5th ESO-ESMO Latin American Masterclass in Clinical OncologyMelanoma+-+Michielin.pdfKey efficacy...

Melanoma and introduction to immunotherapy

Prof. Olivier Michielin, MS, MD-PhD

Head of Personalized Analytical Oncology,

Department of oncology, CHUV, Lausanne

Swiss Institute of Bioinformatics, Lausanne

March 25th 2019, Berlin, GermanyESMO/ESO Masterclass in Clinical Oncology

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Targeted therapies

Two simultaneous revolutions in stage IV melanoma

Immune therapies

1 Chapman & al. NEJM 2011; 2 Hauschild & al. Lancet 2012; 3 Hodi & al. NEJM, 2010; 4 Flaherty, ASCO 2016; 5 Hodi, AACR 2016; 6 Postow, AACR 2016

2nd Generation I-O: • PD-1 blockade5

• Combined CTLA-4 + PD-16

2nd Generation TKI: • Dual BRAF + MEK

inihibition4

BRAFi1,2

Early clinical benefit

CTLA-4 blockade3

Late clinical benefit

Early and lateclinical benefit

• 2nd generation strategies can both deliver early and late clinical benefits, challenging treatment plans

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Overview of stage IV outcome

1 Ugurel, EJC 2017

• Targeted therapies provide better early outcome…

• … but immuno-oncology curves are crossing at around 14 months 1 …

• … and the difference seems to increase with time


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What is the best endpoint to describe such a benefit?

1 Asierto, Lancet Oncology 2017

• mOS or mPFS are not adequate to describe the long term benefit

• P. Ascierto and G. Long have proposed to use landmark PFS 1

• PFS is not dependent on subsequent lines

• Another endpoint to drive stage IV development is CR rate…


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Overview of therapeutic options in melanoma

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Overview of therapeutic options in melanoma

Surgery Radio-therapy

Chemo-therapy

Immuno-therapy

Targeted-therapy

Stage I Standard No! No! ? ???

Stage II Standard No! No! Ongoing! ??

Stage III Standard Option?Cave!

No! Standard Standard

Stage IV Option forselected

Option forpalliation

Option Standard Standard

Ad

juva

nt

Me

tasta

tic

Loco-regional Systemic

A multidisciplinary team is needed specially for early stage disease!

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Brief introduction to cancer immunotherapy

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Escaping the immune system is a hallmark of cancer!

Hanahan & Weinberg, Cell 2011

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CD8+

TCR

MHC-I

Tum

or

cell

Lym

ph

ocy

te

Cytotoxic T Lymphocyte: Shortman, Brunner, Cerottini, J.Exp. Med. 1972

Demonstration of the activity of cytotoxic T lymphocytes

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Various types of tumor antigens

CD8+

TCR

MHC-I1) Differentiation2) Overexpression3) Cancer-Testis4) Mutations

(Neo-antigens)

P53Mutation

P53 Antigenin MHC-1

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Nivolumab, pembrolizumab,

and atezolizumab approval in NSCLC

Nivolumab approval in RCC

Nivolumab and Pembrolizumab

approval in SCCHN

Nivolumab and Atezolizumab

approval in Bladder cancer

Nivolumab and pembrolizumab

approval in Melanoma

PD-1/PD-L1 inhibition successes across multiple tumors

1000

100

10

1

0.1

0.01

n=22

Rh

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Pro

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CLL

Low

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Bre

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Mel

ano

ma

20 52 134 26 23 81 227 91 57 121 13 63 214 11 394 219 20 49 181 231 76 88 35 335 179 121So

mat

ic M

uta

tio

n

Freq

uen

cy (

/Mb

)1

1. Lawrence, Nature. 20135t

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Inflamed

Immune excluded

Immune desert

Immune phenotypes andimmunotherapy

Adapted from• Chen & Mellman, Immunity, 2013• Kim & al. Ann Oncol, 2016

1

Antigenrelease

2Antigenpresentation

3Priming &activation

4

Trafficking

5 Tumor infiltration

6 Tumor recognition

7

Tumor killing

Tumor cells

No T cells

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Immunotherapy:Checkpoints inhibitors

αCTLA-4

αPD-1

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Checkpoints act at different stages of the immune cycle

PD-1 or

PD-L1

CTLA-4

?

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CTLA-4 blockade:ipilimumab(Yervoy)

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B7

Canonical mode of action (MoA) of ipilimumab

DendriticCell

CTLA-4

✗Inhibition

Cellule dendritique

DendriticCell

Ipilimumab

Activation

B7

CD28

CTLA-4

DendriticCell

++ + -

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However, ipilimumab MoA is much more complex!

1 Krummel, J. Exp. Med 1995; 2 Romano, PNAS 2015; 3 Reviewed in Walker, Nat Rev Immunol 2011

2 Treg depletion by ADCC2

Treg

CTLA4

MȻ

FC-γ

APCT cell

CTLA4 CD80

p-MHCTCR

1 Blocking CTLA4 inhibitory signal1

T cell

CTLA4 CD80

APC

IDO TRP

3 Blocking IDO expression by APC3

4 Blocking inhibitory cytokines3

T cell

CTLA4 CD80

APC

TGF-𝛽

T cell

5 Blocking CD80 capture3

T cell

Soluble CTLA4

APC

T cellCD28

CD80

T cell

APC

6 Blocking CTLA4 ligands capture3

CD80

No Signal II

Endo-cytosis

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Long term benefit of CTLA-4 blockade: pooled analysis1

• Long term benefit can be in part explained by the larger number of antigen recognized

• Upon loss of an antigen by the tumors, growth can be controlled by the other ones

• Ipilimumab has been shown to increase the antigenic repertoire

• Kvistborg & al. Science Transl Med 2014

?

Checkpoint

1 Schadendorf, JCO 2015

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Tumor

antigen

Tumor cell MHC-I

CD8+

T cell

TCR

+

-

Oncogenic

event

2 PD-L1 expression resulting from oncogenic events

Tumor cell MHC-I

CD8+

T cell

TCR

STAT

IFN-γ

+

-

1 PD-L1 expression induced by IFN

Taube, Sci Transl Med 2012

Green, Blood 2010:9p24.1 amplification leads toincreased PD-L1 expression inHodgkin

Dynamic PD-L1 expression

Constitutive PD-L1 expression

PD-1 / PD-L1 axis: deciphering PD-L1 expression mechanisms

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PD-1 / PD-L1 pathway: biological interpretation

Tumor cell Lymphocyte

+

-

=

INF-γ

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However, the biology of PD-1/PD-L1 is much more complex!

Image courtesy

from J. Allison

PD-1 / PD-L1 Interactions

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Nivolumab, pembrolizumab,

and atezolizumab approval in NSCLC

Nivolumab approval in RCC

Nivolumab and Pembrolizumab

approval in SCCHN

Nivolumab and Atezolizumab

approval in Bladder cancer

Nivolumab and pembrolizumab

approval in Melanoma

PD-1/PD-L1 inhibition successes across multiple tumors

1000

100

10

1

0.1

0.01

n=22

Rh

abd

oid

tu

mo

r

Ewin

g sa

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ma

Thyr

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AM

L

Me

du

llob

last

om

a

Car

cin

oid

Neu

rob

last

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a

Pro

stat

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CLL

Low

-gra

de

glio

ma

Bre

ast

Mu

ltip

le m

yelo

ma

Pan

crea

s

Kid

ney

cle

ar c

ell

Kid

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illar

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llO

vari

an

Glio

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sto

ma

Cer

vica

l

DLB

CL

Hea

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nd

nec

k

Co

lore

ctal

Eso

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agea

lad

eno

carc

ino

ma

Sto

mac

h

Bla

dd

er

Lun

g A

D

Lun

g SQ

Mel

ano

ma

20 52 134 26 23 81 227 91 57 121 13 63 214 11 394 219 20 49 181 231 76 88 35 335 179 121So

mat

ic M

uta

tio

n

Freq

uen

cy (

/Mb

)1

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Toxicity

managment:

detailed

guidelines

exist, e.g.

ESMO

+

-

Haanen, Ann Oncol. 20175t

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Clinical management of stage III melanoma

pT1b-T4b cN0 cM0

SLNB

Std. FU Adjuvant criteria?

US FU Adjuvant

Relapse

Adjuvant

Relapse

CLND

CLND

Negative Positive

YesNo

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Results from MSLT-2: no benefit to radical lymphadenectomy

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MSLT-2 – Study design

Important:

• The control arm is not follow-up, but active surveillance with 4 monthly ultrasounds!

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Results from MSLT-2: no benefit to radical lymphadenectomy

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Possible stage III

melanoma

management

algorithm

pT1b-T4b cN0 cM0

SLNB

Std. FU Adjuvant criteria?

US FU Adjuvant

Relapse

Adjuvant

Relapse

CLND

CLND

Negative Positive

YesNo

Figure legends:• SLNB: sentinel lymph

node biopsy• CLND: complete lymph

node dissection• FU: follow-up

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Adjuvant treatments

100%

0%

Overall Survival

Time

Control arm

Adjuvant arm

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Risk / benefit ratio: number needed to treat

With 11% gain at 5 years, 89% of the population is exposed to treatment with no benefit and the number needed to treat is 9.1 compared to 35 for INF1

100%

0%

Overall Survival

Time

Adjuvant did notchange outcome:patient death

Adjuvant benefit: 11% @ 5y

Adjuvant did notchange outcome:patient is cured

Control arm

Adjuvant arm

1 Mocellin, Cochrane Review, 2013

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Key efficacy landmarks in the adjuvant setting of melanoma

Olivier Michielin, MD-PhD

EORTC 1325 • Pembrolizumab vs placebo, • Stage IIIA-C; RFS HR 0.57, OS HR NA

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

453 353 311 249 5 0399 332 291 71NIVO

453 314 252 184 2 0364 269 225 56IPI

Number of patients at risk

NIVO

IPI

66%

53%

71%

61%

Checkmate 238

• Ipilimumab 10 mg/kg vs nivolumab, • Stage IIIB-C + IV; RFS HR 0.65,

OS HR NA

Months

Nivo > Ipi

Months

Pembro > Pbo

COMBI-AD • Dabrafenib + trametinib vs placebo• Stage IIIA-C; RFS HR 0.47, OS HR 0.57

Months

D+T > Pbo

EORTC 18071 • Ipilimumab 10 mg/kg vs placebo, • Stage IIIA-C; RFS HR 0.76, OS HR 0.72

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

264 475 283 217 184 161 77 13 1

323 476 261 199 154 133 65 17 0

Ipilimumab

Placebo

Ipi > Pbo

Years

Current adjuvant options shown in orange

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EORTC 18071/CA184-029: adjuvant ipilimumab

Stratification factors:

• Stage (IIIA vs IIIB vs IIIC 1-3 positive lymph nodes vs IIIC ≥4 positive lymph nodes)

• Regions (North America, European countries and Australia)

Enrollment Period: June 2008 – July 2011

Randomized, double-blind, phase 3 study evaluating the efficacy and safety of

ipilimumab in the adjuvant setting for high-risk melanoma

Treatment up to a maximum 3 years, or until disease progression, intolerable toxicity, or

withdrawal

N=475

N=476

Week 1 Week 12 Week 24

N=951

Q3W = every 3 weeks; Q12W = every 12 weeks.

High-risk, stage III, completely resected

melanomaR

INDUCTIONIpilimumab 10 mg/kg

Q3W X4

MAINTENANCEIpilimumab 10 mg/kgQ12W up to 3 years

INDUCTIONPlaceboQ3W X4

MAINTENANCEPlacebo

Q12W up to 3 years

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HIGHLY CONFIDENTIAL

Pa

tie

nts

a

liv

e (%

)

*Stratified by stage at

randomization

Ipilimumab Placebo

Deaths/patients 162 / 475 214 / 476

Hazard ratio (95.1%

CI)*0.72 (0.58 - 0.88)

Log-rank P value* 0.001

EORTC 18071: Overall Survival

65%

54%

5-year

difference

11%

CI = confidence interval; NR = not reached.

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 :

162 475 431 369 325 290 199 62 4

214 476 413 348 297 273 178 58 8

Ipilimumab

PlaceboEggermont, ESMO 2016

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Checkmate-238: adjuvant nivolumab vs. ipilimumab

Patients with high-risk, completely resected stage

IIIB/IIIC or stage IV melanoma

Enrollment period: March 30, 2015 to November 30, 2015

Follow-up

Maximum treatment duration of

1 year

NIVO 3 mg/kg IV Q2W and

IPI placebo IV Q3W for 4 doses

then Q12W from week 24

IPI 10 mg/kg IV Q3W for 4 doses

then Q12W from week 24 and

NIVO placebo IV Q2W

1:1

n = 453

n = 453

Stratified by:

1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c

2) PD-L1 status at a 5% cutoff in tumor cells

Weber, NEJM 2017

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RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 273 9 15 21

453 353 311 249 5 0399 332 291 71NIVO

453 314 252 184 2 0364 269 225 56IPI

Number of patients at risk

NIVO

IPI

NIVO IPI

Events/patients 154/453 206/453

Median (95% CI) NR NR (16.6, NR)

HR (97.56% CI) 0.65 (0.51, 0.83)

Log-rank P value <0.0001

66%

53%

71%

61%

Checkmate-238: primary endpoint – relapse free survival

Weber, NEJM 20175t

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Adjuvant BRAFi + MEKi: COMBI-AD

Key eligibility criteria• Completely resected, high-risk stage

IIIA (lymph node metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma

• BRAF V600E/K mutation• Surgically free of disease ≤ 12 weeks

before randomization• ECOG performance status 0 or 1• No prior radiotherapy or systemic

therapy

R

A

N

D

O

M

I

Z

A

T

I

O

N

Stratification• BRAF mutation status (V600E, V600K)• Disease stage (IIIA, IIIB, IIIC)

1:1

Dabrafenib 150 mg BID + trametinib 2 mg

QD(n = 438)

2 matched placebos

(n = 432)

Treatment: 12 monthsa

Follow-up until end of study

• Primary endpoint: RFSd

• Secondary endpoints: OS, DMFS, FFR, safety

N = 870

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438 413 405 392 382 373 355 336 325 299 282 276 263 257 233 202 194 147 116 110 66 52 42 19 7 2 0432 387 322 280 263 243 219 203 198 185 178 175 168 166 158 141 138 106 87 86 50 33 30 9 3 0 0

Months From RandomizationDabrafenib plus trametinibPlacebo

No. at Risk

0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Pro

po

rtio

n A

live

and

Rel

apse

Fre

e1 y, 88%

2 y, 67%

3 y, 58%1 y, 56%

2 y, 44%3 y, 39%

NR, not reached.

GroupEvents,

n (%)Median

(95% CI), moHR

(95% CI)Dabrafenib+trametinib

166 (38)NR

(44.5-NR) 0.47(0.39-0.58);

P < .001Placebo 248 (57)16.6

(12.7-22.1)

P = .0000000000000153

Adjuvant BRAFi + MEKi: COMBI-AD

Hauschild, JCO 20185t

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Comparison of stage subgroup eligibility criteria

Stage - AJCC 7th Edition (All patients NED)

Study Design IIC IIIA IIIB IIIC IV

EORTC 18071

Ipi 10 vs. placebo

✓ SN > 1mm ✓✓ no in

transit mets

EORTC 1325

Pembro vs. placebo

✓ SN > 1mm ✓✓ no in

transit mets

Checkmate 238

Ipi 10 vs. nivo ✓ ✓ ✓

ECOG 1609

Ipi 10 vs ipi 3 vs. HD INF-α2b ✓ ✓ ✓M1a-b


BRIM-8 Vem vs. placebo ✓ ✓ SN > 1mm ✓ ✓

COMBI-AD

Dabra + trame vs. placebo

✓ SN > 1mm ✓ ✓

NA, Not Available; NE, Not Estimated1 AJCC 8th Edition staging

FDA

11

.15

FDA

12

.17

FDA

04

.18

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Adjuvant in melanoma: important data are still missing!

Efficacy data

Study Design HR RFS HR DMFS HR OS

EORTC 180711

Ipi 10 mg vs. placebo

0.76 0.76 0.72

EORTC 13252

Pembro vs. placebo

0.57 0.536 NA

Checkmate 2382

Ipi 10 vs. nivo 0.65 0.737 NA

ECOG 1609

Ipi 10 vs ipi 3 vs. HD INF-α2b

1.0 NA NA


BRIM-84 Vem vs. placebo0.54 (IIC-IIIB)

0.8 (IIIC)NA NA

COMBI-AD5


0.47 0.51 0.57

Data not randomized head to head, should not be compared directly; NA, Not Available; NE, Not Estimated; 1 AJCC 8th Edition staging

1Eggermont, NEJM 2016; 2Eggermont NEJM 2018; 3Weber, NEJM 2017; 4Maio, Lancet Oncol 2018; 5Long, NEJM 2017;6Preliminary, Eggermont, AACR 2018; 7Exploratory; 8Faries, NEJM 2017; 9Leiter, Lancet 2016; Time in months;NA: Not Available;

Stage III patients from these trials were required to have complete lymph node dissection!

How do we integrate those results in a post MSLT-2/ DeCOG8,9 trial era?

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Overview of PFS outcome per stage subgroup

Stage - AJCC 7th Edition (All patients NED)

Study Design IIC IIIA IIIB IIIC IV

EORTC 18071

Ipi 10 mg vs. placebo

SN > 1mm, HR 0.98

HR 0.75HR 1.00, 1-3 nHR 0.48, ≥ 4 n

EORTC 1325

Pembro vs. placebo

SN > 1mm,HR 0.38

HR 0.58 HR 0.58

Checkmate 238

Ipi 10 vs. nivo HR 0.67 HR 0.65HR 0.63 M1a/b,

HR 1.0 M1c2

ECOG 1609

Ipi 10 vs ipi 3 vs. HD INF-α2b

HR NA HR NAM1a-b,HR NA


BRIM-8 Vem vs. placebo HR 0.0-NESN > 1mm,

HR 0.52HR 0.63 HR 0.8

COMBI-AD


SN > 1mm,HR 0.44

HR 0.50 HR 0.45

Data not randomized head to head, should not be compared directly; NA, Not Available; NE, Not Estimated; 1AJCC 8th Edition staging; 2CI 0.37-2.66!

FDA

11

.15

FDA

12

.17

FDA

04

.18

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Adjuvant immunotherapy: review of existing toxicity data


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AEs comparison: EORTC 18071, Checkmate 067 & CA 184-169

ToxicityIpilimumab

10 mg/kg1,2, data2

Nivolumab 3 mg/kg2

Pembrolizumab200 mg3,4

Dabrafenib + trametinib5,6

All values in % All G 3-4 All G 3-4 All G 3-4 All G 3-4

Any AE 99 55 97 25 93 32 97 41

Any drug related AE 96 46 85 14 78 15 916 316

Fatigue 33 1 35 <1 37 1 47 4

Rash 29 3 20 1 16 <1 24 0

Diarrhea / colitis 46/10 10/8 24/2 2/1 19/4 1/2 33/NR 1/NR

Increased AST/ALT 13/15 4/6 6/6 <1/1 NR/NR NR/NR 14/15 4/4

Pneumonitis 2 1 1 0 3 1 - -

Hypophysitis 11 3 2 <1 2 1 - -

Adrenal disorder 3 1 1 <1 1 <1 - -

Thyroid disorder 13 1 20 1 21 <1 - -

Type I diabetes <1 <1 <1 0 1 1 - -

Olivier Michielin, MD-PhD1 Eggermont, NEJM 2016; 2 Weber, NEJM 2017; 3 Eggermont, NEJM 2018; 4 Eggermont, AACR 2018;5 Long, NEJM 2017; 6 Long, SMR 2017; NR – Not Reported5t

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Targeted therapies for stage IV melanoma

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Preclinical programs:• Allosteric inhibitors 1

Targeted therapies in stage IV melanoma: main trials R

TK

RAS

BRAF

MEK

ERK

Melanoma cell

COMBI-d7: BRAFV600

• D+T vs. dabrafenib• RR 67%, mPFS 9.3m• HR OS/PFS: 0.63/0.75

COMBI-v6: BRAFV600

• D+T vs. vemurafenib• RR 64%, mPFS 11.4m• HR OS/PFS: 0.69/0.56

1 Ostrem, Nature 2013; 2 McArthur, Lancet Oncol 2014; 3 Hauschild, Lancet 2012; 4 Flaherty, NEJM 2012; 5 Dummer, Lancet Oncol 2017; 6 Robert NEJM 2015; 7 Long, Lancet 2015; 8 Larkin NEJM 2014; 9 Dummer, EADO 2015; 10 Wong, Molecular Cancer 2014; NA: Not Available

Co-BRIM8: BRAFV600

• V + cobi vs. V• RR 68%, mPFS 9.9m• HR OS/PFS: 0.51/0.65

COLOMBUS9: BRAFV600

• enco + bini / enco / V• RR 63%, mPFS 14.9• HR OS/PFS: NA/0.54

Preclinical & clinical:• Allosteric and ATP

competitors 10

• GDC-0994 in phase I

BREAK-33: BRAFV600

• dabrafenib vs. DTIC• RR 47%, mPFS 5.1m• HR OS/PFS: 0.61/0.30

BRIM-32: BRAFV600

• vemurafenib vs. DTIC• RR 57%, mPFS 6.9m• HR OS/PFS: 0.70/0.38

Metric4: BRAFV600

• trametinib vs DTIC• RR 22%, mPFS 4.8m• HR OS/PFS: 0.54/0.45

NEMO5: NRASmut

• binimetinib (MEK162)• RR 15%, mPFS 2.8m• HR OS/PFS: 1.0 / 0.62

• Dabrafenib• Vemurafenib• …

• Trametinib• Cobimetinib• …

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COMBI-d: study design

Presented by Keith Flaherty, ASCO 2016

N = 947 screened

Primary Endpoint: investigator-assessed PFS

Secondary Endpoints: OS, overall response rate (ORR), duration of response, safety

N = 423

• BRAF V600E/K• Unresectable stage IIIC/IV• Treatment naive• ECOG PS 0/1• No brain metastases, unless:

Treated Stable ≥ 12 weeks

Stratification• BRAF-mutant (V600E vs K)• LDH (> ULN vs ULN)

Dabrafenib + trametinib150 mg BID + 2 mg QD

n = 211

Dabrafenib + placebo150 mg BID + placebo QD

n = 212

Pre-planned interim OS[95 events]

Primary Analysis

(PFS)[213 events]

Aug 2013

Final Analysis(OS)

[222 deaths]Jan 2015

BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; QD, once daily; ULN, upper limit of normal.

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COMBI-d: 3 year survival estimates

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

Pro

ba

bil

ity

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

PF

S P

rob

ab

ilit

y

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

Presented By Keith Flaherty at 2016 ASCO Annual Meeting

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Baseline Factors Influencing OS in Combi-d, Combi-v and Ph-II

• Regression tree analysis based on:

• BMI

• Age

• LDH(N, > 1- ≤ 2x ULN, ≥ 2x ULN)

• Sex

• ECOG

• Visceral disease

• Number of sites

• Prior adjuvant immunotherapy

• 5 prognostic subgroups with very large OS differences

N=617

Adapted from:GV. Long, SMR 2015, JCO 2016K. Flaherty, ASCO 2016

N=3981Y=85%2Y=75%3Y=57%

N=2191Y=54%2Y=25%3Y=7%

Normal LDH LDH ≥ ULN

N=1491Y=60%2Y=33%3Y=9%

N=701Y=40%2Y=7%3Y=7%

LDH ≥ 2x ULN

LDH > 1-≤ 2x ULN

N=2371Y=90%2Y=75%3Y=70%

N=1611Y=76%2Y=55%3Y=38%

Sites ≥ 3Sites < 3

N=931Y=71%2Y=43%3Y=NE

N=561Y=42%2Y=19%3Y=16%

ECOG ≥ 1ECOG = 1

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3-year OS data from COLOMBUS

Overa

ll S

urv

ival, %

Time (months)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 21 24 27 36 39 42 4815 18 30 33 45

ENCO300

VEM

Censored patients

Median OS in months (95% CI)

ENCO300 VEM

23.5 (19.6–33.6) 16.9 (14.0–24.5)

HR (95% CI), 0.76 (0.58–0.98)

Nominal 2-sided P=0.033

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Preclinical programs:• Allosteric inhibitors 1

Targeted therapies in stage IV melanoma: main trials R

TK

RAS

BRAF

MEK

ERK

Melanoma cell

COMBI-d7: BRAFV600

• D+T vs. dabrafenib• RR 67%, mPFS 9.3m• HR OS/PFS: 0.63/0.75

COMBI-v6: BRAFV600

• D+T vs. vemurafenib• RR 64%, mPFS 11.4m• HR OS/PFS: 0.69/0.56

1 Ostrem, Nature 2013; 2 McArthur, Lancet Oncol 2014; 3 Hauschild, Lancet 2012; 4 Flaherty, NEJM 2012; 5 Dummer, Lancet Oncol 2017; 6 Robert NEJM 2015; 7 Long, Lancet 2015; 8 Larkin NEJM 2014; 9 Dummer, EADO 2015; 10 Wong, Molecular Cancer 2014; NA: Not Available

Co-BRIM8: BRAFV600

• V + cobi vs. V• RR 68%, mPFS 9.9m• HR OS/PFS: 0.51/0.65

COLOMBUS9: BRAFV600

• enco + bini / enco / V• RR 63%, mPFS 14.9• HR OS/PFS: NA/0.54

Preclinical & clinical:• Allosteric and ATP

competitors 10

• GDC-0994 in phase I

BREAK-33: BRAFV600

• dabrafenib vs. DTIC• RR 47%, mPFS 5.1m• HR OS/PFS: 0.61/0.30

BRIM-32: BRAFV600

• vemurafenib vs. DTIC• RR 57%, mPFS 6.9m• HR OS/PFS: 0.70/0.38

Metric4: BRAFV600

• trametinib vs DTIC• RR 22%, mPFS 4.8m• HR OS/PFS: 0.54/0.45

NEMO5: NRASmut

• binimetinib (MEK162)• RR 15%, mPFS 2.8m• HR OS/PFS: 1.0 / 0.62

• Dabrafenib• Vemurafenib• …

• Trametinib• Cobimetinib• …

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3

Study Design and Objectives

COMBO450=encorafenib 450 mg QD + binimetinib 45 mg BID; ECOG PS=Eastern Cooperative Oncology Group performance status; OS=overall survival; PFS=progression-free survival; R=randomization; VEM=vemurafenib 960 mg BID.

*Amendment requested by FDA.†Included in hierarchical testing approach.‡Median follow-up of patients assessed using reverse Kaplan-Meier approach (i.e. median potential follow-up).

Efficacy update with additional follow-up of 18 months:OS:

Secondary endpoint†

Planned after 232 events in the COMBO450 and VEM groups combined

Median duration of follow-up‡: 36.8 months

PFS:

Primary endpoint


R

3:1

(N=344)

COMBO300Encorafenib 300 mg QD +

Binimetinib 45 mg BID (n=258)

ENCO300Encorafenib 300 mg QD (n=86)

COLUMBUS

Part 2* Untreated or progressed

on/after prior first-line

immunotherapy

BRAFV600E and/or BRAFV600K

ECOG PS 0–1

R

1:1:1

(N=577)



VEM Vemurafenib 960 mg BID (n=191)


COLUMBUS Part 1

Reinhard Dummer

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COMBO450 VEM

33.6 (24.4–39.2) 16.9 (14.0–24.5)

HR (95% CI), 0.61 (0.47–0.79)

Nominal 2-sided P<0.0001

Overall Survival: COMBO450 vs VEM

5

1

0

10

20

30

40

50

60

70

80

90

100O

ve

rall S

urv

iva

l, %

COMBO450

VEM

Patients at risk Time (months)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

192 188 182 166 144 132 124 115 108 102 95 82 57 30 9 1 0

191 184 166 140 115 100 89 83 77 71 62 56 30 19 8 1 0

COMBO450

VEM

Censored patients

Reinhard Dummer

COMBO450=encorafenib 450 mg QD + binimetinib 45 mg BID; HR=hazard ratio; OS=overall survival; VEM=vemurafenib 960 mg BID.

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5

2

Ove

rall S

urv

iva

l, %

Time (months)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 21 24 27 36 39 42 4815 18 30 33 45

ENCO300

VEM

Censored patients

194 181 168 147 133 117 109 94 86 83 79 59

191 184 166 140 115 100 89 83 77 71 62 56

ENCO300

VEM

Patients at risk

40 24 5 0 0

30 19 8 1 0

Overall Survival: ENCO300 vs VEM

ENCO300=encorafenib 300 mg QD; HR=hazard ratio; OS=overall survival; VEM=vemurafenib 960 mg BID.


ENCO300 VEM

23.5 (19.6–33.6) 16.9 (14.0–24.5)

HR (95% CI), 0.76 (0.58–0.98)

Nominal 2-sided P=0.033

Reinhard Dummer

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Immuno-therapies for stage IV melanoma

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Checkmate-067: PD-1 blockade as a backbone for combinations1

NIVO

37%32% 31%

Months

PFS

(%

)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 573024 362721 45 5133 39 5442 48

aDescriptive analysis

1 Hodi, ESMO 20182 Sharma, Cell 2017

Innate resistance2:• Lack of antigenic mutations, MHC loss• Constitutive expression of PD-L1• Increase in T-regs, MDSCs, TAMs• Immunosuppressive cytokines: IL-10, TGF-𝛽• Upregulation of checkpoints: LAG-3, TIM-3• …

Acquired resistance2:• Loss of target antigen• 𝛽2m (light chain of MHC)

mutations• Escape mutation in INF

pathway (e.g. JAK/STAT)

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Rational combination or rational sequencing?

Possible strategies for I-O sequences or combos

2nd I-O agentPD-1 PD

1 Sequencing

PD-1 PD-1PD

2nd I-O agent

2 Combo at relapse

PD-1

2nd I-O agent

3 Combo at start

Depending on the type of resistance mechanism, various strategies might be more appropriate to obtain maximal global PFS. Biomarkers are required to guide strategies.

Resistance mechanism

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Rational selection of PD-1 based combo at start

PD-1 + CTLA-4 inhibitor data: Checkmate-067

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Unresectable or

metatastic melanoma

• Previously untreated

• 945 patients

Treat until

progression

or

unacceptable

toxicity

NIVO 3 mg/kg Q2W +IPI-matched placebo

NIVO 1 mg/kg + IPI 3 mg/kg Q3W for

4 doses then NIVO 3 mg/kg Q2W

IPI 3 mg/kg Q3W for 4 doses +

NIVO-matched placebo

Stratify by:

• BRAF status

• AJCC M stage

• Tumor PD-L1 expression <5% versus ≥5%

n = 314

n = 316

n = 315

4-year follow up of a randomized, double-blind,

phase 3 study to compare NIVO+IPI or NIVO

alone with IPI alonea

Database lock: May 10, 2018; minimum follow-up of 48 months for all patients

CheckMate 067: Study Design

57

Co-primary endpointsa were PFS and OS in

the NIVO-containing arms versus IPI alone

R

1:1:1

aThe study was not powered for a comparison between NIVO+IPI and NIVO

Hodi, ESMO 2018; Hodi, Lancet Oncol 2018

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Response to Treatment

NIVO+IPI

(n = 314)

NIVO

(n = 316)

IPI

(n = 315)

ORR, % (95% CI) 58.3 (52.6, 63.8) 44.6 (39.1, 50.3) 19.0 (14.9, 23.8)

Best overall response, %

Complete response 21.3 17.7 5.1

Partial response 36.9 26.9 14.0

Stable disease 12.1 9.5 21.6

Progressive disease 23.6 38.3 50.5

Unknown 6.1 7.6 8.9

Median duration of response, months (95% CI)

50.1 (44.0, NR) NR (45.7, NR) 14.4 (8.3, NR)

58NR = not reached Hodi, ESMO 2018; Hodi Lancet Oncol 2018

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NIVO+IPI (n = 314) NIVO (n = 316) IPI (n = 315)

Median OS, mo (95% CI)NR

(38.2, NR)36.9

(28.3, NR)19.9

(16.9, 24.6)

HR (95% CI) versus IPI0.54

(0.44, 0.67)0.65

(0.53, 0.79)–

HR (95% CI) versus NIVOa 0.84 (0.67, 1.05)

– –

Overall Survival

59

Months

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 573024 362721 45 5133 39 5442 48

Patients at risk:

0IPI 253285315 227 203 181 163 148 135 128 113 107 99 94 93 90 86 50 11

0265292314NIVO+IPI 247 226 221 209 200 198 192 186 180 178 171 166 160 154 96 13

NIVO 0266292316 245 231 214 201 191 181 175 171 164 158 150 144 140 135 85 18

64%58%

53%

59%

51%46%45%

34%30%


OS

(%

)

NIVO+IPI

NIVO

IPI

Hodi, ESMO 2018; Hodi Lancet Oncol 2018

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Current IO developments in 1L stage IV melanoma

NIVO+IPI

NIVO

IPI

Patients at risk:

0IPI 78136315

0175218314NIVO+IPI

NIVO 0151177316

58

155

132

46

136

120

42

131

112

34

124

106

32

117

103

31

110

97

29

104

88

28

101

84

26

95

79

19

93

77

18

89

75

16

88

72

16

81

66

11

53

50

7

19

18

1

3

0

41%

37%

12%

39%

32%

10%

37%

31%

9%

Months

PFS

(%

)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 573024 362721 45 5133 39 5442 48

Checkmate 067:Still a highunmet medicalneed!

Hodi, ESMO 2018

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OS by Tumor PD-L1 Expression, 5% Cutoff

PD-L1 Expression Level <5% PD-L1 Expression Level ≥5%

NIVO+IPI NIVO IPI

Median, mo

(95% CI)

NR

(32.7, NR)

35.9

(23.1, NR)

18.4

(13.7, 22.5)

HR (95% CI)

versus IPI

0.54

(0.42, 0.69)

0.64

(0.50, 0.82)–

HR (95% CI)

versus NIVOa

0.83

(0.64, 1.09) – –

NIVO+IPI NIVO IPI

Median, mo

(95% CI)

NR

(39.1, NR)

NR

(33.6, NR)

28.9

(18.1, 44.2)

HR (95% CI)

versus IPI

0.56

(0.35, 0.90)

0.65

(0.42, 0.99)–

HR (95% CI)

versus NIVOa

0.86

(0.53, 1.41) – –

56%

50%

30%

52%

45%

28%

65%

59%

45%

61%

54%

36%NIVO+IPI

NIVO

IPI

MonthsPatients at risk:

0667275 64 60 55 46 43 40 39 34 34 31 28 28 26 24 13 3IPI

0566368 55 52 50 45 45 45 44 43 43 43 42 41 41 38 24 3NIVO+IPI

0767980 74 69 64 61 58 57 54 53 50 47 46 43 42 41 24 6NIVO

OS

(%

)

0

20

40

60

80

100

0 3 6 9 12 15 18 573024 362721 45 5133 39 5442 48

OS

(%

)

0

20

40

60

80

100

0 3 6 9 12 15 18 573024 362721 45 5133 39 5442 48

0158179202

0178194210

0169189208

140

163

151

124

146

144

107

144

133

99

139

123

89

131

118

80

130

112

77

127

110

69

123

108

64

118

104

59

116

102

58

111

95

57

107

92

56

103

89

55

100

86

31

62

56

6

9

10

NIVO+IPI

NIVO

IPI


IPI

NIVO+IPI

NIVO


63%

55%

41%

68%

71%

54%

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Imperfect current biomarkers for patient selection1

• No good predictive biomarkers have been identified that allow to strongly separate the patient populations

• PD-L1 and BRAF allow to select population with higher benefit, but the biomarker negative population still derives benefit

False positive rate

Tru

e p

osi

tive

rat

e

ROC curves confirm the poor performance of PD-L1 to guide patient selection: Fig. S4

1Wolchok, NEJM 20175t

h ESO-E

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ncolo

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PD-1 based combo at start

Failure of IDO combined with Pembrolizumab

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Tumorcell

INFγ

PD-1 / PD-L1 and IDO in the T cell inflamed phenotype

• INFγ release triggers both PD-L1 and IDO in tumor cells and in the µ-env.

• Could such co-occurrence be an argument to initiate combo at start?

STAT

INFγ

TCR

T cell

MHC

PD-1

Tryptophan

Kynurenine

+

-

PD-L1

- IDO

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Study Design: Phase III Randomized Controlled Trial

6

5

Key Eligibility Criteria

• Unresectable stage III or IV melanoma,

advanced/metastatic disease

– Patients with BRAF mutation could have

received prior BRAF/MEK therapy

– Prior anti-CTLA-4 or interferon in adjuvant

setting permitted

• ECOG performance status 0–1

• No active CNS metastases

Stratification• PD-L1 status (positivea vs negative)

• BRAF mutation status

– Wild type

– Mutant with prior BRAF-directed therapy

– Mutant without prior BRAF-directed therapy

Epacadostat 100 mg PO BID

+

Pembrolizumab 200 mg IV

Q3W

n=354

Placebo

+

Pembrolizumab 200 mg IV

Q3W

n=352

• Primary endpoints: PFS (RECIST v1.1) and OS

• Secondary endpoints: ORR (RECIST v1.1),

DOR, safety

BID, twice daily; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; ORR, objective response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival;

Q3W, every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumors.a1% staining in tumor and adjacent immune cells as assessed by IHC (22C3 antibody).

Georgina V. Long6

5

N=706

R 1:1

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Progression-Free Survival (RECIST v1.1, BICR)

BICR, blinded independent central review; CI, confidence interval; E, epacadostat; HR, hazard ratio; P, pembrolizumab; PFS, progression-free survival; RECIST, Response Evaluation Criteria In Solid Tumors.

PFS defined as time from randomization to disease progression or death, whichever occurred first.

Georgina V. Long6

6

100

90

80

70

60

50

40

30

20

10

0

Pro

gre

ssio

n-F

ree

Su

rviv

al (%

)

0 2 4 6 8 10 12 14 16 18

Time, months

354

352

309

304

181

181

155

151

137

132

114

109

57

65

25

28

5

7

0

0

E + P

Placebo + P

Number at risk

36.9%36.6%

45.8%45.8%

E + P

Placebo + P

HR (95% CI): 1.00 (0.831.21)

P = 0.517

Events,

n (%)

Median PFS, months

(95% CI)

E + P 218 (61.6) 4.7 (2.96.8)

Placebo + P 219 (62.2) 4.9 (2.96.8)

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Overall Survival

CI, confidence interval; E, epacadostat; HR, hazard ratio; NR, not reached; OS, overall survival; P, pembrolizumab.

Georgina V. Long6

7

100

90

80

70

60

50

40

30

20

10

0

Ove

rall

Su

rviv

al (%

)

0 2 4 6 8 10 12 14 16 18

Time, months

354

352

340

342

322

323

290

304

274

285

263

263

183

186

96

115

42

43

5

2

E + P

Placebo + P

Number at risk

74.4%74.1%

84.1%87.2%

E + P

Placebo + P

HR (95% CI): 1.13 (0.86–1.49)

P = 0.807

Events,

n (%)

Median OS,

months

(95% CI)

E + P 106 (29.9) NR (NR, NR)

Placebo + P 98 (27.8) NR (NR, NR)

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Can one explain KN-252 failure?

• Patient population was not selected on baseline biomarkers

• IDO biology could reveal more complex than anticipated. There are partly overlapping enzymes for amino-acid catabolism1

Unresectablestage III / IV melanoma

R

Keytruda + Epacadostat

Keytruda + Placebo

ECHO-301/KEYNOTE-252 Design:

Co-Primary Endpoints:• PFS – failed• OS – likely to fail

• Most IDO-1 inhibitors are not potent inhibitors of TDO

• Epacadostat inhibits TDO very weakly with EC50 > 10 µMol

1 Molinier-Frenkel, FEBS Letter 2017

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Rational selection of PD-1 based combo at start

PD-1 + LAG-3

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LAG-3 and T cell exhaustion

1 Marraco, Front Immunol 2015ESMO IO 2018 | Geneva | December 14th 2018

• The systems biology of T cell exhaustion is now better understood. For a review, see 1

• Antigen persistence together with continuous checkpoint engagement leads to the exhausted phenotype

• Key checkpoints involved:

• PD-1, CTLA, BTLA, TIM3, 2BA, LAG3, …

I-Rlevels

Immune response

TCR

T cellCTLA-4

LAG-3

KLRG1

PD-1

TIM3

2B4

BTLA

TCR

T cell

TIM3

BTLA

TCR

T cellCTLA-4

LAG-3

PD-1

TIM3

2B4

BTLA

⛔️

Naive

Effector(activated)

Exhausted

TCR

T cell

KLRG1

2B4

BTLA

Memory

Persistent Ag + IR:IRL

Ag cleared

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Pink: PD-L1 ≥ 1% Blue: PD-L1 < 1% Gray: PD-L1 unknown

100

80

60

40

20

0

-20

-40

-60

-100

-80

100

80

60

40

20

0

-20

-40

-60

-100

-80

100

80

60

40

20

0

-20

-40

-60

-100

-80

45% with tumor

reduction

24% with tumor

reduction

13% with tumor

reduction

Be

st

pe

rce

nt

ch

an

ge

in s

um

of

targ

et

les

ion

dia

me

ters

fro

m b

as

eli

ne

a,b

aSix patients with clinical progression prior to their first scan and 1 with PD due to a new symptomatic brain metastasis prior to getting full

scans were not included. bOne patient with best change from baseline > 30% had a best response of SD.

LAG-3 ≥ 1%n = 29

LAG-3 < 1%n = 17

LAG-3 Unknownn = 8

PD-1 + LAG-3 combo in patient relapsing on PD-1 single agent1

1 Ascierto, ESMO 2017

Towards a rational PD-1 based combo selection based LAG-3?

(ORR 18%vs. 11.5 for total pop.)

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Towards complex, multidimensional predictive biomarkers

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Searching for better biomarkers for stage IV patient selection

?

Wolchok, NEJM 2017

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Checkmate-038 prospective biomarker study1

1Riaz, Cell 2017 (in print)

• 68 advanced melanoma patients

• Multidimensional biomarker analysis at baseline and on treatment reveals molecular actions of anti-PD-1 therapy

a) Anti-PD-1 therapy induces changes in the mutational burden of tumors

b) Distinct changes in gene expression programs associate with clinical response

c) Shifts in the TCR repertoire occur following immune checkpoint blockade

• This study is one example of the level of information that need to be integrated for complex biomarker research

• Many more to come!

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2nd target selection for PD-1 based combos:

APCT cell

CTLA4 CD80Ag

Tumor

T cell

PD-1 PD-L1

αPD-1 +

Non Immune Microenvironment• Anti-angiogenesis (VEGF)• Depleting CAFs (NOX4, …)

Tumor cell intrinsic• Driver oncogenes (BRAFi, MEKi)• AXL, Wnt, TGF𝛽 inhibition• Radiotherapy

Priming• Oncolytic viruses (TVEC)• Other IT agents

(TLR agonists)• Checkpoints (CTLA-4, …)• Radiotherapy

CD8+ T cell intrinsic• T cell proliferation (IL-2)• Exhaustion checkpoints

(LAG-3, TIM-3, VISTA, …)• Suppressive metabolites

(IDO, TDO, Arginase, A2a)• Epigenetic reprogramming

(HDACi)

T cell tumor site homing• Tumor endothelium modulation

(Endothelin receptors)• Anti-angiogenesis (VEGF)• Fas/Fas-L inhibition

T Reg

Non CD8 Immune Microenvironment(T, MDSC, Neutrophils)• T reg depletion (CTLA-4)• MDSC depletion• M2 Macrophage

depletion (CSF-1R)• Neutrophils

(neutrophil trap)

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Conclusion and outlook

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Conclusion: modern treatment of melanoma, a whole new world!

• In less than 10 years, the treatment of melanoma has been completely rewritten

• Two strategies have provided unprecedented overall survival benefits

• Targeted and immuno-therapies

• Our challenge for the years to come is

• to optimally combine and/or sequence them

• to define predictive biomarkers for precise patient selection and maximal benefit, i.e. a cure!

BRAFi1,2

Early clinical benefit

CTLA-4 blockade3

Late clinical benefit

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Possible treatment algorithm for stage IV melanoma1

stLi

ne

2n

dLi

ne

3rd

Lin

e

BRAF WT BRAF Mutated NRAS Mutated

Trial

Trial

Trial

PD-1

CTLA-4

Chemo

PD-1/CLTA-4

BRAFi/MEKi

Chemo

BRAFi/MEKi

PD-1/CLTA-4

Chemo

PD-1/CLTA-4

MEKi

Chemo

PD-1

BRAFi/MEKi

CTLA-4

Chemo

PD-1

CTLA-4

MEKi

Chemo

PD-1/CLTA-4

Chemo

I-O Re-challenge

? ? ? ?

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Thank you for your attention!


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Counteracting BRAF/MEKiresistance mechanisms

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Strategies to overcome BRAFi + MEKi resistance

• Combination based on molecular escape

• E.g: LOGIC-2 trialCombo

Rational 3rd TKI

PD

Combo

Combo Combo Combo

Combo PD

Combo

• Sequential regimens

• Ongoing

• Treatment beyond PD

• +/- local therapy

• Engaging the immune system

• Synergistic with combo?Combo Combo

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Example of rational combination trial: LOGIC-2

• Strategies for rational combination at PD based on molecular escapes are now emerging

• An example is the LOGIC-2 trial: NCT02159066

• Primary endpoint: ORR

• Secondary endpoints: PFS, OS, …

• Recruitment has been completed

• First data expected for 12.2017!

Binimetinib (MEK)

PD

Encorafenib (BRAF)140 stage IVBRAFV600

patients

LEE011

BGJ398

BKM120

INC280

CDK4/6 inhibitor or

FGFR inhibitor or

PI3K inhibitor or

MET inhibitor or

Mandatory baselineand PD biopsies

Binimetinib (MEK)Encorafenib (BRAF)

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Adding CDK4i to the BRAFi and MEKi backbone?

• Results from a phase I/II trial testing the triple combination of BRAF, MEK and CDK4 presented at ASCO1

• 42 patient in the phase II, BRAFi naïve were given

• encorafenib 200 mg (BRAF)

• binimetinib 45 mg (MEK)

• ribociclib 600 mg (CDK4) (3w out of 4)

• ORR was 52% compared to 63% in combo arm of COLOMBUS

• mPFS 9.2 m compared to 14.9 m in combo arm of COLOMBUS

• Explanation?

• Lower dosage of BRAF and / or MEK?

• High discontinuation rate?

• PK/PD with triple combination?1Abstract 9518, Ascierto, ASCO 2017, Discussed by G. McArthur

Need more TR correlative data

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Strategies to overcome BRAFi + MEKi resistance

• Combination based on molecular escape

• E.g: LOGIC-2 trialCombo

Rational 3rd TKI

PD

Combo

Combo Combo Combo

Combo PD

Combo

• Sequential regimens

• Ongoing

• Treatment beyond PD

• +/- local therapy

• Engaging the immune system

• Synergistic with combo?Combo Combo

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Rechallenge: prospective trial!

Schreuer, Lancet Oncol 2017

• BRAF + MEKi rechallenge, prospective phase II trial

• Patients having failed BRAFi or BRAF + MEKi with a drug free interval of 3+ months

• RR 32% (8/25)

• Baseline BRAF v600Mut cfDNA was not associated with clinical benefit, but reponders had a statistically more important cfDNA decline at W2

• Could resistance mechanisms predict clinical benefits in rechallenge?

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3

Study Design and Objectives

Untreated or progressed

on/after prior first-line

immunotherapy

BRAFV600E and/or BRAFV600K

ECOG PS 0–1

R

1:1:1

(N=577)



VEM Vemurafenib 960 mg BID (n=191)


COLUMBUS Part 1

Time (mo)

Pro

gre

ss

ion

-Fre

e S

urv

ival

(%)

100

0 4 8 12 16 20 24 28

0

20

40

60

80

COMBO450VEM

Median PFS in months (95% CI)

COMBO450 VEM

14.9 (11.0–18.5) 7.3 (5.6–8.2)

HR (95% CI), 0.54 (0.41–0.71)

P<0.0001

Dummer, R et al. Lancet Oncol. 2018; 19(5):603-615

Efficacy update with additional follow-up of 18 months:OS:

Secondary endpoint†

Planned after 232 events in the COMBO450 and VEM groups combined


PFS:

Primary endpoint


Reinhard Dummer

COMBO450=encorafenib 450 mg QD + binimetinib 45 mg BID; ECOG PS=Eastern Cooperative Oncology Group performance status; OS=overall survival; PFS=progression-free survival; R=randomization; VEM=vemurafenib 960 mg BID.

*Amendment requested by FDA.†Included in hierarchical testing approach.‡Median follow-up of patients assessed using reverse Kaplan-Meier approach (i.e. median potential follow-up).

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Therapeutic opportunities:towards a rational selection of PD-1 based combos?

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A large number of checkpoints are targeted in clinical trials

T cell

TCR

CTLA-4

PD-1

TIM-3

BTLA

VISTA

LAG-3

CD28

OX40

GITR

CD137

HVEM

CD27

InhibitoryCheckpoints

ActivatingCheckpoints

Blocking

MABs

Agonistic

MABs

Adapted from Mellman, Nature 2011

Combinatorial issue!• 12*11=132

possible doublets☞We need to guidetrial development!

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Towards a rational selection of PD-1 based combo?

• Either baseline or on treatment biopsies can help guide decision

• All combos are being tested within clinical trials

• Complex biomarker will help optimal patient selection

PD-L1 positivity ≥ 1% αPD-1 alone?

PD-L1 positivity < 1% αPD-1 + αCTLA-4?

High content in TAM αPD-1 + αCSF1R?

High IDO expression αPD-1 + IDOi?

T cell exhaustion, LAG3+? αPD-1 + αLAG3?

T cell exhaustion, TIM3+? αPD-1 + αTIM3?

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Selected PD-1-based checkpoint combos tested for melanomaIndication,

clinical phaseCompound Checkpoint target PD-1 inhibitor ClinicalTrial.gov ID

Melanoma, P I-II Ipilimumab CTLA-4 Inh

ibito

ry Inh

ibito

ry Inh

ibito

ry

Pembrolizumab NCT02089685

Solid tumors, P I-II BMS-986218 CTLA-4 Nivolumab NCT03110107

Solid tumors, P I-II BMS-986016 LAG-3 Nivolumab NCT01968109

Solid tumors, P I-II LAG525 LAG-3 PDR001 NCT02460224

Solid tumors, P I-II Lirilumab KIR Nivolumab NCT01714739

Solid tumors, P I-II BMS-986207 TIGIT Nivolumab NCT02913313

Solid tumors, P I MK-7684-001 TIGIT Pembrolizumab NCT02964013

Solid tumors, P I Enoblituzumab B7-H3 Pembrolizumab NCT02475213

Melanoma, P III Epacadostat IDO Pembrolizumab NCT02752074

Solid tumors, P I-II BMS-986205 IDO Nivolumab NCT02658890

Solid tumors, P I-II Urelumab CD137 (4-1BB) Activatin

gNivolumab NCT02253992

Solid tumors, P I-II BMS-986156 GITR Nivolumab NCT02598960

Solid tumors, P I-II BMS-986178 OX40 Nivolumab NCT02737475

Solid tumors, P I-II Varlilumab CD27 Nivolumab NCT02335918

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Rational combination or rational sequencing?

Possible strategies for I-O sequences or combos

2nd I-O agentPD-1 PD

1 Sequencing

PD-1 PD-1PD

2nd I-O agent

2 Combo at relapse

PD-1

2nd I-O agent

3 Combo at start

…

Depending on the type of resistance mechanism, one strategy or the other might be more appropriate to obtain maximal global PFS. Biomarkers are required to guide such strategies.

Resistance mechanism

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OS in Patients With BRAF Wild-type and Mutant Tumors

BRAF Wild-type BRAF Mutant

NIVO+IPI NIVO IPI

Median, mo

(95% CI)

39.1

(27.5, NR)

34.4

(24.1, NR)

18.5

(14.1, 22.7)

HR (95% CI)

versus IPI

0.60

(0.47, 0.77)

0.65

(0.51, 0.83)–

HR (95% CI)

versus NIVOa

0.92

(0.71, 1.20)– –

NIVO+IPI NIVO IPI

Median, mo

(95% CI)NR

45.5

(26.4, NR)

24.6

(17.9, 31.0)

HR (95% CI)

versus IPI

0.45

(0.30, 0.67)

0.64

(0.44, 0.93)–

HR (95% CI)

versus NIVOa

0.70

(0.46, 1.07)– –


IPI

NIVO+IPI

NIVO

0165194215

0169193211

0180199218

146

156

164

132

143

156

117

141

145

105

132

134

95

126

127

86

125

124

81

119

119

72

115

116

70

109

111

64

108

106

62

102

102

61

99

98

58

98

96

57

94

93

33

54

56

9

6

12

53%

49%

32%

49%

45%

28%

NIVO+IPI

NIVO

IPI

68%

56%

37%

62%

50%

33%


IPI

NIVO+IPI

NIVO

08891100

09699103

0869398

81

91

81

71

83

75

64

80

69

58

77

67

53

74

64

49

73

57

47

73

56

41

71

55

37

71

53

35

70

52

32

69

48

32

67

46

32

62

44

29

60

42

17

42

29

2

7

6

NIVO+IPI

NIVO

IPI

OS

(%

)

0

20

40

60

80

100

0 3 6 9 12 15 18 573024 362721 45 5133 39 5442 48

OS

(%

)

0

20

40

60

80

100

0 3 6 9 12 15 18 573024 362721 45 5133 39 5442 48

aDescriptive analysis 5th

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Moving towards phase II/III: CA224-047

Phase II

Adapted from Ascierto, ASCO 2018ESMO IO 2018 | Geneva | December 14th 2018

Unresectable or metastatic melanoma• Previously untreated• Tissue available for

LAG-3, PD-L1, TMB assessment

Stratified by:• LAG-3 status• PD-L1 status• BRAF status• AJCC M-stage

R

Relatlimab + Nivolumab160/480 mg IV Q4W

Nivolumab480 mg IV Q4W

• Phase II primary endpoint: ORR assessed by a BICR

• Phase II secondary endpoint: ORR, DOR, DCR, PFS rates, and 1- and 2-year OS rates according LAG-3 and

PD-L1 status, safety and tolerability

• Phase III primary endpoint: PFS

• Phase III secondary endpoint: ORR, OS

Phase III

Relatlimab + Nivolumab160/480 mg IV Q4W

Nivolumab480 mg IV Q4W

InterimAnalysis R

400 pts 300 pts

Clinicaltrial.gov identifier NCT03470922

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5th ESO-ESMO Latin American Masterclass in Clinical OncologyMelanoma+-+Michielin.pdfKey efficacy...

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