Richard Carvajal discusses navigating treatment options for uveal melanoma, focusing on immunotherapeutic strategies. He outlines several systemic treatment approaches including genetic, epigenetic, and immunological targeting. Checkpoint blockade with ipilimumab and nivolumab has shown some efficacy in uveal melanoma but responses are lower than in cutaneous melanoma potentially due to lower tumor mutation burden and PD-L1 expression. Adoptive T cell therapy clinical trials have also shown responses. Ipilimumab and nivolumab are being studied in the adjuvant and metastatic settings. Additional immunotherapies including T cell redirecting therapies targeting gp100 are in clinical trials. Combination strategies may be necessary to improve outcomes for

1. Navigating the Treatment Landscape of Uveal Melanoma:
Focus on Immunotherapeutic Strategies
Richard D. Carvajal, M.D.
Director, Experimental Therapeutics
Director, Melanoma Service
Associate Professor of Medicine
Columbia University Medical Center

2. Consulting:
Array, BMS, Castle Biosciences, Compugen, Foundation Medicine, Immunocore, I-
Mab, Incyte, Merck, Roche/Genentech, PureTech Health, Sanofi Genzyme,
Sorrento Therapeutics
Clinical/Scientific Advisory Boards:
Aura Biosciences, Chimeron, Rgenix
Research Funding to Columbia University:
Amgen, Astellis, AstraZeneca, Bayer, Bellicum, BMS, Corvus, Eli Lilly, Immunocore,
Incyte, Macrogenics, Merck, Mirati, Novartis, Pfizer, Plexxikon, Roche/Genentech
Disclosures

3. Factors in Decision Making
Resources
• Available expertise
• Clinical trials
You
• Your health status
• Your preferences
• HLA status
Your Disease
• Tumor growth pattern
• Sites of involvement
• Molecular
characteristics
• PRAME status
Treatment
Recommendations

4. Broad Therapeutic Categories
Treatment
Recommendations
Locoregional
Therapies
Systemic
Therapies
Supportive
Care
Concurrent
Strategies

5. Systemic Treatment Strategies for Uveal Melanoma
Hanahan and Weinberg. Cell 2000.
Jones et al. Nat Rev Genetics 2016.
Genetic Targeting Epigenetic Targeting Immunological Targeting

6. T cell
Tumor cell
MHC
TCR
PD-L1PD-1
- - -
T cell
Dendritic
cell
MHC
TCR
CD28
B7 CTLA-4
- - -
Activation
(cytokines, lysis, proliferation,
migration to tumor)
B7
+++
+++
CTLA-4 Blockade PD1/PDL1 Blockade
anti-CTLA-4 anti-PD-1
Tumor Microenvironment
+++
PD-L2PD-1
anti-PD-1
- - -
Antigen Presentation
Blocking CTLA-4 versus Blocking PD1/PDL1

7. Ipilimumab and
Nivolumab
Week 12
Nivolumab
Baseline
Immunological Checkpoint Blockade in Cutaneous Melanoma

8. PD1 Blockade can be Effective in Uveal Melanoma
Rodriguez M et al. Nature Communications 2018.
76 yo female with left choroidal melanoma (monosomy 3, GNAQ Q209L mut, BAP1 mut) s/p enucleation who
developed metastases to the liver, lungs and bones. She was treated in the frontline setting with pembrolizumab.

9. Why Doesn’t Checkpoint Blockade Work as Well in UM?
Yarchoan M et al. N Engl J Med 2017.
Javed A et al. Immunotherapy 2017.
Tumor Mutation Burden Tumor PDL1 (SP142) Expression*
* SP142 PDL1 Positive: ≥ 5% membranous
staining of tumor detected with 2+/3+ intensity

10. Response to Combined Checkpoint Blockade
Baseline 10 months
52 year old female with Decision DX Class 2, GNA11 Q209L mutant, right ciliary body
melanoma s/p enucleation with the development of metastatic disease 26 months later to the
liver, lung, bone and soft tissue
3 months
Ipi/Nivo Observation

11. Phase II Trial of Adjuvant Ipilimumab and Nivolumab (n = 50)
Primary Endpoint
o RFS at 3 years
Secondary Endpoints
o RFS, OS
High Risk Definition
o GEP Class 2
o Impact Genetics 3 yr
recurrence risk > 50%
o Monosomy 3 with
tumor ht > 8mm
Participating Centers: Georgetown, Columbia University,
MD Anderson Cancer Center, UCSF, Washington University

12. Immune Related Adverse Events (irAEs)
Postow MA et al. N Engl J Med 2018;378:158-168
• Checkpoint inhibition can lead to varied toxicities
caused by an augmented immune response and
decrease in immune self-tolerance
• Toxicities can be organ-specific
– Skin
– GI tract
– Lungs
– Endocrine system
– Heart
– Neurologic system
• Toxicities can also be generalized
– Fatigue
– Fever
– Infusion reactions

13. Adoptive T Cell Therapy
Rosenberg et al. Science 2015.

14. Phase II Trial of Adoptive T Cell Therapy in Uveal Melanoma
Chandran SS et al. Lancet Oncol. 2017.
35% Response Rate
(n = 7/20)
Response
Duration:
3-21+ Months
• 3 of 7 responses occurred in patients who progressed on prior CPB
• 6 of 27 patients enrolled were excluded from treatment due to insufficient TILs or ineligibility for
protocol treatment

15. Targeting gp100 in Uveal Melanoma
TCR affinity increased
3,500,000 fold from 85μM
to 24 pM
KD ~24 pM
Residence T½
~24 hrs at 37ºC
KD nM
Residence T½
mins
Targeting
TCRend
Effector
scFvend
RNAseq data generated from
The Cancer Genome Atlas Program
Cutaneous
Melanoma
Uveal
Melanoma

16. IMCgp100 Program Registration Strategy
Accelerated approval strategy: Single arm trial approval strategy is based on either ORR or OS with
RWE as comparator
IMCgp100-102:
Second or third
line in the
metastatic setting
IMCgp100 at RP2D from Ph I
N ~ approx 150
Interim Analysis Final Analysis
Real World Evidence (ORR, OS via one of three platforms: Meta-
analysis, global patient registry or Flatiron derived comparator)
Opportunities
for approval
IMCgp100-202:
First line
metastatic setting
R
Investigator Choice (dacarbazine, pembrolizumab or ipilimumab)
N = approx 109
Sample size Interim Analysis Final Analysis
re-estimation
Primary endpoint: Median OS
Traditional approval strategy: Randomized study of IMCgp100 v. Investigator choice with OS as endpoint
IMCgp100 at RP2D from Ph I
N = approx 218
Opportunities
for approval

17. Conversion of Tumor from “Cold” to “Hot” with IMCgp100
Baseline C1D2 C1D16
CD8 (green) X PD-1 (magenta) X PD-L1 (red)
Baseline C1D16
Patient 1
Patient 2
C1D16
MHC Class I (yellow) X
gp100 (orange)
Sato T et al. ASCO Annual Meeting. June 2018.

18. Response to Combined Checkpoint Blockade
12/2017 09/2018
52 year old female with Decision DX Class 2, GNA11 Q209L mutant, right ciliary body
melanoma s/p enucleation with the development of metastatic disease 26 months later to the
liver, lung, bone and soft tissue
03/2018
Ipi/Nivo Observation
Dev mets to liver, bone, lung,
soft tissue and received:
• Ipilimumab x 4
• Pembrolizumab +
radioembolization x 7
months
• IMCgp100 x 20 months
• Ipi/Nivo

19. (* - accrual held/complete)
Mechanism Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID
Checkpoint
Blockade
Adjuvant Ipilimumab/Nivolumab II Hoosiers NCT02359851
Ipilimumab/Nivolumab * II MDACC NCT01585194
Pembolizumab + Entinostat
(PEMDAC)
II
Vastra Gotaland Region,
Sweden
NCT02697630
Ipi/Nivo + Immunoembolization * II Thomas Jefferson NCT03472586
Ipi/Nivo + Radioembolization 0 CPMC NCT02913417
CVA21 + Ipilimumab (CLEVER) * I Viralytics NCT03408587
ADV/HSV-tk + SBRT + Nivolumab
(ENSIGN)
II Methodist Hospital NCT02831933
Vaccination Dendritic Cell Vaccine II
University Hospital
Erlangen
NCT01983748
TILS
Adoptive T Cell Therapy II UPMC NCT03467516
Cellular Adoptive Immunotherapy
+ Ipilimumab
I MDACC NCT03068624
T Cell
Redirection
IMCgp100 * I Immunocore NCT02570308
IMCgp100 II Immunocore NCT03070392
Immunotherapy Trials for Uveal Melanoma
(as of 03/27/2019)(* - accrual held/trial complete)

20. • Our understanding of the biology of uveal melanoma introduces new opportunities and
challenges for the successful development of effective treatments
• Progress is being made in the translational and clinical development of molecularly
targeted, epigenetic and immunological therapies
• Combinatorial treatment strategies may be necessary for optimal results
• Collaboration within the academic community (laboratory, ocular oncology, medical
oncology, pathology, radiation oncology) and with the patient community is critical for us
to rapidly and successfully move the field forward
Concluding Thoughts