U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Uwe TrefzerKlinik für Dermatologie, Venerologie und

Allergologie

KNOTIGES BASALIOM

TeleangiektasienWachsartige glatte

Oberfläche

Basalzell Naevus Syndrom (Gorlin

Syndrom)

LH Goldberg, et al. Arch Dermatol 2010

„Old School“ vs. Targeted Therapies

Basalzell Naevus Syndrom (Gorlin

Syndrom)

LH Goldberg, et al. Arch Dermatol 2010

oral therapy with GDC-0449

Veratrum californicum -

Kalifornischer Germer

Cyclopamin

Hunting the Hedgehog

Binns, W., et al. Congenital cyclopian-type malformation in lambs induced by maternal ingestion of a

range plant, Veratrum californicum. Am. J. Vet. Res. 1963Keeler, R.F. et al. Teratogenic compounds of Veratrum californicum. Comparison of cyclopian effects

of steroidal alkaloids from the plant and structurally related compounds from other sources.

Teratology 1968

Hunting the Hedgehog

• Normaler HH Signalweg als Bestandteil embryonaler

Entwicklung und Zellwachstum

• Aberranter HH Signalweg bei ca. 25 % aller Tumoren des

Menschen nachgewiesen

Weiss GD, von Hoff DD. Clinical pharm Therap 2010

HH Inhibitor Studienstatus

GDC-0449 Phase II

BMS-833923 Phase I

IPI-926 Phase I

LDE-225 (Novartis) Phase I

PF-04449912 Phase I

GDC-0449 in der Behandlung multifokaler

Basalzellkarzinome (Basalzell-Naevus-Syndrom)

Therapie mit Imiquimod 5% Creme

E. Stockfleth et al

E. Stockfleth et al

Topische Therapie von AK mit 3%

Diclofenac in 2.5% Hyaluronsäure

Melanoma: Overall Survival by Stage

Survival (years)

Stage I (n=9175)

Stage II (n=5739)

Stage III (n=1528)

Stage IV (n=1158)

0 1 2 3 7 8 9 10 11 12 13 14 15654

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

port

ion S

urv

ivin

g

1.0

Adjuvante IFN-Therapie: Metaanalyse

• 6067 Patienten aus 10/13 publizierten Studien

zu IFN versus unbehandelte Kontrollen

• > 3.000 Todesfälle (für OS-Analyse) und >

3.700 „Rezidive“ (für RFS-Analyse)

auswertbar

Wheatley et al, ASCO 2007 (Abstract 8526)

Adjuvante IFN-Therapie: Metaanalyse

• Ergebnisse: RFS (OR = 0.87; CI 0.81-0.93)

p = 0.00006

OS (OR = 0.9; CI 0.84-0.97)

p = 0.008

• RFS und OS-Überlebensunterschied nach 5

Jahren: 7% bzw. 3%

Wheatley et al, ASCO 2007 (Abstract 8526)

Schema Dosis Frequenz Dauer Indikation

Niedrigdosis-

schema

3 Mio. IU

sc.

Tag 1,3 u. 5

jeder

Woche

18–24

MonateStad II – III

Hochdosis-

schema:

Initiierung

20 Mio IU/

m2

iv. als Kurz-

infusion

Tag 1-5

jeder

Woche

4 Wochen

Erhaltung10 Mio

IU/m2 sc.

Tag 1,3, u.

5 jeder

Woche

11 Monate Stad III

Stad III

Relapse Free Survival

Survival Time [months]

0 20 40 60

Su

rviv

al

Pro

bab

ilit

y

0,0

0,2

0,4

0,6

0,8

1,0

Arm A

Arm B

IFNa2a - 18 versus 60 Months

A.Hauschild et al.

Overall Survival

Survival Time [months]

0 20 40 60

Su

rviv

al

Pro

bab

ilit

y

0,0

0,2

0,4

0,6

0,8

1,0

Arm A

Arm B

IFNa2a - 18 versus 60 Months

A.Hauschild et al.

KNN Classifier

• MAGE-A3 screening

• Predictive signature to MAGE-A3 ASCI

MAGE-3-Protein-Signatur

AS15

HR: 0.29 [95% CI: 0.12 - 0.71]

KNN ClassifierLouahed, ASCO 2008

• MAGE-A3 screening

• Predictive signature to MAGE-A3 ASCI

Klinische Resultate mit MAGE3-Protein

im Stadium IV

Median

GS-: 2.3 months [95% CI: 2.3 - 4.4]

GS+: 10.3 months [95% CI: 6.7 - 12.4]HR: 0.31 [95% CI: 0.13 - 0.76]

AS15

Phase III study – DERMA

ADjuvant immunothERapy with MAGE-A3 in

melanomA

Resected MAGE-A3 (+) Stage IIIB/C Melanoma

Melanoma with macroscopic LN involvement

Randomization

Placebo MAGE-A3 ASCI

13 administrations over 27 months

1300 patients – double-blind, randomized trial

Melanoma: Overall Survival by Stage

Survival (years)

Stage I (n=9175)

Stage II (n=5739)

Stage III (n=1528)

Stage IV (n=1158)

0 1 2 3 7 8 9 10 11 12 13 14 15654

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

port

ion S

urv

ivin

g

1.0

• Lectin

• Elesclomol

• Genasense

• Maxamine

• Thymosin alpha

• Sorafenib

• HDAC-Inhibitor

• Cancer Vax („Morton Vakzine“)

• Vakzine

Chemoth.Targeted

Therapy

Ipilimumab Clinical

Study

1st line +++

not approved

+

2nd line +++ +

3rd line ++ (+)

Metastatic Melanoma

Activity of single agents in melanoma

DTIC 5-15%

Nitrosoureas 10-18%

Cisplatin 14-29%

IL-2 16%

Interferon- 10-14%

Taxol 14%

Vincristine 12%

.

Ives N J et al. JCO 2007;25:5426-5434

OR:

CT vs

BCT

.

Ives N J et al. JCO 2007;25:5426-5434

OS:

CT vs

BCT

Blockade CTLA-4

ASCO 2010

Ipilimumab

Ipilimumab

+

gp100 gp100

12 mo OS rate % 46 44 25

24 mo OS rate % 24 22 14

OS median mo 10.1 10.0 6.4

DCR % 28.5 20.1 11

O´Day et al.

O´Day et al.

June 5, 2011 (10.1056/NEJMoa1104621

EORTC 18071 Ipilimumab

Melanoma

Stage III (TxN1-3M0)

(N = 950)

Lymph node dissection

Randomisation within 56 days (1:1)

Arm A:

Ipilimumab (N=475)

Induction: 4 inf.. over 12 weeks

Maintenance: 1 inf every 12 w. for 3 years

or distant mets

Arm B:

Placebo (N=475)

as Arm A

Changes in the sum of diameters from

baseline by disease stage

Individual patients treated with vemurafenib

60

40

20

0

-20

-40

-60

-80

-100

M1a

M1b

M1c

Disease stage

Pe

rce

nt

ch

an

ge

fro

m b

as

eli

ne

in d

iam

ete

r o

f ta

rge

t le

sio

n

*******

* 7 Confirmed CRs

June 5, 2011

Chemoth.Targeted

Therapy

Ipilimumab Clinical

Study

1st line +

++

+

2nd line ++ +

3rd line ++ (+) (+) (+)

Metastatic Melanoma

55

The Future of Targeted Therapy for

Melanoma

Modified from K Flaherty

XL281

RG7204

GSK 21184338