“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
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
ProliferationSurvival
CRAF
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
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
• Signaling by BRAF and MEK• Clinical Efficacy of Inhibiting the
BRAF/MEK pathway• Toxicity of Inhibiting the BRAF/MEK
pathway• Resistance to BRAF inhibitors
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
ProliferationSurvival
BRAF
V600E
ProliferationSurvival
BRAF
ProliferationSurvival
BRAF
ProliferationSurvival
CRAF
BRAF-inhibitor
BRAF-inhibitor
CRAF
BRAF
V600E
ProliferationSurvival
BRAF
V600E
ProliferationSurvival
BRAF
ProliferationSurvival
CRAF
MEK MEK MEKMEK-
inhibitor
BRAF
ProliferationSurvival
CRAF
MEKMEK-
inhibitor
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
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)
Callahan et al., ASCO, 2013
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
Callahan et al., ASCO, 2013
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
Callahan et al., ASCO, 2013
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
COHORT 7 (3 NIVO)n=8
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
COHORT 2A (3 NIVO, 1 IPI)n=9
0 2 4 6 8 10 120
5
10
15
Weeks on Treatment
Fold
incr
eas
in IC
OS+
CD
8+ C
ells
COHORT 2A (3 NIVO, 1 IPI)n=9
0 2 4 6 8 10 120
5
10
15
Weeks on Treatment
Fold
incr
eas
in IC
OS+
CD
8+ C
ells
COHORT 6 (1 NIVO)n=7
0 2 4 6 8 10 120
5
10
15
Weeks on Treatment
Fold
incr
eas
in IC
OS+
CD
8+ C
ells
COHORT 7 (3 NIVO)n=8
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
Callahan et al., ASCO, 2013
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.