new developments in the treatment of recurrent ovarian cancer and

New Developments in the Treatment of Recurrent Ovarian Cancer and

Evolving New TherapiesAlexi Wright, MD

Dana-Farber Cancer InstituteHarvard Medical School

Email: alexi_wright@dfci.harvard.edu617-632-3857

OutlineMaintenance therapyRecurrent Ovarian CancerPlatinum-Sensitive RecurrencePlatinum-Resistant RecurrenceBiologic Therapies for Ovarian Cancer

Anti-angiogenicsPARP-inhibitorsPI3 kinase inhibitors

Completion of Upfront TherapyDespite 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

CA125 rising

End of therapy:1st remission, 2nd remission, or later remissions…

Maintenance agent:biologic, chemotherapy,immunotherapeutic, etc.

Improvement in PFS due tomaintenance therapy

DocumentedProgression

DocumentedProgression OnMaintenance

Completion of Upfront TherapySeveral 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

1 Foster et al, Gyn Onc 115:290-301, 2009.

Evidence: MaintenanceAdding 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:BiologicsAnti-VEGFBevacizumabSorafenibBIBF1120CediranibEnzastaurinDNA repair inhibitorsOlaparib (AZD2281)Hedgehog inhibitorsGDC-0449Anti-Folate drugsMORAb-003EC145HDAC inhibitorsVorinostat (ph Ib/II)

ImmunotherapiesNY-ESO-1 OLP4OregovomabOPT-821 (adjuvant)DTA-H19 (plasmid containing gene for Dipth toxin A)EMD 273066

OthersChemotherapyIT-101Anticoagulants:Fondaparinux

Upfront/Maintenance: GOG 218Optimal or Suboptimal EOC, PPC, FT cancer

PaclitaxelCarboplatin

Placebo

PaclitaxelCarboplatinBevacizumab

PaclitaxelPaclitaxelCarboplatinCarboplatin

Bevacizumab

Bevacizumab ×15 months

Survival, PFS primary endpointsBiologic & QOL endpoints

Placebo×15 months

Placebo ×15 months

EOC = Epithelial ovarian cancer; PPC = Primary peritoneal cancer; FT = Fallopian tube; PFS = Progression-free survival; QOL = Quality of life.

Recurrent Ovarian CancerMost women (>80%) with advanced ovarian cancer will recur within 6-24 months post-diagnosis.Recurrences often present as asymptomatic rises in CA125Controversial whether to treat CA125 elevations.1Recurrent ovarian cancer is characterized by increasing platinum and chemotherapy resistance.Death occurs via recurring bowel obstructions and malnutrition, PE.

1 Rustin GJ et al, J Clin Oncol 27(18s):Abstr 1, 2009.

Choices of TreatmentTime since diagnosis

Platinum sensitivityType of recurrenceAsymptomatic vs. symptomaticClinical trial availabilityToxicities of prior chemotherapyComorbiditiesPatients’ treatment preferences

Platinum SensitivityPREVIOUS

TREATMENT

0 3 6 12 18 24

RefractoryRefractory

ResistantResistant

SensitiveSensitive

Markman et al, JCO 1991

Treatment for Recurrent DiseaseRecurrence

Platinum-sensitive

Platinum doublets- liposomal dox- gemcitabine- taxane

Platinum-resistant

Single agent:- doxil- topotecan- gemcitabine- paclitaxel, weekly- bevacizumab- others: hexalanVP-15, cytoxan, IFFnavelbine.

NCCN guidelines, 2009

ICON IV: Carboplatin vs. Carbo/Tax

Median follow-up: 42 monthsOR: 54 vs. 66% (P = .06)

Median PFS: 9 vs. 12 months

Median survival: 29 vs. 24 months

Ledermann JA. Lancet. 2003;361:2099-2106.

RANDOMIZE

Gemcitabine 1,000 mg/mGemcitabine 1,000 mg/m22

days 1 + 8days 1 + 8

Carboplatin AUC 4 day 1 Carboplatin AUC 4 day 1 Every 21 days Every 21 days ×× 6 (6 (––10)10)

•• Recurrent ovarian cancer Recurrent ovarian cancer

•• 6+ months after platinum6+ months after platinum

•• StrataStrata

–– PFI (6 PFI (6 -- 12, > 12 months)12, > 12 months)

–– 1st1st--line therapy (platinum line therapy (platinum ±± paclitaxel)paclitaxel)

–– Measurable vs. evaluableMeasurable vs. evaluable

•• Primary endpoint = PFSPrimary endpoint = PFS

AGO-OVAR-2.5: Carboplatin vs. Carboplatin and Gemcitabine

Carboplatin AUC 5 day 1 Carboplatin AUC 5 day 1 Every 21 days Every 21 days ×× 6 (6 (––10)10)

**

Pfisterer J, et al. JCO 2006

AGO-OVAR-2.5

Cb 178 pts / 162 evtsGCb 178 pts / 163 evts

Pro

gres

sion

-Fre

e P

roba

bilit

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 Pts at risk

178178

6

82125

12

2947

18

1017

24

55

30

41

36

20

42

10

months

CbGCb

Hazard ratio = 0.72 (95% CI: 0.57, 0.90)Log-rank P value = .0031

Median = 5.8 mo (5.2 - 7.1 mo)Median = 8.6 mo (8.0 - 9.7 mo)

AGO-OVAR-2.5No 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

Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line

platinum-based therapy (previous taxane

required)

International, Intergroup, Open-label, Randomized Phase III Study

RANDOMIZE

Experimental arm: CDPLD 30 mg/m2 IV d 1Carboplatin AUC 5 d 1

Control arm: CPPaclitaxel 175 mg/m2 IV d 1Carboplatin AUC 5 d 1

Q 28 days x 6 courses*

Q 21 days x 6 courses*

*or progression in patients with SD or PR

ASCO 2009

CALYPSO: PFS improvedCD CP

Median PFS, mo 11.3 9.4

HR (95% CI) 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)

*P< 0.001

CD (n=466) CP (n=501)Toxicity Grade 2 Grade 3/4 Grade 2 Grade 3/4Nausea/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

CALYPSO: Toxicities (Heme)

Toxicity, grade

CD (n=464) CP (n=500)

P ValueNumber of patients (%)

Neutropenia, grade 3

grade 4

144 (31)

20 (4)

121 (24)

108 (22)

<0.01

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

Platinum Resistant RecurrenceNo best drug exists with regards to efficacyFDA approved ones are topotecan and liposomal doxorubicin (doxil)RR of non-platinum drug depends on degree of platinum sensitivityRR around 10-20% Problem with platinum re-use is accumulating toxicities and allergies. Duration of response <3 months

Platinum Resistant RecurrenceVP-16NavelbineGemzarTaxanesHexalanCytoxan5-FUHormonal agents – AI’s, tam.

Biologic Therapies for Ovarian Cancer

Targeting Growth/Survival PathwaysMutations and amplifications send signals for abnormal growth and survival in cancer cellsTargeted therapies are directed specifically against these signaling pathways

Greater specificity against cancer cellsReduced toxicity to patients

Sub-classification of Ovarian Cancers

All epithelial ovarian cancers

Thru 2008: alltreated the same. 2009 and moving forward:

BRCA+ cancers

PI3kinase

VEGF-driventumors

Low grade serous tumors

Clear cell cancers

All otherovarian cancers

VEGF-Directed Therapies

Kowanetz, M. et al. Clin Cancer Res 2006.

Single Agent Bevacizumab

Study # pts Plat status RRMedian

PFSMedian

OS Toxicities

Burger et al, JCO 2007

62 42% plat res 58% plat sens

21% 4.7 mos 17 mos No GI perforations

Cannistra et al, JCO 2007

44 All resistant. 83.7% 1° plat resistant

15.9% 4.4 mos 10.7 mos 11.4% GI perforations

Bevacizumab Combination TherapiesStudy Trial design Eligibility # of pts/plat

statusResults 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 resistant60% plat sensitive

24% ORR7.2 months PFS16.9 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/refrovarian, up to 2 lines for recurrence

13 patients 15% ORR2 responses 7 SD

2 fatal GIP’s and study was closed.

Azad et al, JCO 26:3709

Ph I of bevacizumab + oral sorafenib

PS of 0 or 1. no line limit. (Median=4).

39 pts; 13 ovarian cancer

46% PR6/13 EOC pts

2 EOC pts developed fistulas. Fatal hemoptysis.

PARP Inhibitors: Synthetic LethalityPARP: poly (adenosine diphosphate ribose)(ADP) polymerasePARP1 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 LethalityBRCA1 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

Ratnam, K. et al. Clin Cancer Res 2007

PARP Inhibitors

Olaparib: oral PARP inhibitor recurrent ovarian

TotalPlatinum 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 ToxicitiesToxicity 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 DevelopmentCompany Drug Name Clinical studies

Kudos (Astrazeneca)

AZD2281 (PO) Ph 1: carbo + 2281Ph 1: cisplatin + 2281Ph 2: 2281 versus liposomal doxorubicinPh 2: maintenancePh 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 + ABT888CPT-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-201Ph 2: BSI-201 in BRCA-def. recurrent ov cancerPh2: carbo + gem + BS-201 (plat sens/resis)

PI3K/AKT pathway

PI3K/AKT pathway

PI3K/AKT pathway in gynecologic malignancies

Mutation:•30% uterine•10% ovarian

Amplification:•30% ovarian•70% cervical

Lost in 50% uterine

Activated in 70% ovarian

PI3K/AKT pathway inhibitorsmTOR inhibitors (Phase II trials)

Active in uterine cancer30-40% clinical benefit

PI3K inhibitors (Phase I trials)Ovarian cancer

Stable disease >6 monthsResponse close to 12 months

Uterine cancerStable disease >3 months

AKT inhibitors (Phase I trials)3/3 ovarian cancer patients with decrease in CA125

Small molecule TKIs

Other Biologics Being TestedHER family inhibitorsHedgehog inhibitorsNotch signaling pathway inhibitorsAnti-folate receptor agents

SummaryAt 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 InhibitorsDrug Target Mechanism RouteSmall molecule tyrosine kinase inhibitorsCI-1033 HER1,HER2,

HER3,HER4acts 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

Monoclonal AntibodiesTrastuzumab HER2

signalingBlocks HER2 dimer signaling IV

Pertuzumab HER2/HER3 signaling

Blocks HER2/HER3 signalling

Heat shock protein inhibitors17-AAG HSP90 →

HER2Reduces stability of HER2 leading to decreased signaling

IV