Targeted Therapy in Ovarian Cancer - UAB · Targeted Therapy in Ovarian Cancer Rebecca C. Arend, MD Division of Gyn Oncology 2015 US Female Cancer Statistics New Cases Deaths Lung

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Targeted Therapy in Ovarian CancerRebecca C. Arend, MDDivision of Gyn Oncology

2015 US Female Cancer Statistics

New Cases Deaths

Lung 105,590 71,660

Breast 231,840 40,290

Genital tract 98,280 30,440

Colon 47,200 23,600

Pancreas 24,120 19,850

New Cancer Diagnoses and Estimated Deaths in the U.S.

Tumor Type

PredictedCases

Predicted Deaths

Breast 234,190 40,730Breast 234,190 40,730

Uterine 54,870 10,170

Ovary 21,290 14,180

Cervical 12,900 4,100

Vulvar 5,150 1,080

Siegel R et al. CA Cancer J Clin 2015

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Histologic types of Epithelial Ovarian Cancer

•High Grade Serous (70%) – resembling fallopian tube

•Endometrioid (10%) – resembling endometrium (associated with endometriosis)

•Clear Cell (10%) – glycogen rich cells resemble ( ) g y gendometrial glands in pregnancy (associated with endometriosis)

•Mucinous (3%) – resembling endocervix

•Low Grade serous (<5%) – see above

•Transitional cell (<1%) – resembling bladder

Ovarian Cancer Statistics and Standard of Care in 2015

• 21,290 new cases and 14,180 deaths estimated in the US in 2015 ~75% diagnosed at late stage(stage III/IV)

• Most treated with surgical cytoreduction followed by• Most treated with surgical cytoreduction followed by adjuvant platinum‐ taxane based chemotherapy

• Most patients recur within 2 years and receive multiple rounds of chemotherapy

• 34% survive >10 years

34

46

58

70

CISPLATIN

AGGRESSIVESURGERY,

COMBINATION

viva

l (m

o)

Ovarian Cancer Ovarian Cancer -- Progress in OutcomeProgress in Outcome

IP THERAPY

-2

10

22

34

1975 1980 1985 1990 1995 2000 2005

YEAR

PACLITAXEL

CHEMOTHERAPY

Surv

Modified from David Spriggs

PACLITAXELCARBO

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FDA approved drugs for Ovarian Cancer ‐Timeline

1978 Cisplatin

1990 Altretamine

1991 Carboplatin

1992 Paclitaxel

19781978

1992 Paclitaxel

1996 Topotecan

1999 Liposomal Doxorubicin (Accelerated)

2005 Liposomal Doxorubicin (Full)

2006 Gemcitabine

2014 Bevacizumab

2014 Olaparib (BRCA mutation carriers)20152015

New Chemotherapy Approaches in Advanced Ovarian Cancer

• Intraperitoneal chemotherapy

• Neoadjuvant chemotherapyj py

• Dose dense taxanes

• Anti‐angiogenic therapy

• PARP inhibitors

Anti‐angiogenic therapy

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VEGF Inhibition

Biologically‐Targeted Drugs (Ovarian Cancer)

30

35

40

45

s(%

)

Bevacizumab

Sorafenib Temsirolimus

GOG 170 Series: Track Record

FDA Approval: November 2014

0

5

10

15

20

25

0 5 10 15 20 25Response Rate (%)

PFS ≥ 6 m

o

Vorinostat

Lapatinib

GefitinibImatinib

Enzastaurin

Mifepristone

Dasatinib

A6

Bevacizumab

• FDA approved for use in combination with chemotherapy in the treatment of women with platinum‐resistant, recurrent ovarian cancer

• Studied as primary therapy and consolidation with paclitaxel and carboplatin (GOG 218)

• Not FDA approved

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Angiogenesis as a target: Ovarian cancer

Study Agent Target HR‐PFS (95% CI)

HR‐OS (95% CI)

GOG 2181 Bevacizumab

VEGF Ligand

0.72 (0.63‐0.82) 0.89 (0.75‐1.04)

ICON72 Bevacizumab 0.81 (0.70‐0.94) 0.99 (0.85‐1.14)

AURELIA5 Bevacizumab 0.48 (0.38‐0.60) 0.85 (0.66‐1.08)

OCEANS7 Bevacizumab 0.53 (0.41‐0.70) 0.96 (0.76‐1.21)

GOG 2139 Bevacizumab 0 61 (0 52 0 72) 0 83 (0 68 1 005)

1. Burger RA et al. N Engl J Med. 2011;365:2473‒2483.2. Perren TJ et al . N Engl J Med. 2011;365:2484‒2496.3. du Bois A et al. J Clin Oncol. 2013;31(18suppl):LBA5503.4. du Bois A et al. LBA ESGO 2013 Liverpool, UK5. Pujade‐Lauraine E et al. J Clin Oncol.

2012;30(18suppl):LBA5002.6. Monk BJ, et all., LBA ESGO, Liverpool, UK7. Aghajanian C et al. J Clin Oncol. 2012;30:2039‒2045.8. Ledermann JA et al . Eur J Cancer. 2013;49(suppl):LBA 9. Coleman, RL, SGO 2015 LBA3

GOG‐2139 Bevacizumab 0.61 (0.52‐0.72) 0.83 (0.68‐1.005)

AGO‐OVAR123 Nintedanib

VEGFR, FGFR, PDGFR0.84 (0.72‐0.98) NR

AGO‐OVAR164 Pazopanib 0.77 (0.64‐0.91) 0.99 (0.75‐1.32)

ICON68 Cediranib VEGFR 0.57 (0.44‐0.74) 0.70 (0.51‐0.99)

TRINOVA‐16 Trebananib Ang ligand 0.66 (0.57‐0.77) 0.86 (0.69‐1.08)

Previously untreated epithelial

ovarian, primary peritoneal, or

fallopian tube cancer

• Stage III optimal (macroscopic)

RANDOM

1:1:1

Paclitaxel 175 mg/m2

Carboplatin AUC 6

Placebo

IArm

(CP + PLA → PLA)

Carboplatin AUC 6

l l / 2 II

Frontline Anti‐VEGF Therapy: GOG‐0218

• Stage III suboptimal

• Stage IV

n=1873

Stratification variables:• GOG performance status• Stage/debulking status

MIZ E

15 monthsCytotoxic (6 cycles)

Maintenance(16 cycles)

Paclitaxel 175 mg/m2

PlaceboBevacizumab15 mg/kg

II(CP + BEV→ PLA)

Bevacizumab 15 mg/kg

Carboplatin AUC 6

Paclitaxel 175 mg/m2 III(CP + BEV

BEV)

Burger et al. NEJM 2011

Frontline Anti‐VEGF Therapy: GOG‐0218

Burger et al., NEJM 2011

HR: 0.7310.4 vs. 13.9 mosMedian Δ: 3.5 mos

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Frontline ICON7: Similar findings for PFS

HR 0 81

Perren et al., NEJM 2011

HR = 0.81 (95% CI 0.70–0.94)

p=0.0041 17.3 19.0

PARP inhibitors

Poly ADP ribose polymerase inhibitor that blocks enzymes in repairing damaged DNA

Olaparib approved for women with advanced ovarian cancer with defective BRCA genes

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Proportion Of Hereditary Ovarian Cancer

Ovarian Cancer

15%

Sporadic Sporadic HereditaryHereditary

Ovarian Cancer: GENETICS

• BRCA 1&2– Autosomal dominant inheritance– Tumor suppressor gene with loss of function when mutated BRCA1 cancers median age 42– BRCA1 cancers median age 42

– Lifetime ovarian cancer risk 39‐54%– BRCA2 cancers – median age 52– Lifetime cancer risk 11‐23%– Tend to have better outcomes than matched non‐carrier controls

BRCA and PARP

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Synthetic Lethality Concept

Can we combine an anti‐angiogenic and Parp Inhibitor?

A Randomized Phase 2 Trial Comparing Efficacy of the Combination of the PARP-inhibitor Olaparib and the Anti-angiogenic Cediranib Against Olaparib Alone in Recurrent Platinum-sensitive Ovarian Cancer

Presented By Joyce Liu at 2014 ASCO Annual Meeting

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Primary Outcome: Cediranib/olaparib significantly increased PFS compared to olaparib alone


Cediranib/olaparib significantly increased PFS in patients without a BRCA mutation


Conclusions


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Other targeted agents….

Molecular Classification

Type I Type II

Histology Low Grade SerousMucinousClear CellEndometrioidLow Malignant Potential

High Grade Serous =High Grade “Endometrioid” ?

Mutations KRAS BRAF PTEN P53 BRCA lossMutations KRAS, BRAF, PTEN, ARID1A

P53, BRCA loss

Overexpression HLA-G, HER2, AKT

Presentation Associated with Endometriosis

Advanced Stage

Specific Pathways

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(AGO‐OVAR16) Study: Multikinase Inhibitor

• Background: Maintenance (Consolidation) therapy following successful primary treatment in ovarian cancer has been largely disappointing. This trial attempted to evaluate the utility of an oralattempted to evaluate the utility of an oral multikinase inhibitor (pazopanib) for maintenance following primary therapy.

• Randomized double‐blind, phase III trial of pazopanibversus placebo in women who have not progressed after first‐line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer

Results:

• 940 patient randomized (91% had Stage III/IV disease)

• Median PFS:

• Pazopanib: 17.9 months

• Placebo: 12.3 months (p=0.0021)

• HR 0.766 (95% CI: 0.64 – 0.91)

• Higher mean exposure to placebo (11.7 months) than pazopanib (8.9)

• Similar OS between arms although only 189 events [20.1% of study] have occurred

• Adverse events:

• Not surprisingly, pazopanib was associated with more AE

Conclusions:

• Pazopanib improved PFS in patients following primary therapy. OS data is immature.

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How do we individualize treatment?

Ovarian cancers are molecularly heterogeneous

• 489 tumors: Genomic alterations observed in nearly every chromosome

• with the exception of TP53 mutations, any one genomic alteration is found in only a small fraction of patient tumors

• One drug is unlikely to be effective for all patients Drugs must be developed for specific molecular tumor types Profiling of individual tumors using a broad profiling panel is necessary

• Data provided by Dr. D. Levine [TCGA study: Nature 474, 609- 615 (2011)]

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Background on OVCA PMI Project at UAB

• Tumor Cancer Genome Atlas (TCGA) ‐> heterogeneity of high grade papillary serous ovarian cancer

• Chemo refractory recurrent ovarian cancer (n=48)• Chemo‐refractory recurrent ovarian cancer (n=48) identified 67 “actionable” genomic alterations

‐ predicted sensitivity or resistance to a FDA approved drug or standard therapy OR one that was either inclusion or exclusion criteria for a specific experimental therapy in an NCI registered clinical trial.

• Genotype‐guided therapy: significantly improved lung cancer outcomes

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Aim

• Capture patients that have a potential molecular target that may allow for the “off‐label” use of targeted therapy against these “actionable” aberrationsaberrations

• This number will continue to grow within the 3 years

• Phase 1 Trial Center also starting to grow

Recurrent Ovarian Cancer

~250/year


~250/year

Patient Consent

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~250/year

Patient Consent

Next Generation Sequencing

(NGS)

MTB


~250/year

Patient Consent


(NGS)

ElectronicElectronic Medical Record

(EMR)


~250/year

Patient Consent


(NGS)

Electronic

FDA approved targeted agent

Electronic Medical Record

(EMR)1.

.

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~250/year

Patient Consent


(NGS)

Electronic

FDA approved targeted agent Clinical Trial


(EMR)1.

2.


~250/year

Patient Consent


(NGS)

Electronic

FDA approved targeted agent Clinical Trial Clinician drug

of choice


(EMR)1.

2. 3.


~250/year

Patient Consent


(NGS)

Electronic


of choice


(EMR)

Personalized Medicine Clinic Note

1.2. 3.

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~250/year

Patient Consent


(NGS)

Electronic


of choice


(EMR)

Personalized Medicine Clinic Note Outcomes followed

1.2. 3.

MTB Patient Example

Patient XX

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Patient XX

Specific Pathways

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Clinical Trials

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http://www.novartisoncology.com/ct/pipelineDetails?compound=BYL719&diseaseAcr=OC

Specific Pathways

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Future

• US‐based cohorts and networks

• eMERGE consortium

• Regeneron

ORIEN (Th O l R h I f i E h• ORIEN (The Oncology Research Information Exchange Network)

• Now multi‐institutional with 120,000 pts

• Combines EMR with genomic data and pairs these patients up with treatment options

Questions?

Documents

Targeted Therapy in Ovarian Cancer - UAB · Targeted Therapy in Ovarian Cancer Rebecca C. Arend, MD Division of Gyn Oncology 2015 US Female Cancer Statistics New Cases Deaths Lung