“braf and mek inhibition in melanoma” -...

“BRAF and MEK Inhibition in Melanoma” Grant McArthur MB BS PhDPeter MacCallum Cancer Centre

Melbourne, Australia

Disclosure Information

• I have the following financial relationships to disclose–Research support from: Pfizer,

Millennium & Novartis

Talk Overview

• Signaling by BRAF and MEK• Clinical Efficacy of Inhibiting the

BRAF/MEK pathway• Toxicity of Inhibiting the BRAF/MEK

pathway• Resistance to BRAF inhibitors

The KIT/RAS/RAF/ERK Pathway and Therapeutic Targets in Melanoma

BRAFSHCGRB2

SOSNRAS

MEKERK

MET

MITF

CDK2

Tyrosinase

HMB45BCL2

KITMutated in 2-3%

Mutated in 15%Mutated in 35-45%

CDK4CCND1

Amplified in 10%

Amplified in 30%

Amplified in 10-20%

ERK

MEK

BRAF

RAS

SPRYDUSP

GPCRRTK

Multiple signals

Multiple outputs

ERK

MEK

BRAF

RAS

SPRY DUSP

GPCRRTK

Multiple signals

Multiple outputs

BRAF

V600E

ProliferationSurvival

BRAF


CRAF

Talk Overview




CT Response to BRAF Inhibition- Phase 1 PLX06/02 Study of Vemurafenib

Flaherty et al, NEJM. 2010Flaherty et al, NEJM, 2010

Bollag et al, Nature 2010

Pharmacodynamic analyses suggest >90% inhibition of pERK is required for response in BRAFV600E melanoma patients

Survival- Phase 1 PLX06/02 Study

Flaherty et al, NEJM. 2010Kim et al, Society of Melanoma Research, 2012

Phase III BRIM3 Study design

BRAFV600E mutation

Stratification• Stage• ECOG PS (0 vs 1)• LDH level (↑ vs nl)• Geographic region

Screening960 mg po bid

(N=337)

1000 mg/m2 iv q3w (N=338)

Dacarbazine

Vemurafenib

RandomizationN=675

Chapman, NEJM, 2011

1009080706050403020100

Ove

rall

surv

ival

(%)

No. of patients in follow upDacarbazineVemurafenib

0 1 2 3 4 5 6 7 8 9 10 11 12

Vemurafenib (N=336)Est 6 mo survival 84%

Months

336336

283320

192266

137210

98162

64111

3980

2035

16

11

Dacarbazine (N=336)Est 6 mo survival 64%

914

Hazard ratio 0.37 (95% CI; 0.26 - 0.55)Log-rank P<0.0001

Overall survival (Dec 30, 2010 cutoff)

Chapman, NEJM, 2011

BREAK-3 study design

ScreenedN = 733 Dabrafenib

150 mg twice dailyn = 187

DTIC1000 mg/m2 IVevery 3 weeks

n = 63

Enrolledn = 250

3:1 randomization dabrafenib (150 mg po bid) or DTIC (1000 mg/m2, IV, q3w).

Dabrafenib150 mg twice daily

n = 36

15

Time from Randomization (Months)0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

187 184 173 145 139 103 96 83 78 71 48 31 14 13 4 1 165 53 31 23 21 15 14 12 11 4 3 1 1 0 0 0 0

Prop

ortio

n A

live

With

out P

rogr

essi

on

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Primary endpoint: PFS Investigator-Assessed (June 2012)

Dabrafenib:median PFS 6.9 months

DTIC: median PFS 2.7 months

Hazard ratio 0.37 (95% CI: 0.23–0.57); P < 0.0001

Number at risk

• On randomized study treatment at cut-off: dabrafenib 38%, DTIC 8%• Median follow-up time: dabrafenib 10.5 months, and DTIC 9.9 months• Median PFS following crossover was 4.4 months (n=35; 95% CI: 4.1, 6.3)

16

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

187 185 184 181 171 166 156 148 143 141 133 131 124 115 106 95 78 50 25 13 6 1 163 60 57 56 55 52 49 46 44 42 37 37 33 29 27 22 16 8 6 2 1 1 0

Prop

ortio

n A

live

With

out P

rogr

essi

on

Time from Randomization (Months)

0.00.10.20.30.40.50.60.70.80.91.0

Overall survival by randomized treatment (December 2012)

Number at risk

DTIC

Dabrafenib

Dabrafenib DTIC

No. of death/No. of patients randomized(%)

78/187(42)

28/63(44)

Median(95% CI)

18.2(16.6, NR)

15.6(12.7, NR)

HR (95% CI) 0.76 (0.48, 1.21)

• Percent alive at 15 months follow-up: dabrafenib 63%, DTIC 51%

17

METRIC: Phase III Melanoma StudyBRAF mutation status

Using allele-specific PCR at RGI

Stratification factorsLDH (> ULN vs. < ULN) and

Prior chemotherapy (Yes vs. No)

PopulationsITT (all randomized patients) n=322;

Primary efficacy (subset of ITT) n=273

Primary endpointProgression-Free Survival (PFS) in BRAFV600Epositive melanoma

Secondary endpointsPFS in ITT

Overall Survival, Response rate and Safety

( )

V600E/K mutation (n=322)

Chemotherapy(n=108)

Trametinib2mg QD (n=214)

Trametinib2mg QD

PFS

FSFV: Dec 2010, LSFV: July 2011

Cross-over*

Screened (N=1059)

Chemotherapy = DTIC or paclitaxel*Allowed after independent confirmation of progression

METRIC Investigator-Assessed PFS – ITT

0 1 2 3 4 5 6 7 8 9

Number at riskTrametinib 214 205 163 100 88 28 22 5 0 0Chemotherapy 108 87 43 24 21 10 6 1 0 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time From Randomization (Months)

Events n (%)

Median(months)

HR (95%CI)P-value

Trametinib 118 (55) 4.8 0.45 (0.33, 0.63)<0.0001Chemotherapy 77 (71) 1.5

Prop

ortio

n A

live

and

Prog

ress

ion-

Free

METRIC Overall Survival – ITT Pr

opor

tion

Aliv

e

Time From Randomization (Months)0 1 2 3 4 5 6 7 8 9 10

Number at riskTrametinib 214 208 203 192 170 105 53 24 5 0 0Chemotherapy 108 96 94 90 72 47 28 15 4 1 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Events,n (%)

Median(months)

HR (95% CI)P-value

6 Month OS(95% CI)

Trametinib 35 (16) -- 0.54 (0.32, 0.92)0.0136

81 (73, 86)

Chemotherapy 29 (27) -- 67 (55, 77)

47% of the patients in the chemotherapy arm crossed over to trametinib

Updated Overall Survival Data BRIM3 Study

Flaherty et al, NEJM. 2010McArthur et al, Lancet Oncology, 2014

Frequency of non-V600E BRAF mutations-Primary melanoma, Victoria, Australia

n=234

V600E 69%

V600K 20%

L597 5%

K601E 4%

V600R 1% V600D 1%

M. Voskoboynik, C.Hewitt A. Dobrovic, A. Rynska, S. Wong, V. Mar

BRAF V600 Mutant melanoma- Precision Medicine

% c

hang

e fro

m b

asel

ine

in s

um o

f tar

get l

esio

ns

-100

-50

0

50

100

Individual patients treated with vemurafenib and cobimetinib

720mg Vem + 60mg cobi 21/7 (N=14)960mg Vem + 60mg cobi 21/7 (N=39)720mg Vem + 60mg cobi 28/0 (N=1)960mg Vem + 60mg cobi 28/0 (N=4)720mg Vem + 100mg cobi14/14 (N=2)960mg Vem + 80mg cobi 14/14 (N=3)

Best change in sum of target lesions

McArthur et al, ESMO 2013

Melanoma BRAF Mutation: BRAF inhibitor + MEK-inhibitorMelanoma BRAF Mutation: BRAF inhibitor + MEK-inhibitor

Talk Overview




Selected adverse events (% of patients) Vemurafenib

Vemurafenib, n=336 Dacarbazine, n=287Adverse events All Grade 3 Grade≥ 4 All Grade 3 Grade ≥4

Arthralgia 53 4 - 3 <1 -Rash 37 8 - 2 - -Fatigue 38 2 - 33 2 <1Photosensitivity 33 3 - 4 - -LFTs 22 8 <1 5* 1* -*Cutaneous SCC 17 16 - <1 <1 -Keratoacanthoma 9 9 - - - -Skin papilloma 21 <1 - - - -Nausea 35 2 - 43 2 -Neutropenia <1 - <1 12 6 3Uveitis** 3 <1 - - - -Discontinuations due to AE: 7% vemurafenib; 4% dacarbazine

Median length of time on vemurafenib treatment: 4.2 months

*Data from OS IA Dec 30, 2010, not updated for March 1, 2011 cutoff. **Data obtained from a manual count rather than a statistical output.

Photosensitivity

33% in phase III

Dummer et al. N Engl J Med. 2012;366:480‐481.

Dabrafenib n (%) DTIC n (%)AE All Grade 3 Grade 4 All Grade 3 Grade 4

Skin

Hyperkeratosis 67 (36) 2 (1) 1 (<1) 1 (2) 0 0

Alopecia 50 (27) 1 (<1) 0 2 (3) 0 0

Skin papilloma 42 (22) 0 0 0 0 0

Palmar-plantarhyperkeratosis 36 (19) 4 (2) 0 1 (2) 0 0

Rash 56 (30) 0 0 0 0 0

SCC/KA 18 (10) 14 (7) 0 0 0 0

Gastrointestinal Nausea 26 (14) 0 0 23 (39) 0 0

Other

Arthralgia 36 (19) 2 (1) 0 0 0 0

Fatigue 33 (18) 2 (1) 0 13 (22) 0 0

Headache 34 (18) 0 0 2 (3) 0 0

Pyrexia 30 (16) 5 (3) 0 0 0 0

Asthenia 27 (14) 0 0 7 (12) 0 0

Treatment-Related AEs in ≥ 10% of Dabrafenib Patients (June 2012)

Photosensitivity: dabrafenib 4 (2%), DTIC 2 (4%)KA, keratoacanthoma; SCC, sqamous cell carcinoma

27

Trametinib – Adverse Events (>15% of patients) Preferred Term (>15% of subjects) Trametinib

n=211Chemotherapy

n=99

Rash 121 (57%) 10 (10%)Diarrhoea 91 (43%) 16 (16%)Oedema peripheral 54 (26%) 3 (3%)Fatigue 54 (26%) 27 (27%)Dermatitis acneiform 40 (19%) 1 (1%)Nausea 38 (18%) 37 (37%)Alopecia 36 (17%) 19 (19%)Hypertension 32 (15%) 7 (7%)Constipation 30 (14%) 23 (23%)Vomiting 27 (13%) 19 (19%)

28

MEKi known events with Trametinib:• Decreased Ejection Fraction / Ventricular dysfunction = 14 (7%)• Chorioretinopathy = 1 (<1%)No reported case of cutaneous SCC or hyperproliferative skin lesions

Trametinib – Grade 3/4 AEs (> 1% of patients)Trametinib Chemotherapy

Preferred Term Grade 3 Grade 4 Grade 3 Grade 4

Hypertension 26 (12%) 0 3 (3%) 0Rash 15 (7%) 1 (<1%) 0 0Fatigue 8 (4%) 0 3 (3%) 0

Pruritus 4 (2%) 0 0 0

Alanine aminotransferases increased 4 (2%) 0 0 0

Anaemia 4 (2%) 0 0 0

Vomiting 2 (<1%) 0 2 (2%) 0

Pain in extremity 1 (<1%) 0 2 (2%) 0

Neutrophil count decreased 0 0 4 (4%) 0

Neutropenia 0 0 1 (1%) 2 (2%)

Diarrhoea 0 0 1 (1%) 1 (1%)

Peripheral sensory neuropathy 0 0 2 (2%) 0

Cholecystitis 0 0 2 (2%) 0

29

Dabrafenib + Trametinib: Key Treatment-Related Skin Toxicities

1Skin toxicities include multiple terms

All Part B Patients(N = 135)

Grade ≥ 3,n (%)

Any grade event, n (%)

Rash/Skin toxicities1 3 (2%) 61(45%)

Skin papilloma 0 (0%) 3 (2%)

Squamous cell carcinoma 4 (3%) 4 (3%)

Actinic keratosis 0 (0%) 7 (5%)

Hyperkeratosis 0 (0%) 5 (4%)

BRAF

V600E


BRAF

V600E


BRAF


BRAF


CRAF

BRAF-inhibitor

BRAF-inhibitor

CRAF

BRAF

V600E


BRAF

V600E


BRAF


CRAF

MEK MEK MEKMEK-

inhibitor

BRAF


CRAF

MEKMEK-

inhibitor

Talk Overview




Progression‐free Survival BRIM3(Censored at Crossover; February 2012 Survival Update)

34

338337

63186

2277

316

00

100269

37113

1449

03

No. of patients at risk

Hazard ratio 0.38 (95% CI: 0.32–0.46)Log‐rank p<0.001

DacarbazineZelboraf

Vemurafenib (n=337)

Dacarbazine (n=338)

CI = confidence interval; PFS = progression‐free survival.Figure from Chapman PB, et al. Presented at ASCO 2012. Oral Presentation 8502.

Vemurafenibmedian PFS: 6.9 months

Dacarbazinemedian PFS: 1.6 months

0 2 4 18 246 8 10 12 14 16 20 22

100

90

80

70

60

50

40

30

20

10

0

Progression‐free

survival (%)

Vemurafenib: Response is Homogeneous Progression is not

Baseline

Response

Progression

Testing on progression- multiple mechanisms of resistance

Adapted from Poulikakos….Rosen, Nature 2010; Nazarian…..Lo, Nature 2010; Johannessen…..Garraway, Nature 2010; Villanueva…..Herlyn, Cancer Cell, 2010; Wagle…..Garraway, JCO, 2011, Poulikakos….Solit, Nature 2011, Shi….Lo, Nature Comm, 2012, Trunzer…Ribas, JCO, 2013

NRAS mut

BRAF amplif

BRAF splice

CDKN2A mut MEK mut

Other

MEK/ERK activation

MEK/ERK independent

2/3

1/3

Resistance to BRAF inhibition

Nazarian et al. Nature 2010; Johannessen et al. Nature 2010; Poulikakos et al. Nature 2011; Shi et al. Nature Com 2012; Villanueva et al. Cancer Cell 2010; Wagle et al. JCO 2011, Strausman et al. Nature 2012; Wilsonet al. Nature 2012; Van Allen et al. Cancer Disc 2013

Survival

BRAFV600E

MEK

ERK

P

P

BRAF inh

NRASQ61

COTCRAF

COT overexpressionCOT overexpression

A. MEK-dependentprogression

MEK1/2 mutationsMEK1/2 mutations

NRAS mutationsNRAS mutations

BRAFV600 truncationBRAFV600 amplificationBRAFV600 truncationBRAFV600 amplification

RTK overexpression

PDGFRb IGF1R cMET

PI3K

AKT

B. MEK-independentprogression

RTK ligand overexpression

Resistance to BRAF inhibition does not involve mutation in BRAF itself

PIK3CA mutation

PTENmutation

Heterogeneity of ERK phosphorylation at progression

• Recovery of ERK and MEK phosphorylation at disease progression was observed in some but not all patients

300

250

200

150

100

50

0

H-S

core

Baseline Day 15 PD

pERK1/2 cytoplasmic H-Score300

250

200

150

100

50

0H

-Sco

reBaseline Day 15 PD

pMEK1/2 cytoplasmic H-Score

McArthur ASCO, 2011

Overcoming Resistance to BRAF inhibition

Nazarian et al. Nature 2010; Johannessen et al. Nature 2010; Poulikakos et al. Nature 2011; Shi et al. Nature Com 2012; Villanueva et al. Cancer Cell 2010; Wagle et al. JCO 2011, Strausman et al. AACR 2012

Survival

BRAFV600E

MEK

ERK

P

P

BRAF inh

NRASQ61

COTCRAF

COT overexpressionCOT overexpression

A. MEK-dependentprogression

MEK1 mutationsMEK1 mutations

NRAS mutationsNRAS mutations

BRAFV600 truncationBRAFV600 amplificationBRAFV600 truncationBRAFV600 amplification

DabrafenibVemurafenibDabrafenibVemurafenib

TrametinibCobimetinibTrametinibCobimetinib

AcknowledgementsKeith FlahertyPaul Chapman

Keith NolopAxel HauschildNick ChoongAntoni RibasJeff Sosman

Kevin KimIgor PuzanovJoe Grippo

Gideon BollagRichard Lee

Rene GonzalezStudy

CoordinatorsPatients & their

families

PD-1 and ipilimumab in sequence

Antoni Ribas, M.D., Ph.D.Professor of MedicineProfessor of Surgery

Professor of Molecular and Medical PharmacologyDirector, Tumor Immunology Program, Jonsson

Comprehensive Cancer Center (JCCC)University of California Los Angeles (UCLA)

Chair, Melanoma Committee at SWOG

PD-1/PD-L1 inhibiting reagents in clinical development

Target Agent Class KD

PD-1 Nivolumab (MDX1106, BMS936558, BMS-ONO)

IgG4 fully human antibody 3 nM

MK-3475 (lambrolizumab, Merck)

IgG4 engineered humanized antibody

29 pM

Pidilizumab (CT-011, CureTech-Teva)

IgG1 humanized antibody -

AMP-224 (Amplimmune-GSK) Fc-PD-L2 fusion protein -

PD-L1 BMS935559 (MDX-1105, BMS-ONO)

IgG4 fully human antibody -

MPDL3280A (Genentech) IgG1 engineered fully human antibody

-

MEDI4736 (MedImmune, AZ) IgG1 engineered fully human antibody

-

MSB0010718C (Merck-Serono)

NA -

Nivolumab

18% ORR

28% ORR27% ORR

MK-3475

MK-3475

ORR: 38% Highest dose ORR: 52%

(by RECIST 1.1 with confirmationassessed by ICR)

Clinical activity of MK-3475 in a patient progressing to 3 prior lines of therapy Baseline: April 13, 2012

72-year-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab

April 9, 2013

A. Ribas, ASCO 2013

Baseline Jan/2012 Apr/2012

B. Chmielowski M.D., Ph.D.Paul Tumeh M.D.

54 yrs old male with desmoplastic melanoma after progressing on ipilimumab

Clinical activity in a patient with a metastatic desmoplastic melanoma

A. Ribas, ASCO 2013

MK-3475 (lambrolizumab) single agent therapy: Maximum Change From Baseline in Tumor Size

(Independent Central Review per RECIST 1.1)

Individual Patients Treated with MK-3475‒100

‒80

‒60

‒40

‒20

0

20

40

60

80

100

Perc

ent C

hang

e Fr

om B

asel

ine

in

Long

est D

iam

eter

of T

arge

t Les

ion

IPI-NaiveIPI-Pretreated

160

Ribas et al. ASCO 2013

Time to Response and On-Study Duration (Independent Central Review per RECIST 1.1)

0 10 20 30 40 50 60 70Weeks

Indi

vidu

al P

atie

nts

Trea

ted

With

MK

-347

5

IPI-PretreatedIPI-NaiveComplete ResponsePartial ResponseOn Study

The median duration of response had not been reached at the time of analysis, with median follow-up time of 11 months.

Ribas et al. ASCO 2013

Drug-Related Adverse EventsObserved in >5% of Patients (N = 135)

Adverse Event All Grades, n (%) Grade 3-4, n (%)Any 107 (79.3) 17 (12.6)Fatigue 41 (30.4) 2 (1.5)Rash 28 (20.7) 3 (2.2)Pruritus 28 (20.7) 1 (0.7)Diarrhea 27 (20.0) 1 (0.7)Myalgia 16 (11.9) 0Headache 14 (10.4) 0Increased AST 13 (9.6) 2 (1.5)Asthenia 13 (9.6) 0Nausea 13 (9.6) 0Vitiligo 12 (8.9) 0Hypothyroidism 11 (8.1) 1 (0.7)Increased ALT 11 (8.1) 0Cough 11 (8.1) 0Pyrexia 10 (7.4) 0Chills 9 (6.7) 0Abdominal pain 7 (5.2) 1 (0.7)

Frequent development of vitiligo (skin depigmentation) in responding patients

PD-1 blockade with single agent MK-3475 improving other skin conditions

Before After

PD-1 blockade with single agent MK-3475 leading to the disappearance of a pigmented

birth markBefore After

Nivolumab + Ipilimumab combination therapy:Best Responses in Concurrent Cohorts

(WHO response criteria)

After ~13 months of follow-up, for all concurrent cohorts, 90% of all responding patients continue to respond as of Feb 2013.

Patients

Cha

nge

in ta

rget

lesi

ons

from

bas

elin

e (%

)

-80

Wolchok et al. ASCO 2013

WHO waterfalls with combinationnivolumab + ipilimumab or single agent MK-3475

In d iv id u a l P a t ie n ts T re a te d w ith L a m b ro liz u m a b-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0

1 6 0

Per

cent

Cha

nge

from

Bas

elin

e in

Tar

get L

esio

n

(2

-Dim

esni

on M

easu

rem

ent)

P r io r ip i l im u m a b t r e a tm e n tN o p r io r ip i l im u m a b t r e a tm e n t

Nivolumab + Ipilimumab MK-3475

The “depth of the response” is in part an artifact of how the data is presented when using WHO (bidimensional measurements) in a waterfall plot

Cha

nge

from

bas

elin

e us

ing

WH

O m

easu

rem

ents

Treatment-Related Adverse Events (≥10% of all patients)Treatment-Related Adverse Event

Number of Patients (%)

ConcurrentAll Cohorts (n=53)

SequencedAll Cohorts (n=33)

All Gr Gr 3-4 Al Gr Gr 3-4

Any adverse event 49 (93) 28 (53) 24 (73) 6 (18)

Rash 29 (55) 2 (4) 3 (9) 0

Pruritus 25 (47) 0 6 (18) 0

Fatigue 20 (38) 0 3 (9) 0

Diarrhea 18 (34) 3 (6) 3 (9) 0

Nausea 11 (21) 0 1 (3) 0

Pyrexia 11 (21) 0 1 (3) 0

AST 11 (21) 7 (13) 0 0

ALT 11 (21) 6 (11) 1 (3) 0

Lipase 10 (19) 7 (13) 4 (12) 2 (6)

Amylase 8 (15) 3 (6) 1 (3) 1 (3)

Cough 7 (13) 0 2 (6) 0

Vomiting 6 (11) 1 (2) 0 0

Vitiligo 6 (11) 0 0 0

Headache 6 (11) 0 0 0

Presented by J. Wolchok, ASCO 2013

What is the decision making for 1st line treatment of advanced melanoma?

BRAF testing

Positive Negative

“Growth kinetics”

Slow Fast

What is the decision making for 1st line treatment of advanced melanoma?

BRAF testing

Positive Negative

“Growth kinetics”

Slow Fast

Predictive factors for response to PD-1/L-1 blockade

Positive Negative

Conclusions• PD-1/PD-L1 blockade therapy should be

used as single agent in patients who have a chance of responding to this therapy

• Combination therapies with PD-1/PD-L1 blockade should only be used in patients with a low likelihood of a tumor response to single agent therapy

Combination Checkpoint Blockade Therapy for Melanoma

JeddWolchok

Ludwig Center at Memorial Sloan‐Kettering Cancer Center, New York

Ipilimumab Augments T‐Cell Activation and Proliferation

Adapted from O’Day et al. Plenary session presentation, abstract #4, ASCO 2010.

T-cell

APC

TCR

HLA CD80/CD86

T-cell inhibition

CTLA-4

CD28

T-cell

APC

TCR

HLA

T-cell activation

CD28TCR

HLA

T-cell

APC

CD80/CD86

T-cell remains active

IpilimumabblocksCTLA-4

T-cell

APC

CTLA-4

CD80/CD86

TCR

HLA

Patients at RiskIpilimumab 4846 1786 612 392 200 170 120 26 15 5 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72 84 96 108 120

Ipilimumab

CENSORED

Pooled OS Analysis Including EAP Data: 4846 Patients

Median OS (95% CI): 9.5 (9.0–10.0)

3-year OS Rate (95% CI): 21% (20–22%)

Prop

ortio

n A

live

Months

3Hodi et al., ESMO, 2013

Immune‐Related Adverse Events

• Rash• Colitis/enteritis• Elevated AST/ALT• Thyroiditis• Adrenal insufficiency• Hypophysitis

Severity is inversely related to vigilance of surveillance.If detected early, most are easily treated and reversible.

MHC

PD‐L1

PD‐1 PD‐1

PD‐1 PD‐1

NivolumabPD‐1 Receptor Blocking Ab

Recognition of tumor by T cell through MHC/antigen interaction mediates IFNγ release

and PD-L1/2 up-regulation on tumor

Priming and activation of T cells through MHC/antigen & CD28/B7 interactions with

antigen-presenting cells

T‐cellreceptor

T‐cellreceptor

PD‐L1PD‐L2

PD‐L2

MHC

CD28 B7

T cell

NFκBOther

PI3KDendritic

cellTumor cell

IFNγ

IFNγR

Shp‐2

Shp‐2

Role of PD‐1 Pathway in Suppressing Anti‐tumor Immunity

5Sznol et al., ASCO, 2013

Tumor Burden in Patients with Melanoma Receiving Nivolumab 3 mg/kg

6

Vertical line at 96 weeks = maximum duration of continuous nivolumab therapyHorizontal line at −30% = threshold for defining objective response (partial tumor regression) in absence of new lesions or non‐target disease according to RECIST

Unconventional response = response patterns that did not meet RECIST criteria (e.g., persistent reduction in target lesions in the presence of new lesions, or regression following initial progression)

All Mel patients treated with 3 mg/kg nivolumab 4 Mel patients treated with unconventional responses from nivolumab

1st occurrenceof new lesion

3 mg/kg

Weeks since treatment initiation

Cha

nge

in ta

rget

lesi

ons

from

bas

elin

e (%

)

1st occurrenceof new lesion

Weeks since treatment initiation

Cha

nge

in ta

rget

lesi

ons

from

bas

elin

e (%

)

1 mg/kg

1 mg/kg1 mg/kg

10 mg/kg

Sznol et al., ASCO, 2013

Select Drug‐Related Adverse Events (≥1%) Occurring in Melanoma Patients Treated with Nivolumab

Category Any Grade % (n) Grade 3‐4 % (n)

Any select AE 54 (58) 5 (5)

Skin 36 (38) 2 (2)

Gastrointestinal 18 (19) 2 (2)

Endocrinopathies 13 (14) 2 (2)

Hepatic 7 (7) 1 (1)

Infusion reaction 6 (6) 0

Pulmonary 4 (4) 0

Renal 2 (2) 1 (1)

• Select AE: AE with potential immunologic etiologies that require more frequent monitoring and/or unique intervention

• All patients have ≥1 year of follow‐up

7

MK‐3475: Maximum Change From Baseline in Tumor Size (Independent Central Review per RECIST 1.1)

Ribas et al., ASCO, 2013

Individual Patients Treated With Lambrolizumab‒100

‒80

‒60

‒40

‒20

0

20

40

60

80

100

Perc

ent C

hang

e Fr

om B

asel

ine

in

Long

est D

iam

eter

of T

arge

t Les

ion

IPI-NaiveIPI-Pretreated

160

Clinical Activity, MK‐3475

Ribas et al., ASCO, 2013

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

MPDL3280A Phase Ia: Tumor Burden Over Time (Melanoma)

10

Chan

ge in Sum

of L

onge

st Diameters

(SLD

) From Bas

eline, %

100

50

-50

0 21 42 63 84 105Time on Study (Days)

0

126 147 168 189 210 231 252 273 294 315 336

-100

New LesionsDiscontinued Study

20 mg/kg (n = 7)

10 mg/kg (n = 8)1 mg/kg (n = 2)

15 mg/kg (n = 16)

Patients first dosed at 1-20 mg/kg prior to Aug 1, 2012 with at least 1 post-baseline evaluable tumor assessment; data cutoff Feb 1, 2013.

* ≥ 100%

*

Hamid et al., ASCO, 2013

Phase I Study: Schedule

• Following prior ipilimumab, patients received nivolumab every 2 weeks for a maximum of 48 doses

• First tumor assessment at 8 weeks

Sequenced Cohorts

• Tumor assessments by mWHO and immune‐related response criteria

• Data as of Feb 2013 for 86 patients

Concurrent Cohorts

Weeks 0 3 6 12 15 18 219 24 36 48 60 72 84 96 108

Nivolumab once every 12 weeks(8 doses)

Nivolumab once every 3 weeks(8 doses)

Ipilimumab once every 12 weeks(8 doses)

Ipilimumab once every 3 weeks(4 doses)

• First tumor assessment at 12 weeks

Treatment‐Related Select Adverse Events

Select Adverse Event

Number of Patients (%)

Concurrent RegimenAll Cohorts (n=53)

Sequenced RegimenAll Cohorts (n=33)

All Gr Gr 3‐4 All Gr Gr 3‐4

Pulmonary 3 (6) 1 (2) 1 (3 ) 0

Renal 3 (6) 3 (6) 0 0

Endocrinopathies 7 (13) 1 (2) 3 (9) 2 (6)

Uveitis 3 (6) 2 (4) 0 0

Skin 37 (70) 2 (4) 8 (24) 0

Gastrointestinal 20 (38) 5 (9) 3 (9) 0

Hepatic 12 (23) 8 (15) 1 (3) 0

Infusion reaction 1 (2) 0 0 0

Lipase 10 (19) 7 (13) 4 (12) 2 (6)

Amylase 8 (15) 3 (6) 1 (3) 1 (3)

Presented by: Jedd D. Wolchok, MD, PhD

Clinical Activity: Sequenced Regimen

Nivolumab(mg/kg)

Response EvaluablePatients

nCRn

PRn

Objective Response

Rate%

[95% CI]

Aggregate Clinical

Activity Rate%

[95% CI]

≥80% TumorReduction at 8 wk n (%)

1 16 1 5 38 [15‐65] 69 [41‐89] 4 (25)

3 14 0 0 0 14 [2‐43] 0

Sequenced 30 1 5 20 [8‐39] 43 [26‐63] 4 (13)

• With sequenced nivolumab after prior ipilimumab, 20% of patients had confirmed objective responses

• 13% of patients had ≥80% tumor reduction at their first scheduled 8‐week tumor assessment (rapid and deep responses)

Best Responses in All Evaluable Patients in Sequenced Cohorts

Patients who had radiographic progression with prior ipilimumab treatment.Patients who had stable disease with prior ipilimumab treatment.

Patients

Chan

ge in ta

rget le

sion

s from

bas

eline (%

)

‐80

Clinical Activity: Concurrent Regimen

Dose (mg/kg)Response EvaluablePatients

nCRn

PRn

Objective Response

Rate%

[95% CI]

Aggregate Clinical Activity Rate%

[95% CI]

≥80% Tumor

Reduction at 12 wk n (%)

Nivolumab Ipilimumab

0.3 3 14 1 2 21 [5‐51] 50 [23‐77] 4 (29)

1 3 17 3 6 53 [28‐77] 65 [38‐86] 7 (41)

3 1 15 1 5 40 [16‐68] 73 [45‐92] 5 (33)

3 3 6 0 3 50 [12‐88] 83 [36‐100] 0

Concurrent 52 5 16 40 [27‐55] 65 [51‐78] 16 (31)

• With 1 mg/kg nivolumab + 3 mg/kb ipilimumab, 53% of patients had confirmed objective responses (3 CRs and 6 PRs)

• All 9 of these had ≥80% tumor reduction, 7 at 12 weeks and 2 at their first assessment, which was after week 12

• ≥80% tumor reductions appear infrequently (<10%) in the nivolumab and ipilimumab monotherapy experiences

Best Responses in All Evaluable Patients in Concurrent Cohorts

Patients

Chan

ge in ta

rget le

sion

s from

baseline (%

)

‐80

Rapid and Durable Changes in Target Lesions

1 mg/kg nivolumab + 3 mg/kg ipilimumab

First occurrence of new lesion

• A 52‐year‐old patient presented with extensive nodal

and visceral disease

• Baseline LDH was elevated (2.3 x ULN); symptoms

included nausea and vomiting

• Within 4 wk, LDH normalized and symptoms resolved

• At 12 wk, there was marked reduction in all areas of

disease as shown Weeks since treatment initiation

Chan

ge in ta

rget le

sion

s from

baseline (%

) Pre‐treatment

12 weeks

Patients at Risk

1 mg + 3 mg

All concurrent

17

53

16

47

16

36

14

29

10

19

5

10

3

7

2

4

2

4

1

3

0

1

0

1

0

0

n=17

n=53

Preliminary Survival of Patients Treated With Concurrent Regimen

Months

9 / 53Censored

All concurrent regimen

1 mg/kg nivolumab+ 3 mg/kg ipilimumab

Died/Treated

2 / 17

1‐year Survival82%

95%CI (69.0%;94.4%)

19

Evaluating PD‐L1 status as a candidate biomarker

0

20

40

60

Obj

ectiv

e R

espo

nse

Rat

e (%

)

Nivolumab monotherapy

(Grosso et al. ASCO 2013)

Combination nivolumab plus ipilimumab

Sequenced nivolumab after ipilimumab

3/21

7/17 9/226/13

1/13

4/8

_ _ _+ + +

Positivity rate = 45% (17/38, monotherapy), 37% (13/35, combination therapy), and 38% (8/21, sequenced therapy)

Callahan et al., ASCO, 2013

20

Obj

ectiv

e R

espo

nse

Rat

e (%

)

0

10

20

30

40

50

Evaluating ALC as a candidate biomarker

Ipilimumab monotherapy

(Ku et al. Cancer 2010)

Combination nivolumab plus ipilimumab

Sequenced nivolumab after ipilimumab

< 1.0 ≥ 1.0 < 1.0 ≥ 1.0 < 1.0 ≥ 1.0

0/8

6/33

6/1415/38

1/65/22

Low ALC rate = 20% (8/41, monotherapy), 27% (14/52, combination therapy), and 21% (6/28, sequenced therapy)


0 2 4 6 8 12-100

0

100

200

300

400

5001000

2000

0 2 4 6 8 12-100

0

100

200

300

400

5001000

2000

Increased frequency of activated (ki67+) CD4+ and CD8+

T cells with concurrent nivolumab + ipilimumab

0 1 2 3 6 12-100

0

100

200

300

400

5001000

2000

Percen

tage cha

nge in ki67+T

cells from

baseline

SequencedConcurrent

Median with interquartile range

0 1 2 3 6 12-100

0

100

200

300

400

5001000

2000

Weeks Since First Nivolumab Dose

SequencedConcurrent

CD4+ ki67+T cells CD8+ ki67+T cells

21

Weeks Since First Nivolumab Dose


0 1 2 3 6 12-100

0

100

200

300

400

5001000

2000

0 1 2 3 6 12-100

0

100

200

300

400

5001000

2000

0 2 4 6 6 12

Increased frequency of activated (ICOS+) CD4+ and CD8+

T cells with concurrent nivolumab + ipilimumabPe

rcen

tage cha

nge in ki67+T

cells from

baseline

SequencedConcurrent SequencedConcurrent

CD4+ ICOS+T cells CD8+ ICOS+T cells

Weeks Since First Nivolumab DoseWeeks Since First Nivolumab Dose

0 1 2 3 6 12

0

200

400

600

800

1000

1200

0 2 4 6 8 12

0

200

400

600

800

1000

1200


0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

incr

eas

in K

I67+

CD

8+ C

ells

COHORT 1 (0.3 NIVO, 3 IPI)n=6

0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

Incr

ease

in k

i67+

CD

8+ T

cel

ls

COHORT 2/8 (1 NIVO, 3 IPI)n=15

0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

Incr

ease

in k

i67+

CD

8+ T

cel

ls

COHORT 2A (3 NIVO, 1 IPI)n=9

0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

Incr

ease

in k

i67+

CD

8+ T

cel

ls

COHORT 3 (3 NIVO, 3 IPI)n=3

0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

Incr

ease

in k

i67+

CD

8+ T

cel

ls

COHORT 6 (1 NIVO)n=7

0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

Incr

ease

in k

i67+

CD

8+ T

cel

ls


Maggie Callahan

Ki67 staining of CD8+ T cells

0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

incr

eas

in IC

OS+

CD

8+ C

ells

COHORT 1 (0.3 NIVO, 3 IPI)n=6

0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

incr

eas

in IC

OS+

CD

8+ C

ells

COHORT 2/8 (1 NIVO, 3 IPI)n=15

0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

incr

eas

in IC

OS+

CD

8+ C

ells


0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

incr

eas

in IC

OS+

CD

8+ C

ells


0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

incr

eas

in IC

OS+

CD

8+ C

ells


0 2 4 6 8 10 120

5

10

15

Weeks on Treatment

Fold

incr

eas

in IC

OS+

CD

8+ C

ells


Maggie Callahan

ICOS Staining of CD8+ T cells by Cohort

COHORT 3 (3 NIVO, 3 IPI)n=3

Phenotype of activated peripheral blood CD8+ T cells after combination

0

103

104

105

<PE-

Cy5

-A>:

CTL

A-4

2.68

0.0741

0102

103

104

105

<PE-

Cy7

-A>:

ICO

S2.48

0.0948

0

103

104

105

<APC

-A>:

PD

-1 (M

IH4)

0.489

1.90

103

104

105

<PE

-Gr-A

>: Ig

G4

8.89e-3

2.33

0 102 103 104 105

0

103

104

105

<PE-

Cy5

-A>:

CTL

A-4

10.9

7.18

0 102 103 104 105

0

103

104

105

<APC

-A>:

PD

-1 (M

IH4)

7.16

10.1

0 102 103 104 105

0

103

104

105

<PE

-Gr-

A>:

IgG

4 7.3

10.7

0 102 103 104 105

0102

103

104

105

<PE-

Cy7

-A>:

ICO

S

10.9

6.48

ki67

Selected M

arke

r

CTLA‐4

CTLA‐4

ICOS

ICOS

PD‐1

PD‐1

Anti‐IgG

4Anti‐IgG

4

Day 7 post treatment

Pre‐treatment

CTLA‐4 ICOS PD‐1 Nivolumab


HDs(n=9)

All Pts(n=90)

10

20

40

60

80

100

%H

LA-D

Rlo

w/-

in C

D14

+ CD

11b+

*P=0.0002

CD14

HLA

DR

Lineage cocktail

HLA DR cut off line

Lineage cocktail CD14

CD

11b

HLA

DR

C

D14

Metastatic Melanoma Patients Have Increased MDSC

Kitano S, Postow M, et al. ASCO 2012

Summary

• Checkpoint blockade is an effective treatment with durable responses in melanoma

• Intense study of both predictive and pharmacodynamicbiomarkers of response and toxicity will allow for more intelligent patient selection and novel target discovery.

• Combination therapy will be necessary for immunotherapy to achieve full potential (other immune modulators, vaccines, radiation, chemotherapy, targeted therapy, anti‐angiogenictherapy).

• Combined checkpoint blockade may allow contraints for monotherapy to be overcome and is now being studied in phase 2 and phase 3 trials for melanoma.

“braf and mek inhibition in melanoma” -...

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