State of the Art in Ovarian cancer

Jan B. Vermorken, MD, PhD

Department of Medical Oncology

Antwerp University Hospital

Edegem, Belgium

3rd EASO Masterclass in Clinical OncologyAmman, 2011

Epithelial Ovarian CancerEpidemiology

• The crude incidence of ovarian cancer in the European Union is 18/100.000 women per year, the mortality is 12/100.000 women per year

• The median age at diagnosis is 63 years. The incidence increases with age and peaks in the 8th decade. Between the age of 70-74 years the age-specific incidence is 57/100.000 women per year

* ESMO minimum Clinical Recommendations

Ann Oncol 19 (suppl 2): ii14-ii16, 2008

Five-year Survival in Ovarian Cancer30 years of experience

Vol. Year Cases Ia IV Overall

(n) %

16 1963-68 4588 66.7 5.0 27.3

19 1976-78 6724 72.3 4.5 29.8

21 1982-86 10912 82.3 8.0 35.0

23 1990-92 7059 83.5 11.1 41.6

25 1996-98 4116 89.3 13.4 46.4

26* 1999-01 4911 89.3 18.6 49.7

Int. J Gynecol Obstet 2006 (Suppl 1)

Epithelial Ovarian CancerMilestones

• Surgery according to FIGO guidelines– At least LNS and peritoneal staging in early

ovarian cancer– Upfront maximal surgical debulking in advanced

ovarian cancer• Chemotherapy evolution

– Introduction of platinum compounds– Introduction of taxanes

• The set-up of the GCIG in 1997

Epithelial Ovarian CancerMilestones

http://ctep.cancer.gov/resources/gcig/index.html

Are There Any New Developments in Early Ovarian Cancer?

FIGO I-IIa

• Grade and completeness of staging are the most strongest prognostic factors

• Low risk patients do not need chemotherapy as an adjuvant treatment (5-yr survival ≥ 95%)

• High-risk patients do need adjuvant platinum-based chemotherapy: combined analysis of ICON-1 and ACTION trial* showed 5-yr OS 82%vs 74%, p=.008

• Three vs six cycles: no significant difference in outcome, but recurrence rate with 6 cycles was 24% lower than with 3 cycles, and significantly more toxicity

*Trimbos et al, JNCI 2003Bell et al, Gynecol Oncol 2006

Prognostic Factors in Advanced-Stage Ovarian CancerStages IIb-IV

Postsurgery During RelapsePre-chemotherapy Chemo • Residual disease Type of chemo Time since last CT• Performance status CA 125 fall Disease bulk• Stage Interval debulking Histology• Grade No. disease sites• Age Perf. Status• Ascites Time since DX• Histology• Proliferation markers• Quantitative pathol. features• Ploidy• Molecular markers (unclear)

Eisenhauer et al, 1999 (modified)

Management of Advanced-Stage Ovarian Cancer

Stages IIb-III (IV)

• Upfront radical cytoreductive surgery

• In case this is not possible, a second attempt should be made

• Platinum-based chemotherapy

• Six cycles

• No second-look

Consensus meeting, 1998 Bergen (the Netherlands)

Optimal First-line Chemotherapy in ADOVCA: Historical Perspective

1970 1975 1980 1985 1990 1995/1997

L-Pam AC CHAP CHAC (C)P TP/TC

VAC HAD EP (C)C TEC

HexaCAF CAP CEP CEP DEC

HexaCAP CAC CAP

HexaMM

Alkylating Cisplatin Carboplatin PaclitaxelAgents

Doxorubicintopotecan?, LPD?gemcitabine?

Epirubicin

Advanced Ovarian Cancer1998-2011 Treatment

• Paclitaxel + Carboplatin (TC)– Generally agreed standard– “Control Arm” of all recent randomized trials– No other regimen shown to outperform it

• However, results far from perfect:– Median TTP: 15-18 mo– Median OS: <3 yrs

Standard of Care

Optimal Surgery

( = «  No residual Disease » )

+ TC Chemotherapy

Lessons from Studies of Histotype

• Histotype matters

• Mucinous, endometrioid and clear cell cancers are distinct entities with different genetic changes, gene expression profiles and sensitivities to chemotherapy

• Separate trials will be required

• Recent discoveries in clear cell cancer suggest changes in chromatine remodeling may provide a target

Bast, presented at Valencia meeting 2011

How to Improve Outcome in Advanced OCBeyond PAC-CARBO

• Increase rate of optimal cytoreduction (definition ODS)– concept of NACT– role for interval debulking?

• Increase efficacy of cytotoxic chemotherapy– adding a third drug– maintenance/consolidation therapy– dose-dense therapy

• Modulate resistance– modulating agents– increase dose / exposure (systemic / regional)

• The use of targeted therapies

New Data for Advanced Ovarian Cancer

• NACT an alternative for not optimal resectable FIGO IIIc (Vergote et al, NEJM 2010)

• No benefit from adding a third drug to TC

• No role for consolidation/maintenance cytotoxic CT?1 study positive for PFS (12 vs 3 cycles paclitaxel PFS 28 vs 21 months, p<.005): Markman et al, JCO 2003)

• Dose dense TC superior (JGOG study)Confirmatory studies ongoing

• IP therapy finally recognized

Targeted Therapies in Ovarian Cancer

Target Drug(s)

ErbB kinases Gefitinib, erlotinib, lapatinib, canertinib, cetuximab,

pertuzumab, matuzumab, trastuzumab

MUC1 / PEM Pemtumomab

MUC16 (CA 125) Oregovomab

mTOR / AKT Temsirolimus, everolimus, deforolimus

Apoptosis pathway AEG35156, OGX-011

Angiogenesis Bevacizumab, sunitinib, sorafenib, pazopanib, cediranib, vatalanib

Endothelial cells Combretastatin, Oxi4503

Matrix metalloproteinases BAY 12-9566, marimastat

First-Line Trial of Bevacizumab in Ovarian Cancer (GOG#218)

Stage III°

Optimal and

Suboptimal or

Stage IV

RANDOMIZE

Paclitaxel/Carbo (PC) + placebo x6

placebo x16

PC+bev* x6 placebo x16

PC+bev x6 bev x16

*Dose of bevacizumab 15 mg/kg q 3 weeks

°Total number of patients 2000

Key Results There is clear clinical effect of bevacizumab on PFS

• Per protocol analysis:

– Significant improvement of PFS in Arm III only

– Per protocol analysis: 3.8 mo increase PFS (med)HR 0.717, p <0.0001

– ~ half of all progression events occurred on therapy

Pro

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Months from randomization

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

+ BEV (Arm II)

Chemo (Arm I)

+ BEV → BEV maintenance (Arm III)

• CA 125 censored PFS (sensitivity analysis):CA 125 censored PFS (sensitivity analysis):– Similar outcomes (HR 0.645), but 25% fewer events Similar outcomes (HR 0.645), but 25% fewer events

• Overall survival and QoL: to be discussedOverall survival and QoL: to be discussed

First-Line Trial of Bevacizumab in Ovarian Cancer (ICON - 7)

Stage Ic - IV°

Excluding those scheduled for further surgery

RANDOMIZE

Paclitaxel/Carbo (PC)

PC+bev* x6 bev x12

*Dose of bevacizumab 7.5 mg/kg q 3 weeks

°Total number of patients 1500

ICON-7: PFS

http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf Accessed 15 October 2010

Academic analysis

Number at riskControl 234 205 98 36 14 2Research 231 213 159 56 10 1

Number at riskControl 234 205 98 36 14 2Research 231 213 159 56 10 1

PFS: FIGO stage III suboptimal and FIGO stage IV with debulking

1.00

0.75

0.50

0.25

0

1.00

0.75

0.50

0.25

0

Pro

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alive w

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Time (months)Time (months)0 3 6 9 12 15 18 21 24 27 300 3 6 9 12 15 18 21 24 27 30

Control(n=234)

Research (n=231)

Events, n (%) 173 (74) 158 (68)Median, months 10.5 15.9Log-rank test p<0.001Hazard ratio (95% CI) 0.68 (0.55–0.85)Restricted mean 13.3 16.5

10.5 15.9

ControlResearch

http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf Accessed 15 October 2010

Kristensen G. et al, ASCO 2011, abstract #LBA5006

Kristensen G. et al, ASCO 2011, abstract #LBA5006

GOG #218: Patient Inconvenience and Toxicity

• 23% risk of developing grade 2 hypertension

• 10% risk for grade 3 to 4 hypertension

• 2.3% risk for ≥ grade 3 GI perforationhemorrhagefistula formation

GOG #218: Cost-Effectiveness

• Based on PFS and bowel perforation rates• Incremental cost-effectiveness ratios (ICERs) per PF live-year saved (PF-LYS)

were estimated

• For the 600 patients entered onto each arm of GOG #218:

Cohn DE et al, J Clin Oncol 2011; 29: 1247-1251

Treatment Total Cost ICER ($) ICER per PF-LYS ($)

TC 2.5 M 247.616 Referent

TCB 21.4 M 1.9 M 479.712

TCB + B 78.3 M 5.6 M 401.088

Recurrent Ovarian Cancer: Important Issues

• Presentation (asymptomatic 55-70%; TFI*)

• Realistic goals

• When to treat

• How to treat

• New combinations and compounds

*<6 months; 6-12 months; <12 months

Realistic Goals of Second-line Therapy in Ovarian Cancer

• Improve cancer-related symptoms

• Optimize overall quality of life

• Delay time to symptomatic disease progression

• Prolong overall survival

• Achieve an “objective response”

Markman M, 2002

Harries and Gore, 2002

When to Treat?

Trial Design

Ovarian cancer in complete remission after first-line platinum based chemotherapy

and a normal CA125

CA125>2 x upper limit of normalRANDOMIZED

Early treatmentClinician and patient informed

Delayed treatmentClinician not informed, treatment delayed until clinically indicated

REGISTERBlinded CA125 measured

every 3 months

Rustin GJ et al, Lancet 2010; vol 376: 1155-1163

Overall Survival

HR=1.00 (95%CI 0.82-1.22) p=0.98

EarlyDelayed

Abs diff at 2 years= 0.1% (95% CI diff= -6.8, 6.3%)

Rustin GJ et al, Lancet 2010; vol 376: 1155-1163

Time from Randomisation to FirstDeterioration in Global Health Score

(or death)P

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Number at risk

Rustin GJ et al, Lancet 2010; vol 376: 1155-1163

Chemotherapy Options in Platinum-Sensitive Recurrent Ovarian Cancer (ROC)

• Traditionally, ROC patients with TFI > 6 mo have been retreated with platinum-based chemotherapyICON-4 trial: Platinum/paclitaxel > Pt-alone (PFS, OS )

• Cumulative toxicity from primary therapy (neuro) can preclude retreatment with paclitaxel/carboplatin– AGO OVAR 2.5: carbo/gemcitabine vs carbo (PFS )– OCEANS: carbo/gemcitabine ± bevacizumab (study)– CALYPSO: PLD/carbo vs paclitaxel/carbo (PFS )

OCEANS Trial : a Randomized, Double-Blind Placebo-Contr. Ph III Trial of CT +/- Bev

In Platinum (Pt) –Sensitive Recurrent EOC

Stratification variables:

• Platinum-free interval (6–12 vs >12 months)

• Cytoreductive surgery for recurrent disease (yes vs no)

Gemcitabine 1,000mg/m2, days 1, 8 q3w

Carboplatin AUC4 q3w

Gemcitabine 1,000mg/m2, days 1, 8 q3w

Carboplatin AUC4 q3w

Platinum-sensitive recurrent ovarian

cancer• Measurable disease• ECOG PS 0/1• No prior

chemotherapy for recurrent disease

• No prior Avastin(n=484)

Placebo q3w

Avastin 15mg/kg q3w

Carboplatin/gemcitabine for 6 (up to 10) cycles

PD

PD

Aghajanin C et al –MSKCC (LBA # 5007)

PFS PFS ??

Main reason for discontinuation of Bev = PD

CALYPSO (n=973 patients)

PLD 30 mg/m², d1Carbo AUC 5

PACL 175 mg/m², d1Carbo AUC 5, d1

Efficacy*PFS 11.3 mo PFS 9.4 mo*

ToxicityPLT, HFS, nausea**mucositis

ANC, alopecia, HSR**sensory neuropathy

*HR 0.82 (95% CI 0.72-0.94), p=0.005**p<0.01Pujade-Laurain et al, J Clin Oncol 2010; 28: 3323-3329

q 4 wks q 3 wks

Chemotherapy Options in Platinum-Resistant Recurrent OC or for those with Partially

Platinum-Sensitive Disease (TFI 6-12 mo)

• Numerous agents are available that can be used as a single agent: – gemcitabine, PLD, topotecan, paclitaxel, docetaxel,

oral etoposide, altretamine, trabectedin, and hormonal agents

• Take into consideration the patient’s anticipated tolerability and cumulative toxicity from front-line therapy

Trabectedin – Structure and Origin

Scotto. Anticancer Drugs 2002; 13 (Sup 1): s3-s6

A

B

C

Trabectedin Structure: 3 tetrahydroisoquinolone rings

• Trabectedin (ET-743; Yondelis®) is a novel, marine-derived anticancer agent originally isolated from marine Caribbean tunicate Ecteinascidia turbinata and is now produced synthetically.

• Chemically comprised of three fused rings (A, B and C), each of them with one or more different functions.

An Open-label Multicenter Randomized Phase 3 Study Comparing DOXIL/CAELYX and

Trabectedin with DOXIL/CAELYX Alone in Advanced ROC

Advanced Recurrent Epithelial Ovarian Cancer

– One prior regimen– Evaluable and measurable

disease– Platinum-sensitive and -

resistant

Accrual Goal: 650 patientsPrimary endpoint: PFS/OSOther endpoints: RR, Safety

Translational Research:• Pharmacokinetics• Pharmacogenomics• Pharmacoeconomics• Quality of Life• Circulating tumor cells

RANDOMIzE

doxil 50 mg/m2 every 4 wks

doxil 30 mg/m2 plustrabectedin 1.1mg/m2

every 3 wks

Monk BJ et al, J Clin Oncol 2010; 28(19):3107-14.

Monk BJ et al, J Clin Oncol 2010; 28(19):3107-14.

An Open-label Multicenter Randomized Phase 3 Study Comparing

DOXIL/CAELYX and Trabectedin with DOXIL/CAELYX Alone in Advanced ROC

Monk BJ et al, submitted

PARP Inhibitors

• Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a key enzyme in the repair of DNA. Inhibition of PARP leads to accumulation of breaks in DS-DNA and cell death.

• PARP inhibitors are in particular exciting in cancers with germline mutations in the BRCA gene, but benefit might be wider (> 50% of patients with high-grade sporadic EOC possibly have loss of BRCA function

– Continuous oral olaparib (AZD 2281) 57.6% clinical benefit

– Phase II ongoing in platinum-sensitive serous OC after 2 or more platinum-containing regimen

Phase 2 Randomized Placebo-controlled Study of Olaparib in Pts with Platinum-

Sensitive relapsed Serous OCLedermann J et al (# 5003)

n = 265n = 265

Phase 2 Random. Placebo-controlled Study of Olaparib in Pts with Platinum-Sensitive

Relapsed Serous OCLedermann J et al (# 5003)

• Overall survival data : immature• QoL : no ≠ in improvement / time to worsening

Take-Home Messages for ADOVCA

• Upfront surgery followed by 6 cycles of Pt-Tax-based CT is still standard

• Paclitaxel + carboplatin (TC) generally agreed standard arm for trials

• NACT followed by surgery in stages IIIc-IV OC showed the same OS and PFS as PDS with less morbidity in one large randomized GCIG trial.

• A dose-dense therapy approach may be of benefit• Intraperitoneal chemotherapy suitable for selected patients• Targeted therapy is promising (in particular anti-angiogenic

approaches), but not yet standard