Catumaxomab

Ovarialkarzinom: Antikörpertherapie-Was
gibt es Neues?
J. Sehouli
Charité Comprehensive Cancer Center
Europäischen Kompetenzzentrum für Eierstockkrebs (EKZE)
Klinik für Gynäkologie
Charité/ Campus Virchow-Klinikum
Universitätsmedizin Berlin
©Sehouli 2010
GOG0182-ICON5: Overall Survival
1.0
Proportion Surviving
0.8
0.6
0.4
0.2
Treatment
Alive
Dead
Total
C+P
C+P+G
C+P+D
C+T->C+P
C+G->C+P
538
546
555
521
529
326
318
307
340
332
864
864
862
861
861
0
0
12
24
36
48
Months from Randomization
Bookman J Clin Oncol 2009
“Circuit Diagram” for Cancer
Hanahan & Weinberg, 2000
Neue Substanzen am Horizont
•
•
•
•
•
•
•
•
•
Chemotherapie: Epothilone, Pemetrexed
TLK 286, LHRH-Doxorubicin
Antikörper: Anti-Epcam, ACA125 (Phase III), …
EGFR: Gefitinib, Erlotinib, Cetuximab,..
Antiangiogenesis and VEGF: Bevacizimab (2 Phase-III) DXMAA, VEGF trap,
PlGFab, Pazopanib (Phase III), BIBF 1120, Endothelin A-Inhibitor, Insulin
Growth Factor Inhibitor
c-erb-Familie (Trastuzumab, pertuzumab, TAK-165, CP724,714, 2C4, IMC225, EMD72000), Lapatinib (GW572016),
FTI (Lonafarnib, SCH6636, R115777, BMS214662),
Raf-1 (Bay 43-90006), MEK (CI-1040), Erbitux, Sorafenib (rand. Phase II)
M-tor inhibitoren
Weitere Substanzen: Enzastaurin, PARP-Inhibitors
und viele viele Andere
Wie sollten zielgrichtete Therapien
eingebaut werden?
108
Operation?
Anzahl Tumorzellen
107
106
105
Chemotherapie?
104
103
Maintenance?
102
10
1
0
Zeit
Rationale for Targeting VEGF in
Treatment of Epithelial Ovarian Cancer
• Human tumors
– VEGF over-expressed in epithelial ovarian cancers,1
associated with
• ascites formation
• malignant progression1-3
• poor prognosis4-7
• Preclinical models of solid tumors
– Anti-VEGF therapy:
• slowing of tumor progression8
• resolution of malignant effusions
• synergy with cytotoxic agents9-11
1Yoneda
J et al. J Natl Cancer Inst 1998;90:447; 2Ferrara. J Mol Med. 1999;77:527; 3Dvorak. J Clin Oncol. 2002;20:4368;
G et al. Int.J.Cancer 1996;69:205; 5Hollingsworth HC et al. Am.J.Pathol. 1995;147:33; 6Paley PJ et al. Cancer
1997;80:98; 7Alvarez AA et al. Clin.Cancer Res. 1999;5:587; 8Byrne et al. Clin Cancer Res 2003;9:5721; 9Gorski et al. Cancer Res.
1999;59:3374;10Lee et al. Cancer Res. 2000;60:5565. 11Hu et al. Am J Pathol. 2002;161:1917
4Gasparini
www-TOC-NETWORK.com
Sinn, Denkert, Sehouli et al, 2009
Clinical Response to Bevacizumab: GOG 170-D
CR
PR
ID
Complete Response (CR): 3 (4.8)
Partial Response (PR): 8 (12.9)
Stable Disease (SD):
34 (54.8)
Increasing Disease (ID): 16 (25.8)
Indeterminate:
1 (1.6)
Response Rate: 17.7%
90% C.I. (10.3 %– 27.7%)
SD
Median Response Duration
10.25 Months
Burger RA et al., ASCO Annual Meeting, Abstract 5009 . 2005
Progression-Free Survival
GOG trials in platinum-resistant ovarian cancer
1,0
GOG 170-D (n = 62)/
Bevacizumab
PFS @ 6 m = 0.40
0,8
0,6
GOG 170 F Series (n = 73)/
Sorafenib
PFS @ 6 m = 0.24
0,4
0,2
0,0
0
6
12
18
Months on Study
Burger, et al. Proc Am Soc Clin Oncol. 24 (abstr 5
Darmperforationen unter Bevaczizumab
Authors
n
Regime
Burger
62
Bev
0
Cannistra
44
Bev
11
Numnum
4
Bev
0
Monk
32
Bev
Garcia
29
Bev + Ctx
3
Wright
23
Bev + Chemo
9
Total
204
Chemo
Perforations (%)
0
4
MO22224 / AURELIA study
Patients with platinumresistant OC and ≤2 prior
chemotherapies
Paclitaxel, topotecan
or PLD*
Paclitaxel, topotecan
or PLD*
+ Avastin
Recruitment status
•
Not yet recruiting (target 300)
Trial closure
• Q4 2011
*Investigator’s choice
Avastin 15 mg/kg q3wk or
10 mg/kg q2wk to
synchronise with choice of
chemotherapy
Bevacizumab Safety During Chemotherapy:
Standard vs. Concurrent/ Maintenance
Arm I
No. Pts (%)
Chemo +
Placebo
Arm III
No. Pts (%)
Chemo + Bev
GI Perforation , fistula, necrosis or
leak (gr ≥2)
7 (1.2)
16 (2.6)
BP (gr ≥2)
43 (7.2)
139 (22.9)
Non-CNS bleeding (gr ≥3)
5 (0.8)
13 (2.1)
Venous thromboembolic
35 (5.8)
41 (6.7)
Discontinued for tox on chemo
57 (9)
59 (9)
Discontinued for tox on maintenance
12 (2)
35 (6)
Frequency of bevacizumab AEs in Arm III similar to other
randomized trials – no “surprises” in this population:
Safety is acceptable
Toxizität: Indirekter Vergleich verschiedener
Tyrosinkinaseinhibitoren
Pazopanib#
Sorafenib*
Sunitinib*
Ph II, 800mg QD
N = 225
Ph III
N = 451
Ph III
N = 375
Hypertension
31%
17%
30%
Fatigue
35%
37%
58%
Diarrhea
56%
43%
58%
Hand foot syndrome
7%
30%
21%
Rash
14%
40%
27%
Mucositis/ Stomatitis
~9%
Not reported (NR)
43%
Alopecia
7%
27%
unk
Lymphopenia
Neutropenia
Thrombocytopenia
Hemoglobin
33%
20%
21%
15%
23%
18%
12%
44%
59%
72%
65%
71%
ALT elevation (gr3/4)
AST elevation (gr3/4)
Bilirubin elevation (gr3/4)
49% (7%)
50% (5%)
29% (2%)
NR
NR
NR
46% (3%)
52% (2%)
19% (1%)
Hemorrhage/ bleeding
all sites
8-11%
15%
30%
# Hutson et al, ASCO 2007
Phase III Trials Evaluating Addition of an Angiogenesis Inhibitor
in Epithelial Ovarian Cancer
Agent
Group or
Sponsor
Line of therapy
Primary
Efficacy
Endpoint(s)
Status
Bevacizumab
GOG0218
First
PFS
Reported
today
ICON7
(GCIG study)
First
PFS and OS
Closed
Pharma/
AGO-OVAR16
Recurrent
PFS
Closed
BIBF
Pharma/
AGO-OVAR12
First
PFS
Active
Cediranib
ICON6
(GCIG study
Recurrent
PFS and OS
Active
Pazopanib
Pharma
First
PFS
(maintenance only)
Active
Bevacizumab in der First-Line Therapie des Ovarialkarzinoms
Stellungnahme der Kommission Ovar der Arbeitsgemeinschaft
Gynäkologische Onkologie (AGO)
Fur die Kommission: S. Mahner, A. du Bois, J. Sehouli, J. Pfisterer, U. Wagner
Zusammengefasst liefert die GOG-218 Studie einen wichtigen Beitrag zur
Behandlung des Ovarialkarzinoms. Die Ergebnisse zum progressionsfreien
Uberleben zeigen einen signifikanten Vorteil. Die Daten zum medianen
Gesamtuberleben und zur Lebensqualitat liegen noch nicht vor und sollten
zur endgultigen Bewertung der Studie abgewartet werden,
da eine Verlangerung des PFS einen limitierten Benefit darstellt und die
Verzogerung des Progresses um 4 Monate durch eine um mehr als 12
Monate langere Therapie erreicht wird.
Zum gegenwartigen Zeitpunkt kann die Kombination Carboplatin/Paclitaxel
+ Bevacizumab nicht als allgemeiner Therapiestandard empfohlen werden
und erst nach Auswertung der ICON 7-Studie und Ergebnissen zum
Gesamtuberleben kann abschliesend eine Risiko-Nutzen-Analyse
vorgenommen werden. Hierbei werden neben den Ergebnissen zum PFS
und Gesamtuberleben auch Aspekte der Lebensqualitat entscheidend sein.
Aszites - Bauch voller Tränen
Bauch voller Tränen - Aszites
geschrieben am 30.05.2007
Meine Augen kam mit dem Weinen nicht
mehr nach, deshalb ist mein Bauch voller
Tränen gelaufen.
Persephone aka Tharanis
©Sehouli 2010
Zusammenfassung maligner Aszites
Woopen et Sehouli/Anticancer Research,2009
• Schwerwiegendes Symptom
– Häufig erhebliche Einschränkung d. Lebensqualität
• Zweifelhafter und nur sehr temporärer Nutzen von Diuretika
• Parazentese nur kurze Erleichterung
• Peritoneovenöse Shunts mögliche aber invasive Alternative
• Unzureichend systematische Untersuchungen zur spezifischen
Therapie
– Kleine Fallzahlen, gemischte Entitäten
– Unterschiedliche Endpunkte
• Vielversprechende neue Therapieansätze
– Antikörpertherapie mit Anti-VEGF
©Sehouli 2010
Trifunctional Antibody Catumaxomab
Induction of an enhanced immune response
Apoptosis
Lysis
IL-2
Tumor Cell
T-Cell
EpCAM
CD3
ADCC
Phagocytosis
Activation
CD40L / CD28 / CD2
CD40 / B7.1-2 / LFA-3
Fc gamma RI/III
IL-1, IL-2
IL-12, IL-6
TNF-alpha,
DC-CK1, IFN-γ
macrophages, DC‘s, NK‘s
Accessory Cells
The postulated Tri-cell-complex.
The intact trifunctional antibody catumaxomab accelerates the recognition and destruction of tumor cells by different
immune cells. ADCC: Antibody dependent cellular toxicity; DC-CK1: Dendritic cell cytokine 1; IL: Interleukin; IFN-γ:
Interferon gamma; LFA: Leukocyte function associated antigen; TNF-alpha: Tumor necrosis factor alpha.
Ruf & Lindhofer, Blood 98, 2526-34, 2001
Riesenberg et al., J.Histochem Cytochem 49:911, 2001
EpCAM-positive Tumoren
Tumorart
EpCAM
expression
Tumorart
EpCAM
expression
Lung carcinoma
+++
Prostate carcinoma
++
Carcinoma of the
small intestine
+++
Ovarian carcinoma
++
Colorectal
adenocarcinoma
+++
Endometrium
carcinoma
++
Transitional cell
carcinoma of the
bladder
++
Cervical carcinoma
Thyroid carcinoma
++
Mammary carcinoma
Level of expression: + low; ++ intermediate; +++ high.
Balzar et al. J Mol Med 1999;77:699-712.
++/+++
++
Study Design/ Parson et al, ASCO 2008
Randomized Part
Study
•recurrent Malignant
129 patients with
Ascites
recurrent
malignant ascites
•EpCAMpositive
due to
ovarian cancer
Cross-Over
Paracentesis
(n=44)
+ catumaxomab
Post
catumaxomab
Catumaxomab treatment:
R
(2:1)



4 i.p.-infusions of 10, 20, 50 and 150 µg catumaxomab
6 hrs i.p. infusion via catheter on day 0, 3, 7 and 10
based on results of phase I/II dose finding study
Paracentesis alone
•recurrent Malignant
129 patients with
Ascites
recurrent
malignant ascites
•EpCAMpositive
due to
non-ovarian cancer
Single-arm
cross-over
Controls
switched to
catumaxomab
Controls
without
cross-over
Puncture-Free Survival (Primärer Endpunkt)
Frauenklinik, CVK
(Kaplan-Meier estimates; full analysis set)
Pooled Analysis of Ovarian and Non-Ovarian Cancer Patients
Estimated Puncture-free Survival
Probability (%)
100
90
80
Treatment:
catumaxomab (n=170)
70
Control (n=88)
60
50
40
30
20
10
0
0
20
40
60
80
100
120
140
160
180
200
Time (days) to event
Median Puncture Free Survival in days
Pooled
Population
Ovarian
Cancer
Stratum
Non-Ovarian
Cancer
Stratum
Gastric
Cancer
Subgroup
Catumaxomab
(Number of pat. with event)
46
(119)
52
(56)
37
(63)
44
(39)
Control
(Number of pat. with event)
11
(82)
11
(42)
14
(40)
15
(18)
Difference
[Factor]
35
[4.2]
41
[4.7]
23
[2.6]
29
[2.9]
< 0.0001
< 0.0001
< 0.0001
< 0.0001
p-value
(log-rank test)
Nebenwirkungsspektrum
Pooled Population (n=157)
Catumaxomab/Treatment Procedure-Related AEs in ≥ 5% of Patients [number of patients (%)]
Other Non Hematological Disorders
Cytokine Release Related Symptoms
Preferred term
Pyrexia
Nausea
Vomiting
Chills
Tachycardia
Hypotension
all
CTCAE
95 (60.5)
52 (33.1)
43 (27.4)
21 (13.4)
15 (9.6)
13 (8.3)
grade ≥ 3
9 (5.7)
5 (3.2)
4 (2.5)
2 (1.3)
1 (0.6)
3 (1.9)
Hematological Disorders
Preferred term
all
CTCAE grade ≥ 3
Lymphopenia
22 (14.0)
6 (3.8)
Leukocytosis
16 (10.2)
2 (1.3)
Anaemia
14 (8.9)
2 (1.3)
CTCAE grade ≥ 3
Preferred term
all
Abdominal Pain
C-reactive protein
increased*
Gamma-glutamyltransferase
(GGT) increased
Fatigue
Diarrhea
Anorexia
Blood alkaline phosphatase
(AP) increased
Aspartate aminotransferase
(AST) increased
Alanin aminotranferase
(ALT) increased
Ileus
Pain
67 (42.7)
23 (14.6)
15 (9.6)
7 (4.5)
18 (11.5)
9 (5.7)
17 (10.8)
16 (10.2)
14 (8.9)
14 (8.9)
5 (3.2)
3 (1.9)
5 (3.2)
4 (2.5)
12 (7.6)
4 (2.5)
10 (6.4)
3 (1.9)
10 (6.4)
8 (5.1)
5 (3.2.)
1 (0.6)
*Most probably related to catumaxomab‘s mode of action.
Besserung der Beschwerden und der QoL
catumaxomab (n=121)
Control (n=50)
* Difference with p<0.05
80
Assessed by interview
Assessed by abdominal
% of patients without symptoms
examination
70
60
50
*
*
*
*
*
*
*
*
*
*
40
30
20
10
0
Clinical signs and symptoms were assessed 8 days after last infusion (catumaxomab group) or 8 days
after paracentesis (control group).
Gesamtüberleben
(Kaplan-Meier estimates; full analysis set)
Pooled Analysis of Ovarian and Non-Ovarian Cancer Patients
100
Estimated Overall Survival
Probability (%)
90
80
Treatment:
70
catumaxomab (n=170)
60
Control (n=88)
50
40
30
20
10
0
0
60
120
180
240
300
360
420
480
540
Time (days) to event
Median Overall Survival in days
Pooled
Population
Pooled
Population
(per protocol)
Ovarian
Cancer
Stratum
Non-Ovarian
Cancer
Stratum
Gastric
Cancer
Subgroup
Catumaxomab
(Number of pat. with event)
72
(144)
86
(107)
110
(66)
52
(78)
71
(43)
Control
(Number of pat. with event)
68
(38)
68
(34)
81
(14)
49
(24)
44
(12)
Difference
[Factor]
4
[1.1]
18
[1.3]
29
[1.4]
3
[1.1]
27
[1.6]
0.0846
0.0085
0.1543
0.4226
0.0313
p-value
(log-rank test)
The trifunctional antibody catumaxomab:
Correlation between immunological response
and clinical outcome – new analysis of a pivotal
phase II/III study
M.G. Ott, H. Lindhofer, M. Hennig, H. Martinius, A. Klein, D. Seimetz
Results - Immunological response and clinical
outcome
N = number of patients, PuFS = puncture-free survival, TTFP = Time to first puncture, OS = overall survival
• 76 % of the tested catumaxomab patients were HAMA-positive 8 days after the fourth
infusion.
• HAMA-positive patients showed a significantly longer puncture-free survival (p<0.0001),
time to next therapeutic puncture (p=0.0002), and overall survival (p=0.0003) – compared to
HAMA-negative patients.
Estimated Puncture-free survival probability
(%)
Results - Puncture-free survival
: Catumaxomab patients with positive HAMA assessment
: Catumaxomab patients with negative HAMA assessment
: Control patients
Time (days) to
event
Puncture-free survival (median, days):
21 (control) versus 27 (HAMA-negative patients) versus 64 (HAMA-positive
Estimated Overall survival probability
(%)
Results - Overall survival
: Catumaxomab patients with positive HAMA assessment
: Catumaxomab patients with negative HAMA assessment
: Control patients
Time (days) to
event
Overall survival (median, days):
62 (control) versus 64 (HAMA-negative patients) versus 129 (HAMA-
Phase II clinical trial to evaluate the safety of
repeated cycle of intraperitoneal catumaxomab
for treatment
of2 malignant
ascites
(SECIMAS)2
1
3
4
K. Pietzner , R. G. Linke , M. Jäger , H. Lindhofer , H. Friccius-Quecke ,
F. Chen1, E.I. Braicu1, G. Oskay-Özcelik1, J. Sehouli1
1Charité
University Medicine of Berlin, Berlin, Germany, 2
Fresenius Biotech GmbH, Munich, Germany;
3TRION Research GmbH, Munich, Germany, 4TRION Pharma
GmbH, Munich, Germany
Frauenklinik, CVK
Catumaxomab: Wer sollte? / Wer sollte eher
nicht therapiert werden?
THERAPIE
EHER NICHT
Therapierefraktärer und
symptomatischer maligner Aszites
Sehr kurze Lebenserwartung (präfinal)
EpCAM pos. Tumor
Stark reduzierter AZ
Zustand erlaubt prinzipiell
weitere symptomatische
bzw. andere (spätere) medikamentöse
Therapie
Ileus, symptomatischer Subileus
Akute (latente) Infektion
Keine alleinigen Enscheidungskriterien
Alter
Laborparameter
Tumorbefallmuster
©Sehouli 2010
Intraoperative immunotherapy with the trifunctional antibody
catumaxomab in patients with ovarian-cancer: Results from a phase II
study
abstract #5039
R. Chekerov1, A. Reinthaller2, D. Reimer3, T. Reimer4,
L. Angleitner-Boubenizek5, M. Halfen6, H. Lindhofer7,
I. Braicu1, G. Oskay-Özcelik1, J. Sehouli1
Aktuelle Studien in Deutschland
(www.eierstockkrebs-forum.de)
•
•
•
•
Erstbehandlung
– Phase-III
AGO-Studie BIBF (Hemmung von
Tumorgefässenwachstum)
TRION (Antikörper,Tumorgefässhemmer)
AGO-LION (Lymphknoten-OP vs keine)
– Phase-II
– Phase-III
Rezidiv OP
– Desktop 3 OP vs keine OP
Spätrezidive
– Phase-III
AGO-ECHO (Paclitaxel + Carboplatin +
Tumorgefässhemmer)
Frührezidive
– Phase I/I
NOGGO-AGO TRIAS (Topotecan +
Tumorgefässhemmer)
– Phase-III
AURELIA (Topotecan/Caelyx/Palitaxel +
Tumorgefässhemmer)
– Phase-III
NOGGO: Präferenz-Studie für ältere Patientinnen
mit Treosulfan
– Phase-III
CASIMAS (Antikörpertherapie bei Bauchwasser)
– Umfrage
NOGGO-Expression-II
(www.expession2.de)