Melanoma and introduction to immunotherapy · Tumor antigen Tumor cell MHC-I CD8+ T cell TCR + -...

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 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology 17th ESO-ESMO M

asterclass in Clinical O

ncology

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 late clinical benefit

• 2nd generation strategies can both deliver early and late clinical benefits, challenging treatment plans 17th ESO-ESMO M


ncology

Overview of stage IV outcome

1 Ugurel, EJC 2017

• Targeted therapies provide better early out o e…

• … ut i u o-oncology curves are crossing at around 14 months 1 … • … a d the differe e seems to increase with time



ncology

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…



ncology

Overview of therapeutic options in melanoma March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology

17th ESO-ESMO Masterclass in

Clinical Oncology

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 Soon standard Stage IV Option for selected Option for palliation Option Standard Standard

Ad

juva

nt

Me

tasta

tic

Loco-regional Systemic

A multidisciplinary team is needed specially for early stage disease!


Clinical Oncology

Brief introduction to cancer immunotherapy March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology


Clinical Oncology

Escaping the immune system is a hallmark of cancer!

Hanahan & Weinberg, Cell 2011 17th ESO-ESMO M


ncology

CD8+ TCR MHC-I

Tumor cell

Lymphocyte

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

Demonstration of the activity of cytotoxic T lymphocytes


Clinical Oncology

Various types of tumor antigens CD8+ TCR

MHC-I 1) Differentiation 2) Overexpression 3) Cancer-Testis 4) Mutations (Neo-antigens) P53 Mutation

P53 Antigen in MHC-1


Clinical Oncology

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

Rhabdoid tu

mor Ewing

sarcoma Thyroid AML

Medullobla

stoma

Carcinoid

Neuroblasto

ma Prosta

te CLL Low-g

rade glioma

Breas

t Multi

ple myelom

a Pancr

eas Kidne

y clear cell Kidne

y papill

ary cell

Ovarian

Glioblastom

a Cervic

al DLBCL

Head and n

eck Colore

ctal Esoph

ageal adeno

carcinoma Stoma

ch Bladd

er Lung A

D Lung S

Q Melan

oma

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

tic Mutation

Frequ

ency (/Mb)1

1. Lawrence, Nature. 2013 17th ESO-ESMO Masterclass in

Clinical Oncology

Inflamed

Immune excluded

Immune desert

Immune phenotypes and immunotherapy

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

1 Antigen release

2 Antigen presentation

3 Priming & activation 4 Trafficking

5 Tumor infiltration

6 Tumor recognition 7 Tumor killing

Tumor cells

No T cells


Clinical Oncology

Imperfect correlation between TIL and PD-L1 status • Tumors can also be classified on the basis of their TIL and PD-L1 status

• Type I: PD-L1 + TIL + • Type II: PD-L1 - TIL - • Type III: PD-L1 + TIL - • Type IV: PD-L1 - TIL +

• In melanoma, type I and II are the most prevalent • Type I: 38% • Type II: 41%

• Cave: such classifications provide a framework for further development but are oversimplifications of the underlying biology complexity Teng, Cancer Research 2015 III

I II

IV 17th ESO-ESMO M


ncology

Immunotherapy: Checkpoints inhibitors

αCTLA-4

αPD-1


Clinical Oncology

Checkpoints act at different stages of the immune cycle

PD-1 or

PD-L1

CTLA-4

?


Clinical Oncology

CTLA-4 blockade: ipilimumab (Yervoy) 17th ESO-ESMO M


ncology

B7

Canonical mode of action (MoA) of ipilimumab

Dendritic Cell

CTLA-4

✗ Inhibition

Cellule dendritique Dendritic Cell

Ipilimumab

Activation

B7 CD28 CTLA-4

Dendritic Cell

+ + + -


Clinical Oncology

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 APC T cell

CTLA4 CD80 p-MHC TCR

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 cell CD28

CD80 T cell

APC 6 Blocking CTLA4 ligands capture3 CD80 No Signal II

Endo- cytosis 17th ESO-ESMO M


ncology

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 17th ESO-ESMO M


ncology

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 to increased PD-L1 expression in Hodgkin

Dynamic PD-L1 expression

Constitutive PD-L1 expression

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


Clinical Oncology

PD-1 / PD-L1 pathway: biological interpretation Tumor cell Lymphocyte

+

-

= INF-γ


Clinical Oncology

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

Rhabdoid tu

mor Ewing

sarcoma Thyroid AML

Medullobla

stoma

Carcinoid

Neuroblasto

ma Prosta

te CLL Low-g

rade glioma

Breas

t Multi

ple myelom

a Pancr

eas Kidne

y clear cell Kidne

y papill

ary cell

Ovarian

Glioblastom

a Cervic

al DLBCL

Head and n

eck Colore

ctal Esoph

ageal adeno

carcinoma Stoma

ch Bladd

er Lung A

D Lung S

Q Melan

oma

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

tic Mutation

Frequ

ency (/Mb)1

1. Lawrence, Nature. 2013 17th ESO-ESMO Masterclass in

Clinical Oncology

Toxicity managment: detailed guidelines exist, e.g. ESMO

+

-

Haanen, Ann Oncol. 2017 17th ESO-ESMO Masterclass in

Clinical Oncology

Clinical management of stage III melanoma March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology


Clinical Oncology

Results from MSLT-2: no benefit to radical lymphadenectomy


Clinical Oncology

MSLT-2 – Study design

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


Clinical Oncology

Results from MSLT-2: no benefit to radical lymphadenectomy


Clinical Oncology

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

Yes No


Clinical Oncology

Adjuvant treatments March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology


Clinical Oncology

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 not change outcome: patient death Adjuvant benefit: 11% @ 5y Adjuvant did not change outcome: patient is cured Control arm Adjuvant arm

1 Mocellin, Cochrane Review, 2013 17th ESO-ESMO Masterclass in

Clinical Oncology

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 melanoma R INDUCTION Ipilimumab 10 mg/kg Q3W X4

MAINTENANCE Ipilimumab 10 mg/kg Q12W up to 3 years INDUCTION Placebo Q3W X4

MAINTENANCE Placebo Q12W up to 3 years


Clinical Oncology

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.

Years 0 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

Placebo Eggermont, ESMO 2016


Clinical Oncology

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, ESMO 2017 17th ESO-ESMO Masterclass in

Clinical Oncology

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 27 3 9 15 21

453 353 311 249 5 0 399 332 291 71 NIVO

453 314 252 184 2 0 364 269 225 56 IPI

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, ESMO 2017 17th ESO-ESMO Masterclass in

Clinical Oncology

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 • Surgi all free of disease eeks 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


Clinical Oncology

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 0 432 387 322 280 263 243 219 203 198 185 178 175 168 166 158 141 138 106 87 86 50 33 30 9 3 0 0

Months From Randomization Dabrafenib plus trametinib Placebo

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

Prop

ortio

n Aliv

e and

Rela

pse F

ree

1 y, 88%

2 y, 67% 3 y, 58% 1 y, 56%

2 y, 44% 3 y, 39%

NR, not reached.

Group Events, n (%) Median (95% CI), mo HR (95% CI) Dabrafenib+ trametinib 166 (38) NR (44.5-NR) 0.47 (0.39-0.58); P < .001 Placebo 248 (57) 16.6 (12.7-22.1)

P = .0000000000000153

Adjuvant BRAFi + MEKi: COMBI-AD


Clinical Oncology

Targeted therapies for stage IV melanoma March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology


Clinical Oncology

Preclinical programs: • Allosteric inhibitors 1

Targeted therapies in stage IV melanoma: main trials RTK

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 • …


Clinical Oncology

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 Sta le eeks Stratification

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

Dabrafenib + trametinib 150 mg BID + 2 mg QD n = 211 Dabrafenib + placebo 150 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. 17th ESO-ESMO M


ncology

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 30 18

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 30 18 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 17th ESO-ESMO Masterclass in

Clinical Oncology

Baseline Factors Influencing OS in Combi-d, Combi-v and Ph-II • Regression tree analysis based on:

• BMI • Age • LDH (N, > 1- ULN, 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 2016 K. Flaherty, ASCO 2016

N=398 1Y=85% 2Y=75% 3Y=57% N=219 1Y=54% 2Y=25% 3Y=7%

Normal LDH LDH ULN

N=149 1Y=60% 2Y=33% 3Y=9% N=70 1Y=40% 2Y=7% 3Y=7%

LDH 2x ULN LDH > 1- ULN

N=237 1Y=90% 2Y=75% 3Y=70% N=161 1Y=76% 2Y=55% 3Y=38%

Sites Sites < 3

N=93 1Y=71% 2Y=43% 3Y=NE N=56 1Y=42% 2Y=19% 3Y=16%

ECOG ECOG = 1


Clinical Oncology

Counteracting BRAF/MEKi resistance mechanisms March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology


Clinical Oncology

Strategies to overcome BRAFi + MEKi resistance • Combination based on molecular escape

• E.g: LOGIC-2 trial

Combo 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


Clinical Oncology

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 • Se o dar e dpoi ts: PFS, OS, …

• Recruitment has been completed • First data expected for 12.2017!

Binimetinib (MEK) PD Encorafenib (BRAF) 140 stage IV BRAFV600 patients

LEE011 BGJ398 BKM120 INC280 CDK4/6 inhibitor or FGFR inhibitor or PI3K inhibitor or MET inhibitor or

Mandatory baseline and PD biopsies

Binimetinib (MEK) Encorafenib (BRAF)


Clinical Oncology

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 17th ESO-ESMO M


ncology

Strategies to overcome BRAFi + MEKi resistance • Combination based on molecular escape

• E.g: LOGIC-2 trial

Combo 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


Clinical Oncology

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?


Clinical Oncology

Immuno-therapies for stage IV melanoma March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology


Clinical Oncology

Therapeutic opportunities: towards a rational selection of PD-1 based combos? March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology


Clinical Oncology

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

Inhibitory Checkpoints Activating Checkpoints

Blocking

MABs

Agonistic

MABs

Adapted from Mellman, Nature 2011

Combinatorial issue! • 12*11=132 possible doublets ☞ We need to guide trial development!


Clinical Oncology

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-L positi it % αPD-1 alone? PD-L1 positivity < 1% αPD- + αCTLA-4? High content in TAM αPD- + αCSF R? High IDO expression αPD-1 + IDOi? T cell exhaustion, LAG3+? αPD- + αLAG ? T cell exhaustion, TIM3+? αPD- + αTIM ?


Clinical Oncology

Selected PD-1-based checkpoint combos tested for melanoma Indication, clinical phase Compound Checkpoint target PD-1 inhibitor ClinicalTrial.gov ID Melanoma, P I-II Ipilimumab CTLA-4 Inhibitory Inhibitory Inhibitory

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) Activating

Nivolumab 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 17th ESO-ESMO Masterclass in

Clinical Oncology

Rational combination or rational sequencing? Possible strategies for I-O sequences or combos

2nd I-O agent PD-1 PD 1 Sequencing

PD-1 PD-1 PD 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


Clinical Oncology

Rational selection of PD-1 based combo at start PD-1 + CTLA-4 inhibitor data: Checkmate-067 March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology


Clinical Oncology

Unresectable or

Metatastic Melanoma

• Previously untreated

• 945 patients

CA209-067: Study Design CheckMate 067: Study Design

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

Randomize

1:1:1

Stratify by:

• BRAF status

• AJCC M stage

• Tumor PD-L1 expression <5% vs ≥5%*

N=314

N=316

N=315

Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone*

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

Database lock: Sept 13, 2016 (median follow-up ~30 months in both NIVO-containing arms)

55 17th ESO-ESMO Masterclass in

Clinical Oncology

Improved survival for the PD-1 arms compared to CTLA-4

Wolchok, NEJM 2017

PD-1 or PD-1 + CTLA-4 are both valid first lines for stage IV melanoma


Clinical Oncology

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 • No clear PD-L1 cutoff • 1% (44% of pts) as basis for patient discussion?

1Wolchok, NEJM 2017 17th ESO-ESMO Masterclass in

Clinical Oncology

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 True p

ositive rate

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

1Wolchok, NEJM 2017 17th ESO-ESMO Masterclass in

Clinical Oncology

Towards complex, multidimensional predictive biomarkers March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology


Clinical Oncology

Searching for better biomarkers for stage IV patient selection ?

Wolchok, NEJM 2017 17th ESO-ESMO Masterclass in

Clinical Oncology

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!


Clinical Oncology

Conclusion and outlook March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology


Clinical Oncology

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


Clinical Oncology

Possible treatment algorithm for stage IV melanoma 1st Line

2nd Line

3rd Line

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

? ? ? ?



ncology

Thank you for your attention! March 25th 2018, Berlin, Germany ESMO/ESO Masterclass in Clinical Oncology


Clinical Oncology

Melanoma and introduction to immunotherapy · Tumor antigen Tumor cell MHC-I CD8+ T cell TCR + -...

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