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1/24/2013
1
Therapie des fortgeschrittenenMelanoms‐ Gestern, Heute, Morgen
Christoph HoellerUniversitätsklinik für DermatologieMedizinische Universität Wien
Zertifiziertes Hautkrebszentrum
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2
GESTERN
C. Höller 2012
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Fernmetastasiertes Melanom“Standard” Chemotherapie
Response Rate (%) Survival (Month)Dacarbazin (DTIC) 5‐23% 5,6 – 7,7Temozolomid 13,5–21% 5,3 – 7,2Fotemustin 7,4–24,2% 5,4 – 7,2Vindesin 12 –26% 5BHD (BCNU, Hydroxyurea, DTIC) 12,7–30,4% ‐‐‐‐‐‐‐BOLD (Bleomycin, Vincristin, CCNU, DTIC) 22–40% 6 – 7,7DVP (DTIC, Vindesin, Cisplatin) 24–45% 6,5DBCT (DTIC, BCNU, Cisplatin, Tamoxifen) 18,5–31,9% 6,4 ‐ 6,7
C. Höller 2012C. Höller 2012
High dose Il‐2 16% NA, 6% CR, 2‐4% durable
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HEUTEC. Höller 2012
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Targeted Immunotherapy – CTLA4
Anti Tumor response throughT‐cells infiltrating the metastases
Anti Tumor responsethrough metastases‐infiltrating T‐cells
+ response
MHCTCR
T-cell CTLA-4
APC
1. Co-stimulation via CD28 ligation transduces T-cell activating signals
MHCTCR
Ipilimumab
T-cell
CTLA-4
APC
T-cell activation
3. Blocking CTLA-4 ligation enhances T-cell responses
MHC
TCR
T-cell
APC
CD28CTLA-4
T-cell inactivation
B7
2. CTLA-4 ligation on activated T-cells downregulates T-cell responses
B7B7
T-cell activation
CD28 CD28
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Ipilimumab – Clinical Data
C. Höller 2012C. Höller 2012
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Patients included irrespective of BRAF status Pretreated (“stable”) CNS metastases allowed
Ipilimumab‐schedule: 4 doses 3 weeks apart First Assessment: week 12
RANDOMISE
Pre‐treated,HLA‐A*0201 positive,metastaticmelanoma(N=676)
(n=137)
(n=136)
(n=403)
gp100 (1mg/kg) + placeboq 3 weeks for 4 doses
YERVOY (3 mg/kg) + placeboq 3 weeks for 4 doses
YERVOY (3 mg/kg) + gp100 (1 mg/kg) q 3 weeks for 4 doses
3:1:1Study Design
C. Höller 2012 Hodi FS et al, N Engl J Med, 2010,711‐23
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Improved Survival With Ipilimumab(> 4.5 Years Of Follow-Up)
Comparison HR P-valueArms A vs C 0.68 <0.001Arms B vs C 0.66 0.003
Years1 2 3 4
Prop
ortio
n al
ive
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
YERVOY + gp100 (A)YERVOY alone (B) gp100 alone (C)
No separation in curves for first three months
Hodi, FS, et al. N Engl J Med 2010;363:711–723
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9
Years1 2 3 4
Prop
ortio
n al
ive
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
BUT…Separation and survival impactoccurs after three months(approx 4 month improvement in median OS)
Improved Survival With Ipilimumab(> 4.5 Years Of Follow-Up)
Survival Rate*YERVOY + gp100 N=403 (95% CI)
YERVOY + placebo N=137 (95% CI)
gp100 + placeboN=136 (95% CI)
1 year 44% (0.39,0.49) 46% (0.37,0.54) 25% (0.18,0.33)
2 year 22% (0.17,0.26) 24% (0.16,0.32) 14% (0.08,0.2)
Hodi, FS, et al. N Engl J Med 2010;363:711–723
Comparison HR P-valueArms A vs C 0.68 <0.001Arms B vs C 0.66 0.003
YERVOY + gp100 (A)YERVOY alone (B) gp100 alone (C)
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Years1 2 3 4
Prop
ortio
n al
ive
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
AND• Near doubling of 1 and 2 year
survival with a plateau after 2 years where we start to see durable long-term survivors– Plateau lasts 4+ years
Improved Survival With Ipilimumab(> 4.5 Years Of Follow-Up)
Hodi, FS, et al. N Engl J Med 2010;363:711–723
Comparison HR P-valueArms A vs C 0.68 <0.001Arms B vs C 0.66 0.003
YERVOY + gp100 (A)YERVOY alone (B) gp100 alone (C)
Survival RateYERVOY + gp100 N=403 (95% CI)
YERVOY + placebo N=137 (95% CI)
gp100 + placeboN=136 (95% CI)
1 year 44% (0.39,0.49) 46% (0.37,0.54) 25% (0.18,0.33)
2 year 22% (0.17,0.26) 24% (0.16,0.32) 14% (0.08,0.2)
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C. Höller 2012
ALL PATIENTS
Gender Male
Female
Age < 65 years
≥ 65 years
M-stage at Study Entry M0, M1A, M1B
M1C
Baseline LDH ≤ ULN
> ULN
Prior Use of IL-2 Yes
No
Hazard Ratio and 95% CI
CNS Metastasis History Yes
No
0.2 0.5 1 2 50.2 0.5 1 2 50.1 1
IpiIpi + gp100 gp100gp100
Ipilimumab – Subgroups
Lebbe C et al, Ipilimumab improves survival in previously treated, advanced melanoma patients with poor prognostic factors: subgroup analyses from a phase III trial
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• CNS metastases:
‐ Phase II trial of ipilimumab monotherapy in melanoma patients with brain metastases:
Patients with CNS mets between 0.3 – 3cm, prior whole brain‐ or stereotactic radiation allowed. Arm A – Pts. wo steroid, Arm B Pts. on steroid medicationIpilimumab 10mg/kg every 3 weeks, evaluation after 12 weeksResults:
Ipilimumab – CNS Metastases
Arm A (n=51) Arm B (n=21)
CNS Non‐CNS CNS Non‐CNS
DCR (SD+PR) 23,5% 27,5% 9,5% 4,8%
C. Höller 2012C. Höller 2012 Lawrence et al, J Clin Oncol 28: 7s, 2010
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Response during therapy
W0
W12
C. Höller 2012
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C. Höller 2012 Harmankaya K et al, Med Oncol 2010
Initial PD with delayed CRCorresponding CT-Scans
Screening Week 12 Week 16 Week 220
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C. Höller 2012
Ipilimumab – Response kinetics
Relative week from first dose date
SPD = Sum of the Product of the perpendicular Diameters (a measure of tumor volume)
1501251007550250
-25-50-75
-100-125
1,2721,12497582767853036223385-64-212
SPD (m
m2)
Relative week from first dose date
50
25
0
–25
–50
–75
–100
–125
Cha
nge
from
bas
elin
e S
PD
(%) 1,272
1,12497582767853036223385-64-212
SPD (m
m2)
Cha
nge
from
bas
elin
e S
PD
(%)
‐9 ‐3 3 9 15 21 27 33 39 45 51
Relative week from first dose date
Cha
nge
from
bas
elin
e S
PD
(%)
SP
D (m
m2)
2,8942,5562,2181,8811,5431,206888530193-145-482
50
25
0
-25
-50
-75
-100
-125
‐9 ‐3 3 9 15 21 27 33 39 45 51
‐9 ‐3 3 9 15 21 27 33 39 45 51
'Stable disease' with slow, steady decline in total tumor volume
Response after initial increase in total tumor volume
Response in index and new lesions After the appearance of new lesions
Response in baseline lesions
Tota
l mea
sura
ble
tum
or v
olum
e
SP
D (m
m2)
2,8102,4822,1541,8261,4951,171843515187-140-466
50
25
0
-25
-50
-75
-100
-125‐63 ‐21 21 63 105 147 189 231 273 315 357
9 months
Relative week from first dose date
PD
PR
CR
7 months 7 months
11 months
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Immune Related Response Criteria
• IrRC have been derived retrospectively during thephase II programm of Ipilimumab.
• They have a broad basis of clinical data supporting theiruse for Ipilimumab treatment
C. Höller 2012
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mWHO vs. irRCCR PR SD PD
mWHOCriteria
All lesions gone
SPD of index lesions decreases > 50%
new lesions not allowed
SPD index lesions neither CR, PR or
PD; new lesions not allowed
SPD index lesions increases
> 25% &/OR PD is based on SPD and/or new
lesions
irCR irPR irSD irPD
irRC
All lesions gone
SPD of index + any new lesions
Decreases > 50%
new lesions allowed
SPD of index + any new lesions neither irCR, irPR nor irPD
new lesions allowed
SPD of index + any new lesions increases > 25%
PD is based on SPD only
SPD = sum of the product of the perpendicular diameters
C. Höller 2012 Wolchok JD, Hoos A, O'Day S, Weber JS, Humphrey R, Hodi FS Clin Cancer Res 2009;15(23):7412-20.
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Overall Survival by mWHO Response Criteria for 10 mg/kg Ipilimumab Monotherapy
BOR=CR/PRCENSORED
BOR=SDCENSORED
BOR=PD/UnknownCENSORED
Prop
ortio
n Alive
SUBJECTS AT RISK
CR/PR 17 17 17 17 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 15 15 13 8 6 3 0 0 0 0
SD 46 46 46 45 45 44 43 43 43 43 43 39 37 36 35 35 32 31 31 30 30 29 25 15 10 4 3 0 0 0
PD/UNK 164 158 140 124 106 93 82 72 65 62 58 50 48 46 42 40 37 35 30 28 26 22 18 12 10 4 3 2 1 0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Months
N = 227
• Survival of SD is similar to survival for objective responders (CR + PR)• Long-term survival is seen in all response groups, including PD
C. Höller 2012
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Overall Survival by irRC Response Criteria for 10 mg/kg Ipilimumab Monotherapy
N=227
BOR=CR/PR/SDCENSORED
BOR=PD and irBOR=irPR/irSDCENSORED
BOR=Other PD or UnknownCENSORED
Prop
ortio
n Alive
SUBJECTS AT RISK
CR/PR/SD 63 63 63 62 61 60 59 59 59 59 59 55 53 52 51 51 48 47 47 46 45 44 38 23 16 7 3 0 0 0PD & irPR/irSD 22 22 22 22 20 20 19 19 19 18 18 17 16 16 14 14 14 14 13 13 12 12 11 10 9 4 3 2 1 0
Other PD/UNK 142 136 118 102 86 73 63 53 46 44 40 33 32 30 28 26 23 21 17 15 14 10 7 2 1 0 0 0 0 0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Months
• 9.7% of patients classified as PD by mWHO criteria had disease control by irRC; • Long‐term survivors included patients with PD per mWHO criteria at first scheduled tumor assessment (week 12)
C. Höller 2012
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20
Every coin has two sides
Anti Tumor response throughT‐cells infiltrating the metastases
Anti Tumor responsethrough metastases‐infiltrating T‐cells
+ response
Immune related AdverseEvents (IrAE) through T‐cell
activation
‐side effects:
MHCTCR
T-cell CTLA-4
APC
1. Co-stimulation via CD28 ligation transduces T-cell activating signals
MHCTCR
Ipilimumab
T-cell
CTLA-4
APC
T-cell activation
3. Blocking CTLA-4 ligation enhances T-cell responses
MHC
TCR
T-cell
APC
CD28CTLA-4
T-cell inactivation
B7
2. CTLA-4 ligation on activated T-cells downregulates T-cell responses
B7B7
T-cell activation
CD28 CD28
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Immune‐related adverse events caused byIpilimumab often correspond to known AI‐disease
Ipilimumab induced irAE Corresponding „real life“ autoimmun‐disease / inflammation
Colitis & Diarrhoe Crohn‘s disease, ulcerative Colitis
Thyreoiditis Hashimoto‘s tyreoiditis
Hepatitis / Hepatopathy Autoimmune‐Hepatitis
Pancreatitis AIP – autoimmune pancreatitis
Uveitis Uveitis as part of various systemicrheumatic diseases
Hypophysitis Anterior pituitary insufficiency
Neuropathy Giullain‐Barré‘s syndome
Thrombocytopenia ITP – idiopathic thrombocytopenia
Skin rash ?? Very heterogenous characteristic ??
C. Höller 2012
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22
Most Common Immune‐Related Adverse EventsIpilimumab 3mg/kg
Study MDX010‐20 ; Steven O’Day1, F. Stephen Hodi2
% of Patients
irAE Ipi + gp100N=380
Ipi + pboN=131
gp100 + pboN=132
All grades
Any 58.2 61.1 31.8Dermatologic 40.0 43.5 16.7GI 32.1 29.0 14.4Endocrine 3.9 7.6 1.5Hepatic 2.1 3.8 4.5
*Across entire study duration
C. Höller 2012
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23
Grade 3, 4 & 5 Immune‐Related Adverse Events Ipilimumab 3mg/kg
Study MDX010‐20 ; Steven O’Day1, F. Stephen Hodi2
% of Patients
irAEIpi + gp100N=380
Ipi + pboN=131
gp100 + pboN=132
Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4Any 9.7 0.5 12.2 2.3 3.0 0Dermatologic 2.1 0.3 1.5 0 0 0GI 5.3 0.5 7.6 0 0.8 0Endocrine 1.1 0 2.3 1.5 0 0Hepatic 1.1 0 0 0 2.3 0
Death due to irAE 1.3 1.5 0
*Across entire study duration
C. Höller 2012
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24
iRAE Management Guidelines
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C. Höller 2012
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Monotherapy 10mg/kg treated subjectsCensored
Monotherapy 10mg/kg treated subjectsCensored
Time to Resolution Grade 2‐4 irAEs – 10 mg/kg
Median: 2.29 weeks Median: 4.00 weeks
Median: 20.1 weeks
GI Liver
Endocrine
Median: 6.14 weeks
Skin
Prop
ortio
n no
t resolved
1.0
0.9
0.8
0.7
0.60.5
0.4
0.3
0.2
0.1
00 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Monotherapy 10mg/kg treated subjectsCensored
Week30 32 34 36 38 40 42 44 46 48 50 52 54
Monotherapy 10mg/kg treated subjectsCensored
Prop
ortio
n no
t resolved
1.0
0.9
0.8
0.7
0.60.5
0.4
0.3
0.2
0.1
00 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Week
30 32 34 36 38 40 42 44 46 48 50 52 54
Prop
ortio
n no
t resolved
1.0
0.9
0.8
0.7
0.60.5
0.4
0.3
0.2
0.1
00 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Week
30 32 34 36 38 40 42 44 46 48 50 52 54 56
1.0
0.9
0.8
0.7
0.60.5
0.4
0.3
0.2
0.1
0
Week30 32 34 36 38 40 42 44 46 48 50 52 54
Lebb
é, C et a
l. Pe
rspe
ctives in
Melan
oma XII 200
8; Abstract O
‐015
. Immune‐related AEs
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Response Rate under steroid treatment
C. Höller 2012 Baurain et al. ASCO 2012, Abstract 8539
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Immune‐related AEsManagement
Successful management of irAEs requires an excellent patient – doctor communication and an experienced interdisciplinary team!
C. Höller 2012
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Inhibition of the BRAFV600E Kinase
CellularProliferation
RTK
RAFVEMURAFENIBATP
ATP
ERK
MEK
BRAFV600E
RAS
40-60% of melanomas
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29
BRIM 3
C. Höller 2012
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BRIM 3 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
RandomisationN=675
Co-primary endpoints:• Overall Survival• Progression Free Survival
Paul Chapman et al, NEJM 2011 & Abstract LBA4, ASCO 2011; Grant McArthur et al, Abstract # LB28, ESMO 2011
C. Höller 2012
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31
BRIM 3A waterfall at last.....
Paul Chapman et al, NEJM 2011 & Abstract LBA4, ASCO 2011; Grant McArthur et al, Abstract # LB28, ESMO 2011
C. Höller 2012
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32
1009080706050403020100
Progression‐free
survival (%
)
No. of patients in follow upDacarbazineVemurafenib
0 1 2 3 4 5 6 7 8 9 10 11 12
Hazard Ratio 0.26 (95% CI; 0.20 ‐ 0.33)Log‐rank P<0.0001
Response Rate:Vemurafenib 48%Dacarbazine 5%
Months
274275
213268
85211
48122
28105
1650
1035
616
34
03
Dacarbazine (N=274)
Vemurafenib (N=275)
BRIM 3: Progression‐free survival (30 Dec 2010, final pre‐planned analysis at IA)
Median 1.6 mos Median 5.3 mos
Paul Chapman et al, NEJM 2011 & Abstract LBA4, ASCO 2011; Grant McArthur et al, Abstract # LB28, ESMO 2011
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BRAF Inhibitor Resistance
Nazarian R et al, Nature 468: 973‐7, Johannessen et al, Nature 468: 968‐72, Paraiso et al, Br J Cancer 102: 1724‐30, all 2010
RTK Activation
BRAF V600E
MEK 1/2
ERK 1/2
NRAS
CRAF
COT
Alternative survival pathways
MAP‐Kinase dependent survival
BRAF splicevariant
C. Höller 2012
1/24/2013
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1009080706050403020100
Overall survival (%
)
0 6 12 18 24
Vemurafenib (n=337)Median f/u 12.5 months
Dacarbazine (n=338)Median f/u 9.5 months
338337
173280
79178
2444
01
244326
111231
50109
47
9.7 13.6
BRIM 3: Overall survival (February 01, 2012 cutoff)
Hazard ratio 0.70 (95% CI: 0.57–0.87)p<0.001 (post‐hoc)
Time (months)
DacarbazineVemurafenib
No. at risk
Immediate separation of curves
Unclear long term separation of curves
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BRIM 1: Overall survival
C. Höller 2012 K. Kim et al, SMR 2012
1/24/2013
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Selected adverse events Vemurafenib (% of patients)Vemurafenib, n= 336 Dacarbazine, n= 282
Adverse events All Grade 3 Grade≥ 4 All Grade 3 Grade ≥4
Arthralgia 49 3 - 3 <1 -Rash 36 8 - 1 - -Fatigue 33 2 - 31 2 -Photosensitivity 30 3 - 4 - -LFTs 18 7 <1 5 1 -Cutaneous SCC 12 12 - <1 <1 -Keratoacanthoma 8 6 - - - -Skin papilloma 18 <1 - - - -Nausea 30 1 - 41 2 -Neutropenia <1 - <1 11 5 3
Discontinuations due to AE: 6% Vemurafenib; 4% Dacarbazine
1/24/2013
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cuSCC / KA
De novo arising melanomas with WT BRAF have been detected in patients treated with
BRAFi.2% of patients in the Vemurafenib arm of
BRIM 3 had secondary melanomas
C. Höller 2012
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B‐raf Inhibition
Wildtype BRAF undergoes an autoinhibition that is lost in BRAF V600E mutated cells. In cells carrying an NRAS mutation BRAF specific inhibitors block the autoinhibition of BRAF, subsequently leading to a superactivation of the MAP-Kinase signaling pathway (Heidorn SJ et al, Cell 2010)
B‐raf Inh.
C. Höller 2012
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c‐KIT
Garrido and Bastian, JID 2009
C. Höller 2012
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40
n=43
C. Höller 2012
1/24/2013
41
c‐KIT
C. Höller 2012
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C. Höller 2012
Phase II study with imatinib in selected patients with c‐kit mutations
51 pts with KIT mutation oramplification
Confirmed Response Rate: 2 CR, 4 PR and 5 SD > 12 weeksMedian time to progression 12 weeks
Carvajal RD, JAMA 2011
1/24/2013
43
Heute
C. Höller 2012
B‐raf/c‐kit mutierter Patient B‐raf/c‐kit wt Patient
Progress mit hoher Tumorlastoder rascher Dynamik,
Lebenserwartung <6 MonateECOG ≥2
Vemurafenib/Imatiniboder kontrollierte Studie
Chemotherapieoder kontrollierte Studie
Progress mit geringerTumorlast , Lebenserwartung
>6 Monate, ECOG 0‐1
Palliative Chemotherapie Ipilimumab
1/24/2013
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MORGENC. Höller 2012
1/24/2013
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Phase II 5 year survival updateStudy 022 and 008 (pretreated)
C. Höller 2012 C Lebbe et al, P1116, ESMO 2012
1/24/2013
46
Phase II 5 year survival updateStudy 007 (treatment‐naive cohorts)
C. Höller 2012 C Lebbe et al, P1116, ESMO 2012
1/24/2013
47
C. Höller 2012
1/24/2013
48
Anti PD‐1 BMS 936558
C. Höller 2012
1/24/2013
49
Response to BMS 936558 is linked to PD‐L1 expression on the tumor
C. Höller 2012
1/24/2013
50
Possible Ipi‐Biomarkers?
C. Höller 2012 Wang W et al, J Transl Med. 2012 Jul 12;10(1):146
1/24/2013
51
Inhibition of the BRAFV600E Kinase
CellularProliferation
RTK
RAFATP
ATP
ERK
MEK
BRAFV600E
RAS
40-60% of melanomas
MEK InhibitorsTrametinib, GDC0973
Preclinical BRAFi +MEKiDelays BRAFi resistance Hyperproliferative skin AE
B-raf InhibitorsDabrafenib, Vemurafenib
V: PFS 5.6 moD: PFS 5.1 mo
T: PFS 4.8 mo
C. Höller 2012
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52
BRIM-7 results: Change in tumoursize from baseline to best response in BRAFi-naïve patients
SLD, sum of longest diameters
*n=24 efficacy evaluable BRAFi-naïve patients with longest diameter measurements are included in this figure.
–30
–100
–50
0
50
100
Individual patients treated with vemurafenib and GDC-0973
Best tumour response for each patient (BRAFi-naïve*)
Cohort 1AExp. Cohort 1ACohort 1BExp. Cohort 1BCohort 2ACohort 4
Per
cent
age
chan
ge in
SLD
of
targ
et le
sion
s
Gonzalez R et al ESMO 2012
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53
C. Höller 2012
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54
PFS V600E+K
C. Höller 2012 Flaherty KT et al, NEJM 2012 Nov; 367(18):1694‐703
1/24/2013
55
Cutaneous Side EffectsDabrafenib mono Dabrafenib/Trametinib
Squamous Cell CarcinomaKeratoakantoma
19% 7%
Skin Papilloma 15% 4%
Hyperkeratosis 30% 9%
Vemurafenib BRIM 3 Vemurafenib/GDC0973
Squamous Cell CarcinomaKeratoakantoma
20% 1.4%
C. Höller 2012
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56
MORGEN
C. Höller 2012
B‐raf/c‐kit mutierter Patient B‐raf/c‐kit wt Patient
B‐raf+MEK Inhibitor /Imatinib
oder kontrollierte Studie
Patient mit hoherTumorlast oderrascher Dynamik,
Lebenserwartung <6 MonateECOG ≥2
Patient mitgeringer Tumorlast , Lebenserwartung
>6 Monate, ECOG 0‐1
Palliative Chemotherapie
Ipilimumaboder PD‐1 Antikörper
Patient mit hoherTumorlast oderrascher Dynamik,
Lebenserwartung <6 MonateECOG ≥2
Patient mitgeringer Tumorlast , Lebenserwartung
>6 Monate, ECOG 0‐1
N‐ras mutMEK
Inhibitor?