Download Recurrent ovarian cancer - Dana-Farber/Brigham and Women`s

New Developments in the Treatment
of Recurrent Ovarian Cancer and
Evolving New Therapies
Alexi Wright, MD
Dana-Farber Cancer Institute
Harvard Medical School
Email: [email protected]
617-632-3857
Outline
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Maintenance therapy
Recurrent Ovarian Cancer
Platinum-Sensitive Recurrence
Platinum-Resistant Recurrence
Biologic Therapies for Ovarian Cancer
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Anti-angiogenics
PARP-inhibitors
PI3 kinase inhibitors
Completion of Upfront Therapy
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Despite aggressive primary therapy and high
initial response rates, most women with
advanced ovarian cancer ultimately develop
drug-resistant disease.
In recurrent setting, chemotherapy response
rates are substantially diminished.
Need to develop better therapeutic agents and
strategies.
Goals of Maintenance Therapy
End of therapy:
1st remission, 2nd remission,
or later remissions…
Documented
Progression
CA125 rising
Maintenance agent:
biologic, chemotherapy,
immunotherapeutic, etc.
Improvement in PFS due to
maintenance therapy
Documented
Progression On
Maintenance
Completion of Upfront Therapy
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Several drugs are being tested for
maintenance therapy after 1st-line therapy and
subsequent lines.
There is no standard of care for use of
maintenance therapy.1
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Foster et al, Gyn Onc 115:290-301, 2009.
Evidence: Maintenance
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Adding single agent topotecan has no benefit.
Adding single agent paclitaxel x 1 year
improves PFS by 7 months (21 versus 28).
NO survival advantage (GOG 178).
Neuropathy.
GOG 212: Ongoing (taxol vs. CT-2103 vs.
placebo)
Several other biologics are being tested in the
maintenance setting for either 1st or 2nd
remission (PARP inhibitors, anti-angiogenics)
Approaches to Maintenance Rx:
Biologics
Immunotherapies
Anti-VEGF
Bevacizumab
Sorafenib
BIBF1120
Cediranib
Enzastaurin
DNA repair inhibitors
Olaparib (AZD2281)
Hedgehog inhibitors
GDC-0449
Anti-Folate drugs
MORAb-003
EC145
HDAC inhibitors
Vorinostat (ph Ib/II)
NY-ESO-1 OLP4
Oregovomab
OPT-821 (adjuvant)
DTA-H19 (plasmid containing gene for Dipth
toxin A)
EMD 273066
Others
Chemotherapy
IT-101
Anticoagulants:
Fondaparinux
Upfront/Maintenance: GOG 218
Optimal or Suboptimal
EOC, PPC, FT cancer
Paclitaxel
Paclitaxel
Paclitaxel
Carboplatin Carboplatin Carboplatin
Placebo Bevacizumab Bevacizumab
Placebo
Placebo Bevacizumab
×15 months ×15 months ×15 months
Survival, PFS primary endpoints
Biologic & QOL endpoints
EOC = Epithelial ovarian cancer; PPC = Primary peritoneal cancer; FT = Fallopian tube; PFS = Progression-free survival;
QOL = Quality of life.
Recurrent Ovarian Cancer
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Most women (>80%) with advanced ovarian cancer
will recur within 6-24 months post-diagnosis.
Recurrences often present as asymptomatic rises in
CA125
Controversial whether to treat CA125 elevations.1
Recurrent ovarian cancer is characterized by
increasing platinum and chemotherapy resistance.
Death occurs via recurring bowel obstructions and
malnutrition, PE.
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Rustin GJ et al, J Clin Oncol 27(18s):Abstr 1, 2009.
Choices of Treatment
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Time since diagnosis
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Platinum sensitivity
Type of recurrence
Asymptomatic vs. symptomatic
Clinical trial availability
Toxicities of prior chemotherapy
Comorbidities
Patients’ treatment preferences
Platinum Sensitivity
P
R
E
V
I
O
U
S
T
R
E
A
T
M
E
N
T
0
3
6
12
18
24
Refractory
Resistant
Sensitive
Markman et al, JCO 1991
Treatment for Recurrent Disease
Recurrence
Platinum-sensitive
Platinum-resistant
Platinum doublets
- liposomal dox
- gemcitabine
- taxane
Single agent:
- doxil
- topotecan
- gemcitabine
- paclitaxel, weekly
- bevacizumab
- others: hexalan
VP-15, cytoxan, IFF
navelbine.
NCCN guidelines, 2009
ICON IV: Carboplatin vs. Carbo/Tax
Median PFS: 9 vs. 12 months
Median survival: 29 vs. 24 months
Median follow-up: 42 months
OR: 54 vs. 66% (P = .06)
Ledermann JA. Lancet. 2003;361:2099-2106.
AGO-OVAR-2.5: Carboplatin vs. Carboplatin
and Gemcitabine
• Recurrent ovarian cancer
R
A
• Strata
N
D
– PFI (6 - 12, > 12 months)
O
– 1st-line therapy (platinum M
± paclitaxel)
I
Z
– Measurable vs. evaluable
E
• Primary endpoint = PFS
• 6+ months after platinum
Gemcitabine 1,000 mg/m2
days 1 + 8
*
Carboplatin AUC 4 day 1
Every 21 days
× 6 (–10)
Carboplatin AUC 5 day 1
Every 21 days
× 6 (–10)
Pfisterer J, et al. JCO 2006
AGO-OVAR-2.5
1.0
Hazard ratio = 0.72 (95% CI: 0.57, 0.90)
Log-rank P value = .0031
0.9
Progression-Free Probability
0.8
0.7
0.6
Median = 5.8 mo (5.2 - 7.1 mo)
Median = 8.6 mo (8.0 - 9.7 mo)
0.5
Cb 178 pts / 162 evts
GCb 178 pts / 163 evts
0.4
0.3
0.2
0.1
0.0
0
Pts at risk
178
178
6
12
18
24
30
36
42
months
82
125
29
47
10
17
5
5
4
1
2
0
1
0
Cb
GCb
AGO-OVAR-2.5
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No overall survival benefit to Carboplatin +
Gemcitabine vs. Carboplatin alone (18.0
months vs. 17.8 months, p=0.73)
More bone marrow suppression (anemia
22.3% vs. 5.7%, neutropenia 41.7% vs.
10.9%, thrombocytopenia 30.3% vs. 10.3%)
CALYPSO Study Schema
International, Intergroup, Open-label, Randomized Phase III Study
Ovarian cancer in late
relapse (> 6 months)
after 1st- or 2nd-line
platinum-based therapy
(previous taxane
required)
R
A
N
D
O
M
I
Z
E
Experimental arm: CD
PLD 30 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Q 28 days x 6 courses*
Control arm: CP
Paclitaxel 175 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Q 21 days x 6 courses*
*or progression in patients with SD or PR
ASCO 2009
CALYPSO: PFS improved
Median PFS, mo
HR (95% CI)
CD
CP
11.3
9.4
0.82 (0.72, 0.94)
Log‐rank p‐value (superiority)
0.005
P‐value (non‐inferiority)
<0.001
Carboplatin/liposomal dox
Carboplatin/paclitaxel
CALYPSO: Toxicities (non-Heme)
CD (n=466)
Toxicity
CP (n=501)
Grade 2
Grade 3/4
Grade 2
Grade 3/4
Nausea/vomiting*
31%
4%
20%
4%
Constipation
19%
2%
20%
2%
Diarrhea
4%
2%
6%
2%
Arthralgia/myalgia*
4%
0%
18%
1%
Hand-foot syndrome*
11%
2%
2%
0%
Mucositis*
13%
2%
6%
1%
Fatigue
31%
7%
34%
7%
Grade 2 alopecia*
7%
-
84%
-
Cardiac disorders
2%
1%
3%
1%
*P< 0.001
*P< 0.001
CALYPSO: Toxicities (Heme)
CD (n=464)
Toxicity, grade
Neutropenia, grade 3
CP (n=500)
Number of patients (%)
P Value
144 (31)
121 (24)
20 (4)
108 (22)
Febrile neutropenia, gr 3-4
10 (2)
21 (4)
NS
Infection, grade 3-4
11 (3)
14 (3)
NS
Thrombocytopenia, grade 3-4
73 (16)
31 (6)
<0.01
Bleeding, grade 3-4
3 (0.6)
0 (0)
NS
Anemia, grade 3-4
37 (8)
27 (5)
NS
grade 4
<0.01
Platinum Resistant Recurrence
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No best drug exists with regards to efficacy
FDA approved ones are topotecan and liposomal
doxorubicin (doxil)
RR of non-platinum drug depends on degree of
platinum sensitivity
RR around 10-20%
Problem with platinum re-use is accumulating
toxicities and allergies.
Duration of response <3 months
Platinum Resistant Recurrence
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VP-16
Navelbine
Gemzar
Taxanes
Hexalan
Cytoxan
5-FU
Hormonal agents – AI’s, tam.
Biologic Therapies for
Ovarian Cancer
Targeting Growth/Survival Pathways
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Mutations and amplifications send signals for
abnormal growth and survival in cancer cells
Targeted therapies are directed specifically
against these signaling pathways
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Greater specificity against cancer cells
Reduced toxicity to patients
Sub-classification of Ovarian Cancers
Low grade
serous
tumors
BRCA+ cancers
All epithelial
ovarian
cancers
PI3kinase
VEGF-driven
tumors
Thru 2008: all
treated the same.
Clear cell
cancers
All other
ovarian
cancers
2009 and moving forward:
VEGF-Directed Therapies
Kowanetz, M. et al. Clin Cancer Res 2006.
Single Agent Bevacizumab
Study
# pts Plat status
RR
Median
PFS
Burger et al,
JCO 2007
62
42% plat res
58% plat sens
21%
4.7 mos 17 mos
All resistant.
83.7% 1° plat
resistant
15.9%
4.4 mos 10.7 mos 11.4% GI
perforations
Cannistra et 44
al, JCO 2007
Median
OS
Toxicities
No GI
perforations
Bevacizumab Combination Therapies
Study
Trial design
Eligibility
# of pts/plat
status
Results
Toxicities
Garcia et
al, JCO
Phase II
bevacizumab 10
mg/kg + cytoxan
50 mg/day PO
Recurrent
ovarian, up to 2
lines of tx for
recurrence
40% plat
resistant
60% plat
sensitive
24% ORR
7.2 months PFS
16.9 months OS
4 GIP and 2
CNS events.
Nimeiri et
al, Gyn
Onc, 2008
Ph II
bevacizumab 15
mg/kg IV +
erlotinib 150 QD
Recurrent/refro
varian, up to 2
lines for
recurrence
13 patients
15% ORR
2 responses
7 SD
2 fatal GIP’s
and study
was closed.
PS of 0 or 1. no
line limit.
(Median=4).
39 pts; 13
ovarian
cancer
46% PR
6/13 EOC pts
2 EOC pts
developed
fistulas. Fatal
hemoptysis.
Azad et al, Ph I of
bevacizumab +
JCO
oral sorafenib
26:3709
PARP Inhibitors: Synthetic Lethality
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PARP: poly (adenosine diphosphate
ribose)(ADP) polymerase
PARP1 activity is required for base-excision
repair (BER), a DNA-damage repair pathway
that recognizes and eliminates DNA bases
damaged by oxidation.
BER is a process that occurs thousands of
times during each normal cell cycle.
PARP Inhibitors: Synthetic Lethality
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BRCA1 and BRCA2 genes recognize and repair
DNA double-stranded breaks, through Homologous
Recombination.
Cells that are deficient in BRCA1 and 2 proteins
become genetically unstable.
“Single-stranded” repair takes over and PARP is an
enzyme that is important in this repair type.
PARP inhibitors block single-strand repair causing
tumor cells to undergo apoptosis.
PARP Inhibitors: Synthetic Lethality
PARP Inhibitors
Ratnam, K. et al. Clin Cancer Res 2007
Olaparib: oral PARP inhibitor recurrent ovarian
Total
Platinum
sensitive
Platinum
resistant
Platinum
refractory
# of patients
46
10
25
11
Response by
RECIST
13 (28%)
5 (50%)
8 (32%)
0
GCIG CA125
18 (39%)
8 (80%)
8 (32%)
2 (18%)
Either RECIST
or CA125
21 (46%)
8 (80%)
11 (44%)
2 (18%)
SD (> 4 mos)
6 (13%)
1 (10%)
4 (16%)
1 (9%)
Median
response
24 weeks
(10-77 weeks)
23 weeks
(16-77 weeks)
24 weeks
(10-65 weeks)
26
(20-32 weeks)
ASCO 2008; 5510, NEJM 2009
Common PARP Toxicities
Toxicity
Grade 1-2
Grade 3-4
Nausea
21 (64%)
2 (6%)
Fatigue
17 (52%)
1 (3%)
Diarrhea
12 (37%)
0
Vomiting
11 (33%)
2 (16%)
Abdominal pain
9 (27%)
1 (3%)
Audeh et al, abs 5500 ASCO 2009
PARP Inhibitors in Development
Company
Drug Name
Clinical studies
Kudos
(Astrazeneca)
AZD2281 (PO)
Ph 1: carbo + 2281
Ph 1: cisplatin + 2281
Ph 2: 2281 versus liposomal doxorubicin
Ph 2: maintenance
Ph 2: carbo + taxol + 2281 (plat-sens)
MGI/Eisai
E7016 (PO)
Ph 1: drug alone in pts with BRCA-def breast and
ovarian cancer
Abbott
ABT888 (PO)
CTEP: carbo/paclitaxel + ABT888
CPT-11 + ABT-888
Pfizer
AG014699
Ph 2: AG014699 for recurrent breast and ovarian
cancer (non-BRCA-def pts) (UK sites only).
BiPar
BSI-201 (IV)
BSI-401 (PO)
Ph 1b: topotecan + BSI-201
Ph 2: BSI-201 in BRCA-def. recurrent ov cancer
Ph2: carbo + gem + BS-201 (plat sens/resis)
PI3K/AKT pathway
PI3K/AKT pathway
PI3K/AKT pathway in gynecologic
malignancies
Lost in 50% uterine
Mutation:
•30% uterine
•10% ovarian
Amplification:
•30% ovarian
•70% cervical
Activated in 70%
ovarian
PI3K/AKT pathway inhibitors
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mTOR inhibitors (Phase II trials)
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Active in uterine cancer
30-40% clinical benefit
PI3K inhibitors (Phase I trials)
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Ovarian cancer
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Uterine cancer
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Stable disease >6 months
Response close to 12 months
Stable disease >3 months
AKT inhibitors (Phase I trials)
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3/3 ovarian cancer patients with decrease in CA125
Small molecule TKIs
Other Biologics Being Tested
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HER family inhibitors
Hedgehog inhibitors
Notch signaling pathway inhibitors
Anti-folate receptor agents
Summary
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At diagnosis, ovarian cancer remains one of the most
chemotherapy-sensitive cancers.
After recurrence, ovarian cancer becomes more and
more chemotherapy resistant.
As our basic understanding of the disease
(pathogenesis) and ovarian cancer subtypes improve,
opportunities to develop more rationale drug strategies.
Newer therapies are needed for both newly diagnosed
cancer as well as recurrent ovarian cancer. Newer
biologics are being tested.
HER Family Inhibitors
Drug
Target
Mechanism
Route
Small molecule tyrosine kinase inhibitors
CI-1033
HER1,HER2,
HER3,HER4
acts directly with the ATP binding
site of EGFR family and blocks
activation/signaling of receptors.
PO
Lapatinib
EGFR, HER2
Blocks activation/signaling of EGFR
and HER2.
PO
IV
Monoclonal Antibodies
Trastuzumab
HER2
signaling
Blocks HER2 dimer signaling
Pertuzumab
HER2/HER3
signaling
Blocks HER2/HER3 signalling
Heat shock protein inhibitors
17-AAG
HSP90 →
HER2
Reduces stability of HER2 leading to
decreased signaling
IV