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New Developments in the Treatment of Recurrent Ovarian Cancer and
Evolving New TherapiesAlexi Wright, MD
Dana-Farber Cancer InstituteHarvard Medical School
Email: [email protected]
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
