Therapie des fortgeschrittenen Melanoms Gestern, Heute, Morgen · 1/24/2013 1 Therapie des fortgeschrittenen Melanoms‐Gestern, Heute, Morgen Christoph Hoeller Universitätsklinik

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Therapie des fortgeschrittenenMelanoms‐ Gestern, Heute, Morgen

Christoph HoellerUniversitätsklinik für DermatologieMedizinische Universität Wien

Zertifiziertes Hautkrebszentrum

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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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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)


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)




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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





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)


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


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


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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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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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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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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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


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


Week30 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

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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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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BRIM 3A waterfall at last.....


C. Höller 2012

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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


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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

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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

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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

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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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n=43

C. Höller 2012

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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

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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

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MORGENC. Höller 2012

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Phase II 5 year survival updateStudy 022 and 008 (pretreated)

C. Höller 2012 C Lebbe et al, P1116, ESMO 2012

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Phase II 5 year survival updateStudy 007 (treatment‐naive cohorts)

C. Höller 2012 C Lebbe et al, P1116, ESMO 2012

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C. Höller 2012

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Anti PD‐1 BMS 936558

C. Höller 2012

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Response to BMS 936558 is linked to PD‐L1 expression on the tumor

C. Höller 2012

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Possible Ipi‐Biomarkers?

C. Höller 2012 Wang W et al, J Transl Med. 2012 Jul 12;10(1):146

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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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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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C. Höller 2012

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PFS V600E+K

C. Höller 2012 Flaherty KT et al, NEJM 2012 Nov; 367(18):1694‐703

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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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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,


Patient mitgeringer Tumorlast , Lebenserwartung


Palliative Chemotherapie

Ipilimumaboder PD‐1 Antikörper

Patient mit hoherTumorlast oderrascher Dynamik,


Patient mitgeringer Tumorlast , Lebenserwartung


N‐ras mutMEK

Inhibitor?

Documents

Therapie des fortgeschrittenen Melanoms Gestern, Heute, Morgen · 1/24/2013 1 Therapie des fortgeschrittenen Melanoms‐Gestern, Heute, Morgen Christoph Hoeller Universitätsklinik