OVARIAN CANCER :TARGETING THE UNTARGETABLE SUPERVISED BY PROF. DR SAMIR SHEHATA HEAD OF CLINICAL ONCOLOGY DEP. BY : SUMMER ELMORSHIDY ASSISTANT LECTURER OF CLINICAL ONCOLOGY

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

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

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?

Prognostic vs Predictive Biomarkers

PROGNOSTIC MARKERS : provide information about the overall outcome regardless of therapyStageResidual diseaseCA-125VEGF

Predictive biomarkers: provide information about the effect of a

therapeutic intervention ER/PR

HER2-neu

EGFR

BRCA: PARP inhibitors?

Met amplification: cMet inhibitors

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

Vascular Endothelial Growth Factor Signaling in the Pathogenesis of Epithelial Ovarian Cancer

VEGF: A Key Mediator of Angiogenesis

Increased VEGF levels

Environmental factors

(hypoxia, pH)

Growth factors, hormones

(EGF, bFGF, PDGF ,IGF-1, IL-1, IL-6,

estrogen

Genes implicated in tumorigenesis

(p53, p73, src, ras, vHL, bcr-abl

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 OXYGENATION .

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 )

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.

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.

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.

Rationale for Combination Anti-VEGF and Cytotoxic Regimens

Complementary, independent activity

Synergy in preclinical models Hypothetical mechanisms

Sensitization to apoptosisReversal of cytotoxic drug resistance

Increased access of chemotherapeutic—vascular “normalization”[2,3]

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.

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

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

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.

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.

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).

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.

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).

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.

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

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 .

Targeting EGF and Other Signal Transduction Pathways

Therapeutic Strategies

Small-molecule inhibitors: inhibit receptor TK domain

Monoclonal antibodies: against extracellular domain

Small Molecule TKIsAgent 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

Monoclonal Antibodies Against EGFR in Ovarian Cancer TrialsTrastuzumab Anti-HER2 HER2 overexpressing breast cancer

Cetuximab Anti-EGFR

HNCC, mCRCMatuzumab(EMD72000 Anti-EGFR

Panitumumab (ABX-EGF) Anti-EGFR EGFR-expressing mCRC

Pertuzumab (rhuMab 2C4) Anti-HER2

Cetuximab in Ph II Ovarian Cancer Trials

Relapsed platinum-sensitive ovarian cancer pts (N = 29)[1]

26 pts had EGFR+ tumors3 CRs, 6 PRs, 8 SDsTTP: 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 PDsMedian PFS: 1.8 mos;

median OS: 13.0 mosStudy terminated due to

inadequate number of responders

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

Pertuzumab + Gemcitabine in Perlatinum-Resistant Pts: Phase II Trial

Pertuzumab 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, respectively 4-month PFS: 49% vs 34% for the combination and gemcitabine arms,

respectively

PARP Inhibition

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.

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.

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

The challenge remains to develop a convenient and accurate method to identify ovarian cancers with BRCAness and, in particular, to identify patients likely to benefit from PARP inhibitor therapy.

Downstream Receptor Targeting: PI3K, mTOR, KRAS, BRAF, MEK

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.

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.

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

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

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)

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