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?

Melanoma Therapy: 2017

¨ Advances in treatment · Molecularly Targeted Therapy· Immunotherapy

¨ Current/Future Research Questions

¨ Relationship to Other Cancers¨ Relationship to Ocular Melanoma

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

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

Selective Inhibition of BRAF mutant tumors

1205Lu C8161

PET Scans at Baseline and Day 15 After Vemurafenib

#63#69

#59#56

Change in Tumor Size in 122 V600EBRAF mutant melanoma patients treated with vemurafenib on BRIM2

RECIST 30% Decrease

Sosman et al NEJM 2012

Rationale for Combination

1. Hauschild et al., Lancet 2012; 2. Flaherty et al., NEJM 2012

pERK

Proliferation SurvivalInvasion

Metastasis

RAS

BRAF

MEK

Preclinical BRAFi +MEKiDelays 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

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

OS

Prob

abili

ty

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

PFS

Prob

abili

ty

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

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

OS

Prob

abili

ty

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 Randomization6 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)

PFS

Prob

abili

ty

OSPFS

Immunotherapy

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

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

Blocking Immunologic Checkpoints

CTLA-4

B7Dendritic cell Cytotoxic

T cellCD28

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.

Tumor

PD-L1

PD1

NivolumabPembrolizumabPidilizumab

IpilimumabTremelimumab MPDL3280A

MEDI4736MSB0010718C

Patients at RiskIpilimumab 1861 839 370 254 192 170 120 26 15 5 0

Prop

ortio

n A

live

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months0 12 24 36 48 60 72 84 96 108 120

N = 1861Median OS (95% CI): 11.4 mo (10.7-12.1)

3-year OS Rate (95% CI): 22% (20% to 24%)

IpilimumabCENSORED

Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24.

Ipilimumab: Pooled Survival Analysis from Phase II/III Trials in Advanced Melanoma

Patie

nts

Aliv

e

(%)

aStratified by stage provided at randomization.

Ipilimumab PlaceboDeaths/patients 162/475 214/476HR (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 80

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk162475 431 369 325 290 199 62 4214476 413 348 297 273 178 58 8

IpilimumabPlacebo

Priming: T-Cell Activation in the Lymph Node

Blocking Immunologic Checkpoints

CTLA-4

B7Dendritic cell Cytotoxic

T cellCD28

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-L1PD1

NivolumabPembrolizumabPidilizumab

IpilimumabTremelimumab Atezolizumab

DurvalumabAvelumab

Interferons

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 treatmentOff treatment

Censored

First responseDeath

0 8 16 24 32 40 48 56 64

Niv

olum

abIC

C

Patie

nts

(Res

pond

ers)

TreatmentMedian 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

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 symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab

April 9, 2013

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-TIPI-NComplete ResponsePartial ResponseProgressionOn Treatment

Time, weeks10 30 50 70 90

Indi

vidu

al P

atie

nts

Trea

ted

With

Pem

brol

izum

ab

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

Single Agent Anti-PD1 Blockade: Future Directions

• Determine when to stop Our current approach

• Adjuvant protocols• Biomarker refinement

• Combinations: Immunotherapy, targeted therapy, RT, Vaccines

CTLA-4 Blockade (Ipilimumab) PD-1 Blockade (Nivolumab)

APC – T-cell Interaction

Activation(cytokine secretion, lysis,

proliferation, migration to tumor)

Tumor Microenvironment

Dendriticcell T cell Tumor cell

MHCTCR

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

Ipi/Nivo Combination

ORR >80% Tumor Reductionipilimumab 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

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 PatientsNIVO + 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)

Prop

ortio

n A

live

and

Prog

ress

ion-

free

NIVO + IPIIPI

Response RatesNivo + Ipi = 61%Ipi = 11%

Postow et al NEJM 2015

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 PatientsNIVO + 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)

Prop

ortio

n A

live

and

Prog

ress

ion-

free

NIVO + IPIIPI

Response RatesNivo + Ipi = 61%Ipi = 11%

Postow et al NEJM 2015

FDA Approval 10/1/15

067 Study Nivo vs Nivo + Ipi: Topline data

Nivo Nivo + IpiMed 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 11.5Tumor Burden change

- 34.5% - 51.9%

Response Duration NR NRMed OS NR NRGrade 3-4 SAEs 16% 55%

Proof of principle that combination immunotherapy can produce greater activity than anti-PD1 alone

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

Majority of Responding patients to Nivo/Ipi will continue to respond after stopping Treatment

15/16 patients continue to respond after stopping Rx5/5 CR; 11/12 PRGibney, Gardner et al

Combination I/0 Achieves “Many” Patients’ Preferred Outcome- Treatment Free Survival or “TFS”

7 deaths in 41 patients Median F/up 18 months

Treatment endsBenefit persists

TFS = Travel Full Survival

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

EA6134: Ipi/Nivo to D/T vs D/T to Ipi/Nivo

ECOG PS1. 02. 1

LDH3. Normal4. Elevated

RANDOMIZE

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, ChmielowskiOpened July 2015

Ipi 3/Nivo 1 mg/kg q 3wks x 4+Maint Nivo

D 150 BID /T 2 mg Qd

PD

PD

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 benefitMelanomaNSCLCaRCC Urothelial Ca

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 cellsRelease of cancer cell antigens

Cancer antigen presentation

Priming and activation

Anti-VEGF

CAR Ts

Anti-PD-L1Anti-PD-1IDO inhibitors

ChemotherapyRadiation therapyTargeted therapy

VaccinesIFN-αGM-CSFAnti-CD40 (agonist)TLR agonists

Anti-CTLA4Anti-CD137 (agonist)Anti-OX40 (agonist)Anti-CD27 (agonist)IL-2IL-12

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?

Solid

tumor

s T

opali

an N

EJM 20

12

Melan

oma

Web

er JC

O 20

13

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%

Melan

oma

Gros

so AS

CO 20

13NS

CLC

Gan

dh A

ACR

2014

Melan

oma

Dau

d AAC

R 20

14

Bladd

er P

owles

ASCO

2014

Head

+Nec

k

Selw

ert A

SCO

2014

*

Melan

oma

Riba

s ASC

O 20

14

ObjectiveResponse rates

Mahoney, Atkins Oncology 2014

Solid

tumor

s H

erbs

t ASC

O

2013 Me

lanom

a H

amid

ASCO

2013

NSCL

C S

oria

ECC

2013

anti-PD-1 Antibody anti-PD-L1 Antibody Treatment:

Immune infiltrateMembranous pattern on tumor cellsAssay:

ORR by PD-L1 Expression in Patients with Solid Tumors

Most Cancers Have Mutations

Mutated proteins represent potential antigens – targets for immune recognition and destruction

Lawrence, Nature 499:214 2013

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

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

Overall Survival for Patients with Stage IV BRAFV600 Mutant Melanoma: The Future

PRESENTED BY: Michael B. Atkins

Years after stage IV diagnosis

Pro

porti

on S

urvi

ving

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

Ocular Melanoma

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

Gβγ Gα

GDP

Gα

GTP

PLCβ

PIP2DAG

PKCIP3

RafRafP

MEKP MEK

ERKERKP

PIP2

PIP3PI3K

Akt

mTOR

GPCR

Tumor growth and proliferation

GNAQ Q209LPTEN

The GαPathway

• 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.

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) vs7.0 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

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) vs7.0 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?

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?

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).

.

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 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

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).

.

Ocular Melanoma Response to Nivo/ipiSept 2015 April 2016

Ocular Melanoma: Adjuvant Therapy ConceptSuthee 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 (vehicle alone).

CD8+ T cell per Tumor Cell

ND MEKi

Class I MHC

ND MEKi

P = 0.0024

Tumor Volume (mm3)

Day

ControlAntiPD-L1

MEKi (38963)

MEKi + antiPD-L1

Intratumoral T cell accumulation

Tumor cell visibility

Efficacy (CT26 syngeneic mouse model)

62

Cobi + Atezo in Cutaneous MelanomaReduction in Tumor Burden

Data cutoff: July 12, 2016.

Best overall response (confirmed, RECIST v1.1)

Max

imum

Red

uctio

n in

Sum

of L

onge

st

Dia

met

ers

From

Bas

elin

e, %

-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 WTBRAF mutant

• 15 (75%) patients experienced tumor reduction 2 (10%) patients with confirmed PRs had complete disappearance of target lesions

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