2. Ovarian Cancer: Overview
Ovarian cancers are the second most frequent
malignancy in the United States
2008 estimates: 21,650 new cases, 15,520 deaths[1]
Account for 54% of all deaths from gynecologic cancers
Ovarian cancers present as stage III/IV disease in ~ 75% of
cases
No effective early diagnostic tests
Requires systemic therapy as the mainstay of treatment
Although the success rate with initial therapy has
improved, most patients will exhibit recurrent or
persistent disease and will require management beyond
initial therapy
3. Recurrent Ovarian Cancer:
Magnitude of the Clinical
Problem
Stage I/II
Essentially all patients will achieve a clinical CR after surgery and
chemotherapy
20% to 25% will relapse
Optimal stage III
> 90% will achieve a clinical CR
75% will recur
Suboptimal stage III/IV
50% will achieve a clinical CR
> 90% will recur
4. Management of Recurrent
Ovarian Cancer: Factors to
Consider
Goals of management
Prolongation of survival or PFS, objective
response, improved quality of life
Extent and nature of disease progression or
recurrence
Is secondary bulk reduction a sensible option?
Type and duration of response to previous
therapy
Is patient chemosensitive or chemoresistant?
Toxicity associated with previous therapy
and persistence at time of progression or
recurrence
Is residual toxicity present that might
necessitate a different systemic therapy?
6. Predictive biomarkers:
provide information about the effect of a
therapeutic intervention
ER/PR
HER2-neu
EGFR
BRCA: PARP inhibitors?
Met amplification: cMet inhibitors
7. Targeted Agents for
Chemoresistant
Disease
Significant activity
Bevacizumab
Tamoxifen
Insufficient activity to warrant further study
by GOG
Trastuzumab, human interleukin 12, gefitinib,
imatinib, lapatinib
Targeted agents still under investigation
with results not yet reported
Sorafenib, temsirolimus
10. Rationale for Targeting VEGF in
Treatment of EOC
Human tumors
VEGF expression and degree of tumor angiogenesis
(microvessel density) associated with
Ascites formation
Malignant progression
Poor prognosis
It was intially concieved as a means of depriving from oxygen
and nutrients.
However subsequent clinical studies demonstrated that inhibition
of angiogenesis may result in NORMALIZATION
OF TUMOR VASCULATURE AND
ENHANCING TUMOR
11. Rationale for Targeting VEGF in
Treatment of EOC (cont’d)
Preclinical models of solid tumors
Anti-VEGF therapy
Slowing of tumor progression
Resolution of malignant effusions
Synergy with cytotoxic agents( by normalization of
tumor vasculature increased oxygenation and
thereby enhanced delivery of cytotoxic drugs )
12. Single-agent bevacizumab in
recurrent ovarian cancer
Two single-agent phase II trials have explored the
utility of bevacizumab in the treatment of
persistent or recurrent disease:
The first and largest single-agent study was
conducted by the Gynecologic Oncology Group
(GOG).
In this trial 62 women with persistent or recurrent
EOC or primary peritoneal cancer received
bevacizumab monotherapy (15 mg/kg IV)
repeated every three weeks.
13. The study allowed up to two prior lines of
chemotherapy and 58% of patients had
platinum-resistant disease.
Encouraging activity was reported as
evidenced by an overall response rate of 21%
and median PFS and OS of 4.7 and 17
months, respectively. In addition, 40% of
patients remained progression-free at 6
months.
14. The second study evaluated the efficacy and
safety of bevacizumab in 44 patients with
platinum-resistant epithelial ovarian carcinoma or
peritoneal serous carcinoma who had
experienced disease progression during or within
3 months of discontinuing topotecan or PLD.
Almost 90% of patients had platinum-resistant
disease. Results included an objective response
rate of 15.9%, median PFS of 4.4 monthsAn
estimated 28% of patients remained progression-
free at 6 months.
15. Rationale for Combination Anti-
VEGF and Cytotoxic Regimens
Complementary, independent activity
Synergy in preclinical models
Hypothetical mechanisms
Sensitization to apoptosis
Reversal of cytotoxic drug
resistance
Increased access of
chemotherapeutic—vascular
[2,3]
16. Bevacizumab in combination with
chemotherapy in platinum-resistant ovarian
cancer
Recently, preliminary results of a phase III
randomized trial evaluating the role of
bevacizumab in platinum-resistant ovarian cancer
were presented at the annual meeting of the
American Society of Clinical Oncology [a
randomized phase III trial evaluating bevacizumab
(BEV) plus chemotherapy (CT) for platinum (PT)-
resistant recurrent ovarian cancer (OC).
{AURELIA}
In this trial 361 patients were randomized to
chemotherapy alone (PLD, weekly paclitaxel, or
topotecan) or with bevacizumab.
17. The primary endpoint of the study was PFS
while secondary endpoints included objective
response rate, OS, and safety.
The addition of bevacizumab significantly
improved PFS (6.7 months versus 3.4
months for chemotherapy alone). Objective
response rate increased from 12.6% with
chemotherapy alone to 30.9% with
chemotherapy and bevacizumab
18. According to the results of this trial ,,, THE
NCCN panel members recommend the
following combination regimens for platinum
resistant patients weekly regiemens of
Bev./paclitaxel
Bev./liposomal doxirubicin
Bev./topotecan
19. Bevacizumab plus
chemotherapy as front-line
treatment
The activity of single-agent bevacizumab
and the ability to combine it with
chemotherapy in recurrent ovarian cancer
led to studies exploring its use as front-line
therapy.
20. The first trial, GOG-0218, was a double-
blinded, placebo-controlled phase III study
enrolling 1873 women with previously
untreated stage III or IV EOC.
Patients were randomly assigned to one of
three groups after maximal surgical
cytoreduction: chemotherapy alone,
chemotherapy plus concurrent
bevacizumab, or chemotherapy plus
concurrent bevacizumab followed by
maintenance bevacizumab.
21. Median PFS, which was the primary endpoint
of the trial, was 10.3 months in the control
group, 11.2 months in the bevacizumab-
initiation group, and 14.1 months in the
bevacizumab-throughout group. The hazard of
progression or death was significantly lower in
the bevacizumab-throughout group compared
with the control group (p < 0.001).
22. The Gynecologic Cancer Intergroup (GCIG) International
Collaboration on Ovarian Neoplasms (ICON7) trial was an
open-label phase III randomized trial.
In this study 1528 women with high risk, early stage disease or
advanced EOC were randomized to chemotherapy alone
(carboplatin and paclitaxel) or chemotherapy with concurrent
bevacizumab, followed by 12 cycles of maintenance
bevacizumab or disease progression, whichever occurred
earlier.
23. PFS at 36 months was 20.3 months for
standard chemotherapy compared with 21.8
months for those who also received bevacizumab (p
= 0.04).
In updated analyses, PFS at 42 months was still
higher with bevacizumab compared with standard
chemotherapy (24.1 months versus 22.4 months; p =
0.04).
24. The results of these two studies led to the
approval by the European Commission of
bevacizumab in combination with standard
chemotherapy (carboplatin and paclitaxel) as a
front-line treatment for women with advanced
ovarian cancer.
However, it is important to note that no
improvement in OS has been reported in these
two studies. In addition, two independent cost-
effective analyses report that with no
improvement in OS the use of bevacizumab as
part of front-line therapy in ovarian cancer is not
cost effective.
25. Bevacizumab plus chemotherapy in recurrent
platinum-sensitive ovarian cancer
n addition to GOG-0218 and ICON7 a third phase III
randomized trial explored the use of bevacizumab in
combination with platinum-based chemotherapy;
OCEANS)
This study evaluated 484 women with platinum-
sensitive ovarian, primary peritoneal, or fallopian tube
cancer, who were randomly assigned to six cycles of
carboplatin plus gemcitabine, with or without
bevacizumab.
Preliminary results showed that PFS was significantly
longer for women given bevacizumab [12.4 months
compared with 8.4 months in the placebo-treated
group
26. Objective response rate increased by 21.1%
(p < 0.0001), from 57.4% in the placebo group
to 78.5% in the bevacizumab-treated group;
duration of response increased from a median
duration of response of 7.4 months to 10.4
months,
According to NCCN ,,, it is a category 2B
recommendation .
29. Small Molecule TKIs
Agent Target /Mechanism
Gefitinib EGFRTK/reversible inhibitor
Erlotinib EGFRTK/reversible inhibitor
Lapatinib ErbB1 and 2/reversible inhibitor
CI-1033 ErbB1, 2, and 4/ Pan reversible
inhibitor
EKB-569 ErbB1 and 2 TKs/ irreversible
30. Monoclonal Antibodies Against
EGFR in Ovarian Cancer Trials
Trastuzumab Anti-HER2
HER2 overexpressing breast cancer
Cetuximab Anti-EGFR
HNCC, mCRC
Matuzumab
(EMD72000 Anti-EGFR
Panitumumab (ABX-EGF) Anti-EGFR
EGFR-expressing mCRC
Pertuzumab (rhuMab 2C4) Anti-HER2
31. Cetuximab in Ph II Ovarian
Cancer Trials
Relapsed platinum-sensitive
ovarian cancer pts (N = 29)[1]
26 pts had EGFR+ tumors
3 CRs, 6 PRs, 8 SDs
TTP: 9.4 mos
First-line with paclitaxel and
carboplatin in advanced
ovarian cancer pts (N = 41)[2]
Median PFS: 14.4 mos;
18-mo PFS: 38.8%
Combination adequately
tolerated; no improved
PFS when compared with
historical data
Recurrent/persistent
epithelial ovarian or PPC
pts (N = 25)[3]
1 PR; 9 SDs; 12 PDs
Median PFS: 1.8 mos;
median OS: 13.0 mos
Study terminated due to
inadequate number of
responders
32. Trastuzumab and HER2
Overexpression: Ph II Study
Platinum-resistant, advanced ovarian cancer pts from
GINECO trial (N = 320) screened for HER2 status
All pts had received trastuzumab + paclitaxel or carboplatin
20 pts had HER2+ disease by IHC and FISH—7 eligible for
present study (measurable lesions: 4 pts; elevated CA-125
and no measurable lesions: 3 pts)
CR: 3 pts (6, 7+, 24+ OS); SD: 2 pts (3 mos)
Toxicity: febrile neutropenia, grade 3 infection, grade 2 neuropathy,
decreased LVEF (after 23 cycles)
Conclusion: trastuzumab + paclitaxel/carboplatin may
reverse platinum resistance in HER2+ pts with advanced
disease
33. Pertuzumab + Gemcitabine in
Perlatinum-Resistant Pts: Phase
II TrialPertuzumab is a humanized monoclonal antibody that inhibits human epidermal growth
factor receptor 2 (HER2) heterodimerization and has demonstrated clinical activity against
both breast and ovarian cancer. To date, it is the most extensively studied HER2 inhibitor in
ovarian cancer.
To date, pertuzumab is the most extensively trialled HER2 inhibitor in ovarian cancer, with
almost 400 patients having been treated in three large Phase II studies.
Patients (N = 133) randomly assigned to gemcitabine 800 mg/m2 on Day 1 and 8 of a 21-
day cycle with or without pertuzumab (840 mg initially, followed by 420 mg IV every 3
weeks)
Primary end point: PFS
Median PFS: 3.0 vs 2.6 months for the combination and gemcitabine arms,
35. Because only 10% to 15% of women who develop
ovarian cancer carry germline mutations of
BRCA1 or BRCA2,
PARP inhibitors were initially expected to benefit
only a small, but important, subset of ovarian
cancer patients with a strong family history of
breast and ovarian cancer.
However, recent data suggest that dysfunction of
BRCA1 and BRCA2, so-called BRCAness, may
be more prevalent than originally assumed.
36. Striking responses to polyadenosine diphosphate-
ribose) polymerase (PARP) inhibitors in patients
with inactivating germline mutations of BRCA1 or
BRCA2 have provided one of the best examples
to date of personalized therapy for ovarian cancer.
Inhibiting the ability to repair double-strand breaks
in DNA through homologous recombination
(HR).
In this setting, cancer cells are selectively
sensitized to inhibitors of other DNA repair
pathways, including base excision repair, a
process that requires PARP.
37. Data from phase I and II trials of PARP inhibitors in women with
germline mutations of BRCA1 and BRCA2 are quite promising, with a
40% objective response rate as single agents in ovarian and breast
cancers and acceptable toxicity.
AZD2281: oral, small molecule
Evidence of tumor response in ovarian cancer pts with BRCA mutation
46% (21/46) of pts responded to therapy (RECIST or GCIG CA125)
SD in 13% of pts
Total clinical benefit in 59%
Ongoing ph II trial of AZD2281 vs PLD in ovarian cancer pts with BRCA
mutation and a platinum-free interval of 0-12 mos
39. Phosphatidylinositol-3-kinases (PI3Ks) are key
regulators of many processes of the neoplastic
cell, including cell proliferation, survival, growth,
and motility.
Upstream receptor tyrosine kinases that feed
into the PI3K pathway include members of the
human epidermal growth factor receptor family
(EGFR and HER2), platelet-derived growth factor
receptor (PDGFR), and the insulin and insulin-
like growth factor 1 (IGF-1) receptors, among
others.
40. mTOR Inhibition in Gynecologic
Malignancies
Following the activation, PIP3 recruits other
downstream molecules, particularly the serin
threonine kinases AKT (also called protein kinase
B, PKB).
Akt stimulates protein synthesis and cell growth by
activating mTOR (mammalian target of rapamycin).
It influences cellular proliferation by inactivating
cell-cycle inhibitors (p27and p21), promoting cell-
cycle proteins (c-Myc and cyclin D1), and also
regulating a wide range of target proteins relevant
for apoptosis.
41. The levels of PIP3 are strictly regulated by
several phosphatases, the most relevant of
which is PTEN (phosphatase and tensin
homolog on chromosome 10), which
converts PIP3 back to PIP2.
Examples : everolimus and temisrolimus ,,,
they are still under trial
42. Temsirolimus + Topotecan: Ph I
in Gynecologic Malignancies
Pts with advanced/ recurrent gynecologic malignancies
(Ov: 5 pts; EM: 2 pts; uterine: 2 pts; Cx: 1 pt)
< 3 prior chemo regimens
Pts with/without whole-pelvis RT dose-escalated separately
Topotecan 1 mg/m2 d 1, 8, 15; temsirolimus 25 mg d 1, 8,
15, 22, 28 of a 29-d cycle
Combination not tolerable in pts with prior
pelvic RT
Best clinical response: SD in 6/7
evaluable pts
43. c-Met Inhibition in Ovarian
Cancer
Role of c-Met in ovarian cancer
Ovarian epithelial cells express higher c-Met levels as they
acquire genetic changes during neoplastic progression
c-Met expression level increased in ovarian cancer and
persists in cultured ovarian surface epithelial cells
Analysis of 138 advanced-stage ovarian cancer tissues c-Met
overexpression is a prognostic factor[
11% (15/138) of samples had c-Met overexpression
Median survival for pts with high c-Met levels was 17 vs 32
mos for those with low c-Met levels (P = .001)
44. Future Potential of Biologic and
Targeted Therapies
Except for bevacizumab, biologic and targeted
therapies have demonstrated poor single-
agent efficacy in ovarian cancer
Current studies focus on adding these agents
to traditional chemotherapy to increase the
apoptotic potential of the cytotoxic agent
There is an unmet need to identify predictive
markers to more efficiently cross the biology-
medicine in the care of women with ovarian
cancer
![Ovarian Cancer: Overview
Ovarian cancers are the second most frequent
malignancy in the United States
2008 estimates: 21,650 new cases, 15,520 deaths[1]
Account for 54% of all deaths from gynecologic cancers
Ovarian cancers present as stage III/IV disease in ~ 75% of
cases
No effective early diagnostic tests
Requires systemic therapy as the mainstay of treatment
Although the success rate with initial therapy has
improved, most patients will exhibit recurrent or
persistent disease and will require management beyond
initial therapy](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)