease?
3. What clinical trials are currently available specifically
for patients with uveal melanoma?
4. How do I find and participate in a clinical trial?

44. Summary
• Uveal melanoma is a distinct disease entity from cutaneous
melanoma, with a unique biology and response pattern to
systemic therapy
• Currently available treatments for cutaneous melanoma have
limited efficacy in uveal melanoma (although further
investigation of ipilimumab in uveal melanoma is warranted)
• Hepatic directed therapy has activity in liver metastases from
uveal melanoma but the role of this treatment in uveal
melanoma must be further defined
• Emerging insights into the biology of uveal melanoma have
led to the development of a series of clinical trials which hold
promise for positive clinical impact in this disease
• Patient participation in clinical trials, both in the adjuvant and
metastatic setting, remains critical to the successful
development of effective treatments

45. Uveal Melanoma Resources
• AIM at Melanoma
– http://www.aimatmelanoma.org/en/
• Melanoma International Foundation
– www.melanomainternational.org
• Melanoma Research Foundation: Cure OM
– http://www.melanoma.org
• Ocular Melanoma Foundation
– http://www.ocularmelanoma.org
• Melanoma Research Alliance
– http://www.melanomaresearchalliance.org
• National Cancer Institute
– http://www.cancer.gov/cancertopics/pdq/treatment/intraocularmelanoma/Patient/page1

46. Thank you

47. Posted online with the express permission of Rich Carvajal, MD