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Advances in Cutaneous Melanoma and
Oncology in general
Michael B. Atkins, M.D.
Deputy Director
Georgetown-Lombardi Compreh...
Melanoma Therapy: 2017
Advances in treatment
 Molecularly Targeted Therapy
 Immunotherapy
Current/Future Research Ques...
Cutaneous Melanoma : Epidemiology
Incidence: ~76,380 / (additional 55,000 cases of MIS)
~ 10,130 deaths
3% of all cancers ...
Cytotoxic Chemotherapy
There is currently no evidence that other single
agents, combination chemotherapy or the
addition o...
Selective Inhibition of BRAF
mutant tumors
1205Lu C8161
#63
#69
#59#56
Change in Tumor Size in 122 V600EBRAF mutant melanoma
patients treated with vemurafenib on BRIM2
RECIST 30% Decrease
Sosma...
Rationale for Combination
1. Hauschild et al., Lancet 2012; 2. Flaherty et al., NEJM 2012
pERK
Proliferation
Survival
Inva...
COMBI-d: PFS and OSa
Presented by: Keith T. Flaherty, MD
a Intent-to-treat population; b Dabrafenib + placebo includes 26 ...
COMBI-d: Normal LDHa and < 3 Disease Sitesb
Presented by: Keith T. Flaherty, MD
a Baseline LDH ≤ ULN; b Any organ at basel...
Immunotherapy
Cancer Immunotherapy Principles (1)
• The host immune system is the dominant
active enemy faced by a developing cancer
• A...
Cancer Immunotherapy Principles (2)
• “Treating the immune system so that it can
treat the cancer” Jedd Wolchok
• Because ...
Blocking Immunologic
Checkpoints
CTLA-4
B7
Dendritic cell Cytotoxic
T cell
CD28
B7
Priming:
T-Cell Activation in the
Lymph...
Patients at Risk
Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0
ProportionAlive
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9...
PatientsAlive(%)
aStratified by stage provided at
randomization.
Ipilimumab Placebo
Deaths/patients 162/475 214/476
HR (95...
Priming:
T-Cell Activation in the
Lymph Node
Blocking Immunologic Checkpoints
CTLA-4
B7
Dendritic cell Cytotoxic
T cell
CD...
Nivo 037 Study Time and Duration of
Response
36/38 (95%) of nivolumab
responses ongoing with
minimum follow-up of 24
weeks...
Frontline Nivolumab vs Chemotherapy in BRAF WT Melanoma
Robert et al NEJM 2014
Pembrolizumab: Clinical Activity
Baseline: April 13, 2012
Images courtesy of A. Ribas, UCLA.
72-year-old male with symptom...
Pembrolizumab: Time to Response and
On-Study Duration
Presented by: Antoni Ribas
aOngoing response defined as alive, progr...
Single Agent Anti-PD1 Blockade: Future Directions
• Determine when to stop
 Our current approach
• Adjuvant protocols
• B...
CTLA-4 Blockade (Ipilimumab) PD-1 Blockade (Nivolumab)
APC – T-cell Interaction
Activation
(cytokine secretion, lysis,
pro...
Ipi/Nivo Combination
ORR >80% Tumor Reduction
ipilimumab 10% <3%
nivolumab 40% <2%
combination (cohort 2) 53% 41%
Cohort 2...
0 6 9 12 15 183
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
069 Data: PFS in All Randomized Patients
NIVO + IPI
(N=95)
IPI...
0 6 9 12 15 183
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
069 Data: PFS in All Randomized Patients
NIVO + IPI
(N=95)
IPI...
067 Study Nivo vs Nivo + Ipi: Topline data
Nivo Nivo + Ipi
Med PFS (months) 6.9 (4.3-9.5) 11.5 (8.9-16.7)
ORR, % (95% CI) ...
Frontline Nivo + Ipi Data: Toxicity
• Toxicities are severe but manageable
 Rate of treatment related AEs is similar acro...
Majority of Responding patients to Nivo/Ipi will
continue to respond after stopping Treatment
15/16 patients continue to
r...
Combination I/0 Achieves “Many” Patients’ Preferred Outcome-
Treatment Free Survival or “TFS”
7 deaths in 41 patients
Medi...
TFS = Travel Full Survival
Additional Issues/opportunities for Combination IO
• Transition into the community
• Sequencing with BRAF inhibitors
• Les...
EA6134: Ipi/Nivo to D/T vs D/T to Ipi/Nivo
ECOG PS
1. 0
2. 1
LDH
1. Normal
2. Elevated
R
A
N
D
O
M
I
Z
E
Arm 1:
Ipi 3/Nivo...
Spectrum of PD-1/PD-L1 Antagonist Activity
• Melanoma
• Renal cancer (clear cell)
• NSCLC – adenocarcinoma and squamous ce...
A Roadmap of Immunotherapy-
Tumor Interactions
Chen DS, et al. Immunity. 2013;39:1-10.
4
5
6
71
2
3
Trafficking of T cells...
Biomarkers for PD-1 Pathway Blockade
Is there a population that benefits as much from
anti-PD1 monotherapy as from anti-PD...
n= 42 44 34 113 129 55 411 94 30 53 65
unselected 21% 32% 29% 40% 19% 18% 40% 21% 29% 23% 26%
PD-L1 + 36% 67% 44% 49% 37% ...
Most Cancers Have Mutations
Mutated proteins represent potential antigens –
targets for immune recognition and destruction...
Optimized Biomarker Model?
Neoantigen
burden
CD8+ T-cell
Density
PD-L1 Expression
All inter-related, but for anti-PD-1 bas...
Melanoma Therapy 2017: Summary
Molecularly targeted therapy and checkpoint inhibitor
therapy have become standard systemi...
Overall Survival for Patients with Stage IV
BRAFV600 Mutant Melanoma: The Future
PRESENTED BY: Michael B.
Atkins
Years aft...
Ocular Melanoma
Ocular Melanoma
• < 3% of all melanoma; 1-2000 cases/yr
• 80% contain activating mutations of GNAQ
or GNA11 signaling prot...
Gβγ
Gα
GDP
Gα
GTP
PLCβ
PIP2
DAG
PKC
IP3
RafRafP
MEKP MEK
ERKERKP
PIP2
PIP3
PI3K
Akt
mTOR
Tumor growth
and proliferation
GN...
Progression-Free Survival is Improved with Selumetinib in
Both the Mutant Only and Overall Population
Exon 5 Gq/11 Mutatio...
Progression-Free Survival is Improved with Selumetinib in
Both the Mutant Only and Overall Population
Exon 5 Gq/11 Mutatio...
Ocular Melanoma: Immunotherapy
• Relatively few mutations (neo-antigens) and
little immune inflammation
• Eye is potential...
Figure 2b. Mutation burden all primary uveal melanoma (n=80), primary uveal
melanoma from stage harboring a BAP1 mutation ...
Proportion of tumors of each TCGA histology
with the T cell-inflamed gene signature
Case History
• 2009: 55 yo physician diagnosed with Ocular
Melanoma R eye
 Treated with enucleation
 Adjuvant sunitinib ...
Figure 2b. Mutation burden of case study (red line) relative to all primary uveal
melanoma (n=80), primary uveal melanoma ...
Ocular Melanoma Response to Nivo/ipi
Sept 2015 April 2016
Ocular Melanoma: Adjuvant Therapy Concept
Suthee Rapisuwon-G-LCCC- Approved
61
MEK and PD-L1 Inhibition: A Rational Combination
Ebert P et al. Immunity 2016.
MEKi, MEK inhibitor; ND, no drug (vehicl...
62
Cobi + Atezo in Cutaneous Melanoma
Reduction in Tumor Burden
Data cutoff: July 12, 2016.
Best overall response (confirm...
Ocular Melanoma: Conclusions
• Ocular melanoma shares some properties with
WT Cutaneous Melanoma
 Sensitivity to MEK inhi...
Advances in Melanoma Oncology - Mike Atkins, MD
Advances in Melanoma Oncology - Mike Atkins, MD
Advances in Melanoma Oncology - Mike Atkins, MD
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Advances in Melanoma Oncology - Mike Atkins, MD

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Mike Atkins, MD speaks about the advances in melanoma oncology at the 2017 CURE OM Patient & Caregiver Symposium.

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Advances in Melanoma Oncology - Mike Atkins, MD

  1. 1. Advances in Cutaneous Melanoma and Oncology in general Michael B. Atkins, M.D. Deputy Director Georgetown-Lombardi Comprehensive Cancer Center How Do These Advances Affect Uveal Melanoma?
  2. 2. Melanoma Therapy: 2017 Advances in treatment  Molecularly Targeted Therapy  Immunotherapy Current/Future Research Questions Relationship to Other Cancers Relationship to Ocular Melanoma
  3. 3. Cutaneous Melanoma : Epidemiology Incidence: ~76,380 / (additional 55,000 cases of MIS) ~ 10,130 deaths 3% of all cancers / 1% of all cancer deaths Lifetime risk: 1 in 50 Americans 1 in 25 Australians 5th most common cancer in men and 7th in women; 2nd in terms of years of potential life lost
  4. 4. Cytotoxic Chemotherapy There is currently no evidence that other single agents, combination chemotherapy or the addition of tamoxifen or IFN to DTIC is superior to DTIC alone Some data suggests possible benefit for carbo/paclitaxel, but may be confounded Nab-paclitaxel may also be better than DTIC RARELY USED Anymore
  5. 5. Selective Inhibition of BRAF mutant tumors 1205Lu C8161
  6. 6. #63 #69 #59#56
  7. 7. Change in Tumor Size in 122 V600EBRAF mutant melanoma patients treated with vemurafenib on BRIM2 RECIST 30% Decrease Sosman et al NEJM 2012
  8. 8. Rationale for Combination 1. Hauschild et al., Lancet 2012; 2. Flaherty et al., NEJM 2012 pERK Proliferation Survival Invasion Metastasis RAS BRAF MEK Preclinical BRAFi +MEKi Delays BRAFi resistance  Hyperproliferative skin AE MEKi (trametinib) OS HR 0.54 v chemo PFS 4.8 mo; RR 22%2 Rash AE mutBRAFBRAFi (dabrafenib) PFS 5.1 mo; RR 53%1 Hyperproliferative skin AEs
  9. 9. COMBI-d: PFS and OSa Presented by: Keith T. Flaherty, MD a Intent-to-treat population; b Dabrafenib + placebo includes 26 patients who crossed over to combination arm; +, censored. Overall Survival 212 175 138 104 84 69 57 7 0 211 187 143 111 96 86 76 13 0 Dabrafenib + Trametinib (n = 211) Dabrafenib + Placebo (n = 212)b 3-y OS, 44% 3-y OS, 32% 1.0 0.8 0.6 0.4 0.2 0.0 0 6 12 3018 Months From Randomization OSProbability D+Pbo D+T Number at risk 2-y OS, 52% 2-y OS, 43% 24 36 42 48 Progression-Free Survival 212 110 67 41 29 11 7 1 0 211 137 84 69 54 45 31 0 1.0 0.8 0.6 0.4 0.2 0.0 0 Months From Randomization PFSProbability D+Pbo D+T Number at risk 6 12 3018 24 36 42 48 3-y PFS, 22% 3-y PFS, 12% 2-y PFS, 30% 2-y PFS, 16% Dabrafenib + Trametinib (n = 211) Dabrafenib + Placebo (n = 212) 58% of D+T patients alive at 3 years still on D+T
  10. 10. COMBI-d: Normal LDHa and < 3 Disease Sitesb Presented by: Keith T. Flaherty, MD a Baseline LDH ≤ ULN; b Any organ at baseline with ≥ 1 metastasis could be counted as a single disease site; +, censored. 96 93 77 65 56 45 36 2 0 76 72 62 52 46 41 35 4 0 D+Pbo D+T Number at risk Dabrafenib + Trametinib (n = 76) Dabrafenib + Placebo (n = 96) 3-y OS, 62% 3-y OS, 45% 1.0 0.8 0.6 0.4 0.2 0.0 0 Months From Randomization OSProbability 2-y OS, 68 % 2-y OS, 61% 6 12 3018 24 36 42 48 96 64 41 25 16 5 3 0 76 56 39 34 28 25 19 0 D+Pbo D+T Number at risk 0 Months From Randomization 6 12 18 24 36 4230 1.0 0.8 0.6 0.4 0.2 0.0 3-y PFS, 15% 3-y PFS, 38% Dabrafenib + Trametinib (n = 76) Dabrafenib + Placebo (n = 96) PFSProbability OSPFS
  11. 11. Immunotherapy
  12. 12. Cancer Immunotherapy Principles (1) • The host immune system is the dominant active enemy faced by a developing cancer • All “successful” cancers must solve the challenges of overcoming defenses erected by host immune system. • Many of these defenses serve to inactivate the immune system
  13. 13. Cancer Immunotherapy Principles (2) • “Treating the immune system so that it can treat the cancer” Jedd Wolchok • Because the activated immune system can target many tumor antigens simultaneously, and deepen and broaden over time, IT can cure patients with metastatic cancer • The hallmark of effective immunotherapy is the tail on the curve
  14. 14. Blocking Immunologic Checkpoints CTLA-4 B7 Dendritic cell Cytotoxic T cell CD28 B7 Priming: T-Cell Activation in the Lymph Node Effector Phase: Peripheral Tissues Ribas A. N Engl J Med. 2012;366:2517-2519. Spranger S, et al. J Immunother Cancer. 2013;1:16. PD1 Nivolumab Pembrolizumab Pidilizumab Ipilimumab Tremelimumab MPDL3280A MEDI4736 MSB0010718C
  15. 15. Patients at Risk Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0 ProportionAlive 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months 0 12 24 36 48 60 72 84 96 108 120 N = 1861 Median OS (95% CI): 11.4 mo (10.7-12.1) 3-year OS Rate (95% CI): 22% (20% to 24%) Ipilimumab CENSORED Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24. Ipilimumab: Pooled Survival Analysis from Phase II/III Trials in Advanced Melanoma
  16. 16. PatientsAlive(%) aStratified by stage provided at randomization. Ipilimumab Placebo Deaths/patients 162/475 214/476 HR (95.1% CI)a 0.72 (0.58, 0.88) Log-rank P valuea 0.001 Adjuvant Ipilimumab: Overall Survival Impact 65% 54% 21 Years0 1 2 3 4 5 6 7 8 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk 162475 431 369 325 290 199 62 4 214476 413 348 297 273 178 58 8 Ipilimumab Placebo
  17. 17. Priming: T-Cell Activation in the Lymph Node Blocking Immunologic Checkpoints CTLA-4 B7 Dendritic cell Cytotoxic T cell CD28 B7 Effector Phase: Peripheral Tissues Ribas A. N Engl J Med. 2012;366:2517-2519. Spranger S, et al. J Immunother Cancer. 2013;1:16. Tumor PD-L1 PD1 Nivolumab Pembrolizumab Pidilizumab Ipilimumab Tremelimumab Atezolizumab Durvalumab Avelumab Interferons
  18. 18. Nivo 037 Study Time and Duration of Response 36/38 (95%) of nivolumab responses ongoing with minimum follow-up of 24 weeks in all patients On treatment Off treatment Censored First response Death 0 8 16 24 32 40 48 56 64 NivolumabICC Patients(Responders) Treatment Median time to response, (range), mo Median duration of response(range), mo Nivolumab 2.1 (1.6, 7.4) NR (1.4+, 10.0+) ICC 3.5 (2.1, 6.1) 3.6 (1.3+, 3.5) Data report date: 30 Apr 2014 “+” denotes patients who are censored (still in response); NR = not reached Time (Weeks) Nivolumab received FDA approval 12/21/14
  19. 19. Frontline Nivolumab vs Chemotherapy in BRAF WT Melanoma Robert et al NEJM 2014
  20. 20. Pembrolizumab: Clinical Activity Baseline: April 13, 2012 Images courtesy of A. Ribas, UCLA. 72-year-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab April 9, 2013
  21. 21. Pembrolizumab: Time to Response and On-Study Duration Presented by: Antoni Ribas aOngoing response defined as alive, progression free, and without new anticancer therapy. IPI-T IPI-N Complete Response Partial Response Progression On Treatment Time, weeks 10 30 50 70 90 IndividualPatientsTreatedWithPembrolizumab 12 months6 months 18 months • 88% of responses ongoinga • Median response duration not reached (range, 6+ to 76+ weeks) Pembrolizumab received FDA approval 9/4/14
  22. 22. Single Agent Anti-PD1 Blockade: Future Directions • Determine when to stop  Our current approach • Adjuvant protocols • Biomarker refinement • Combinations:  Immunotherapy, targeted therapy, RT, Vaccines
  23. 23. CTLA-4 Blockade (Ipilimumab) PD-1 Blockade (Nivolumab) APC – T-cell Interaction Activation (cytokine secretion, lysis, proliferation, migration to tumor) Tumor Microenvironment Dendritic cell T cell Tumor cell MHC TCR TCR PD-L1 PD-L2 MHC PD-1 PD-1 B7 B7 CD28 CTLA-4 anti-CTLA-4 anti-PD-1 anti-PD-1 +++ --- +++ T cell +++ --- --- Biologic Rationale for Combined PD-1 and CTLA-4 Blockade 28
  24. 24. Ipi/Nivo Combination ORR >80% Tumor Reduction ipilimumab 10% <3% nivolumab 40% <2% combination (cohort 2) 53% 41% Cohort 2: 1 mg/kg nivolumab + 3 mg/kg ipilimumab All patients in concurrent cohorts First occurrence of new lesion Wolchok NEJM 2013
  25. 25. 0 6 9 12 15 183 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 069 Data: PFS in All Randomized Patients NIVO + IPI (N=95) IPI (N=47) Death or disease progression, n/N 42/95 32/47 Median PFS, months (95% CI) NR 3.0 (2.8‒5.1) HR (95% CI), p-value 0.39 (0.25‒0.63), p<0.0001 Number of Patients at Risk NIVO + IPI IPI 95 69 58 47 26 1 0 47 22 10 7 2 0 0 PFS per Investigator (months) ProportionAliveandProgression-free NIVO + IPI IPI Response Rates Nivo + Ipi = 61% Ipi = 11% Postow et al NEJM 2015
  26. 26. 0 6 9 12 15 183 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 069 Data: PFS in All Randomized Patients NIVO + IPI (N=95) IPI (N=47) Death or disease progression, n/N 42/95 32/47 Median PFS, months (95% CI) NR 3.0 (2.8‒5.1) HR (95% CI), p-value 0.39 (0.25‒0.63), p<0.0001 Number of Patients at Risk NIVO + IPI IPI 95 69 58 47 26 1 0 47 22 10 7 2 0 0 PFS per Investigator (months) ProportionAliveandProgression-free NIVO + IPI IPI Response Rates Nivo + Ipi = 61% Ipi = 11% Postow et al NEJM 2015 FDAApproval 10/1/15
  27. 27. 067 Study Nivo vs Nivo + Ipi: Topline data Nivo Nivo + Ipi Med PFS (months) 6.9 (4.3-9.5) 11.5 (8.9-16.7) ORR, % (95% CI) 43.7 (38.1-49.3) 57.6 (52.0-63.2) CR % 8.9 11.5 Tumor Burden change - 34.5% - 51.9% Response Duration NR NR Med OS NR NR Grade 3-4 SAEs 16% 55% Proof of principle that combination immunotherapy can produce greater activity than anti-PD1 alone
  28. 28. Frontline Nivo + Ipi Data: Toxicity • Toxicities are severe but manageable  Rate of treatment related AEs is similar across age groups and disease stage  80% AEs resolve within 4-6 weeks with immune modulatory Rx (not endocrine)  Few treatment related deaths (069 = 3, 067 = 0) • Toxicity did not interfere with response Hodi et al, Larkin et al
  29. 29. Majority of Responding patients to Nivo/Ipi will continue to respond after stopping Treatment 15/16 patients continue to respond after stopping Rx 5/5 CR; 11/12 PRGibney, Gardner et al
  30. 30. Combination I/0 Achieves “Many” Patients’ Preferred Outcome- Treatment Free Survival or “TFS” 7 deaths in 41 patients Median F/up 18 months Treatment ends Benefit persists
  31. 31. TFS = Travel Full Survival
  32. 32. Additional Issues/opportunities for Combination IO • Transition into the community • Sequencing with BRAF inhibitors • Less toxic regimens  Less ipi (2 cycles; lower dose)  Better toxicity management (more liberal immune suppression)  Substitute for ipi (many options) • Activity in novel subsets of patients  Brain mets  Variant melanoma populations (mucosal, acral, uveal) • Biomarkers of Response
  33. 33. EA6134: Ipi/Nivo to D/T vs D/T to Ipi/Nivo ECOG PS 1. 0 2. 1 LDH 1. Normal 2. Elevated R A N D O M I Z E Arm 1: Ipi 3/Nivo 1 mg/kg/ q 3wks x 4 +Maint Nivo Arm 2: D 150 BID / T 2 mg Qd ECOG and SWOG protocol – Atkins, Chmielowski Opened July 2015 Ipi 3/Nivo 1 mg/kg q 3wks x 4 +Maint Nivo D 150 BID / T 2 mg Qd PD PD
  34. 34. Spectrum of PD-1/PD-L1 Antagonist Activity • Melanoma • Renal cancer (clear cell) • NSCLC – adenocarcinoma and squamous cell • Head and neck cancer • Urothelial (bladder) cancer • Small cell lung cancer • Gastric and GE junction • Mismatch repair deficient tumors (colon, cholangiocarcinoma) • Triple negative breast cancer • Ovarian cancer • Glioblastoma • Hepatocellular carcinoma • Thymic carcinoma • Mesothelioma • Cervical cancer • Hodgkin Lymphoma • Diffuse large cell lymphoma • Follicular lymphoma • T-cell lymphoma (CTCL, PTCL) • Merkel Cell Active 15 for 16 Phase III Trials Nivo + ipi benefit Melanoma NSCLCa RCC Urothelial Ca
  35. 35. A Roadmap of Immunotherapy- Tumor Interactions Chen DS, et al. Immunity. 2013;39:1-10. 4 5 6 71 2 3 Trafficking of T cells to tumors Infiltration of T cells into tumors Recognition of cancer cells by T cells Killing of cancer cells Release of cancer cell antigens Cancer antigen presentation Priming and activation Anti-VEGF CAR Ts Anti-PD-L1 Anti-PD-1 IDO inhibitors Chemotherapy Radiation therapy Targeted therapy Vaccines IFN-α GM-CSF Anti-CD40 (agonist) TLR agonists Anti-CTLA4 Anti-CD137 (agonist) Anti-OX40 (agonist) Anti-CD27 (agonist) IL-2 IL-12
  36. 36. Biomarkers for PD-1 Pathway Blockade Is there a population that benefits as much from anti-PD1 monotherapy as from anti-PD1/PDL1 + anti-CTLA4 combo? Can we identify the population that benefits from PD1 pathway blockade? Can we identify what combination therapy will work best for a particular tumor?
  37. 37. n= 42 44 34 113 129 55 411 94 30 53 65 unselected 21% 32% 29% 40% 19% 18% 40% 21% 29% 23% 26% PD-L1 + 36% 67% 44% 49% 37% 46% 49% 36% 27% 46% 43% PD-L1 - 0% 19% 17% 13% 11% 11% 13% 13% 20% 15% 11% Objective Response rates Mahoney, Atkins Oncology 2014 anti-PD-1 Antibody anti-PD-L1 AntibodyTreatment: Immune infiltrateMembranous pattern on tumor cellsAssay: ORR by PD-L1 Expression in Patients with Solid Tumors
  38. 38. Most Cancers Have Mutations Mutated proteins represent potential antigens – targets for immune recognition and destruction Lawrence, Nature 499:214 2013
  39. 39. Optimized Biomarker Model? Neoantigen burden CD8+ T-cell Density PD-L1 Expression All inter-related, but for anti-PD-1 based therapies to be optimally effective each biomarker may need to be present. Anti-PD-1 therapy responder profile
  40. 40. Melanoma Therapy 2017: Summary Molecularly targeted therapy and checkpoint inhibitor therapy have become standard systemic therapies  Cytotoxic chemotherapy and cytokine-based immunotherapies rarely used Role of disciplines evolving to prioritize systemic therapy With integrated therapy - longterm survival becoming the rule (goal) rather than the exception
  41. 41. Overall Survival for Patients with Stage IV BRAFV600 Mutant Melanoma: The Future PRESENTED BY: Michael B. Atkins Years after stage IV diagnosis ProportionSurviving Ipilimumab Nivo, BRAF/MEK Optimal immuno to optimal BRAFi 0 1 2 3 4 5 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 ??? Research BRAFi Nivo + ipi
  42. 42. Ocular Melanoma
  43. 43. Ocular Melanoma • < 3% of all melanoma; 1-2000 cases/yr • 80% contain activating mutations of GNAQ or GNA11 signaling proteins • No standard therapy exists • Gene signature can identify 2 distinct prognostic groups • Opportunities – Targeted therapy – Immunotherapy – Adjuvant therapy
  44. 44. Gβγ Gα GDP Gα GTP PLCβ PIP2 DAG PKC IP3 RafRafP MEKP MEK ERKERKP PIP2 PIP3 PI3K Akt mTOR Tumor growth and proliferation GNAQ Q209LPTEN The Gα Pathway • Gnaq/Gna11 mutations are early oncogenic events in uveal melanoma • Exon 5 mutations are found in 75% of primary specimens • Exon 4 mutations are found in 5% of primary specimens Onken et al. Investigative Ophthalmology and Visual Science, 2008; Van Raamsdonk et al. Nature, 2008; Van Raamsdonk et al. NEJM, 2010.
  45. 45. Progression-Free Survival is Improved with Selumetinib in Both the Mutant Only and Overall Population Exon 5 Gq/11 Mutation Positive Overall Population 15.9 weeks (95% CI, 8.4 – 23.1) vs 7.0 weeks (95% CI, 4.3 – 8.4) p = 0.0003 15.4 weeks (95% CI, 8.1 – 16.9) vs 7.0 weeks (95% CI, 4.3 – 11.9) p = 0.009 Selumetinib (n = 38) Temozolomide (n = 42) Selumetinib (n = 47) Temozolomide (n = 49) Presented by: RD Carvajal
  46. 46. Progression-Free Survival is Improved with Selumetinib in Both the Mutant Only and Overall Population Exon 5 Gq/11 Mutation Positive Overall Population 15.9 weeks (95% CI, 8.4 – 23.1) vs 7.0 weeks (95% CI, 4.3 – 8.4) p = 0.0003 15.4 weeks (95% CI, 8.1 – 16.9) vs 7.0 weeks (95% CI, 4.3 – 11.9) p = 0.009 Selumetinib (n = 38) Temozolomide (n = 42) Selumetinib (n = 47) Temozolomide (n = 49) Presented by: RD Carvajal • Is this a lead? • Will a more directed target combination improve this result?
  47. 47. Ocular Melanoma: Immunotherapy • Relatively few mutations (neo-antigens) and little immune inflammation • Eye is potential immune sanctuary • Anti-PD1/PD-L1 produces responses in only 3.6% of patients • Can combinations do better?
  48. 48. Figure 2b. Mutation burden all primary uveal melanoma (n=80), primary uveal melanoma from stage harboring a BAP1 mutation (n=26), primary uveal melanoma from stage III/IV patients (n=43), all cutaneous melanoma (n=363) & cutaneous melanoma from stage III/IV patients (n=163). .
  49. 49. Proportion of tumors of each TCGA histology with the T cell-inflamed gene signature
  50. 50. Case History • 2009: 55 yo physician diagnosed with Ocular Melanoma R eye  Treated with enucleation  Adjuvant sunitinib on protocol • 10/2014 Hepatic recurrence –treated with resection • 8/2015-Liver, lung, bone metastases, LDH > 3000 • Treated with ipi/nivo as part of Expanded Access Protocol
  51. 51. Figure 2b. Mutation burden of case study (red line) relative to all primary uveal melanoma (n=80), primary uveal melanoma from stage harboring a BAP1 mutation (n=26), primary uveal melanoma from stage III/IV patients (n=43), all cutaneous melanoma (n=363) & cutaneous melanoma from stage III/IV patients (n=163). .
  52. 52. Ocular Melanoma Response to Nivo/ipi Sept 2015 April 2016
  53. 53. Ocular Melanoma: Adjuvant Therapy Concept Suthee Rapisuwon-G-LCCC- Approved
  54. 54. 61 MEK and PD-L1 Inhibition: A Rational Combination Ebert P et al. Immunity 2016. MEKi, MEK inhibitor; ND, no drug (vehicle alone). CD8+ T cell per Tumor Cell ND MEKi Class I MHC ND MEKi P = 0.0024 Tumor Volume (mm3) Day Control AntiPD-L1 MEKi (38963) MEKi + antiPD-L1 Intratumoral T cell accumulation Tumor cell visibility Efficacy (CT26 syngeneic mouse model)
  55. 55. 62 Cobi + Atezo in Cutaneous Melanoma Reduction in Tumor Burden Data cutoff: July 12, 2016. Best overall response (confirmed, RECIST v1.1) MaximumReductioninSumofLongest DiametersFromBaseline,% -100 -80 -60 -40 -20 20 40 0 28 15 -1 -2 -9 -13 -45 -45 -56 -80 17 1 -5 -38 -39 -56 -80 -100 -100 44 BRAF WT BRAF mutant • 15 (75%) patients experienced tumor reduction  2 (10%) patients with confirmed PRs had complete disappearance of target lesions
  56. 56. Ocular Melanoma: Conclusions • Ocular melanoma shares some properties with WT Cutaneous Melanoma  Sensitivity to MEK inhibition  Ability to respond to combination immunotherapy • More research needed to identify and target factors leading to immune escape and integrate IT with MTT and other treatments to produce TFS approaching that seen with Cutaneous Melanoma

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