Bowtell DD, et al. Rethinking ovarian cancer II. Nature ...

Innovations in Gynecologic Cancer Care 5/12/2017

1

Michael A Bookman MDChair, Ovarian Committee, NRG OncologyDirector, Gynecologic Oncology Research

US Oncology Network and Arizona OncologyTucson, AZ USA

Targeting Gynecologic Cancers

Bowtell DD, et al. Rethinking ovarian cancer II. Nature Reviews Cancer 15:668-79, 2015


2

Cervical Cancer: Global Mortality

Ferlay J, et al. GLOBOCAN 2008 v2.0: International Agency for Research on Cancer

http://globocan.iarc.fr

Global Mortality from Cervical Cancer exceeds 250,000 per year


3

HPV Infection and Integration

Woodman BJ, et al. Nature Rev Cancer 2007; 7:11-22


4

Cervical Cancer and HPV


5

Impact of HPV Vaccination• Prevention of primary infection with high-risk HPV

subtypes (especially HPV 16, 18)

• No impact on established chronic HPV infection, or pre-invasive disease, or invasive cancer

• Induction of herd immunity (♀♂) with viral transmission

• Reduction in HPV-associated non-cervical cancers

• Foster innovation to reduce barriers (cost, complexity)

• Drive low cost HPV screening and POC technology

• Development of expanded multivalent (n=16) vaccines


6

Cervical Cancer: Interventions

Prognostic factors• CLSI, Stromal Invasion, Tumor Size• Histology, Demographics• Access to care (daily radiation)• Tumor Hypoxia

Surgery Alone

Radiation+/- ConcurrentChemotherapy

? NeoadjuvantChemotherapy

ClinicalStaging

? Fertility-SparingSurgery

? AdjuvantChemoRx

? VaginalBrachyRT

Patterns of spread • Pelvis, Distant sites, Combined• Nodal vs Parenchymal vs Direct Extension

Recurrence

Chemotherapy+/- anti-VEGF

CellularImmunityVaccines

ImmuneCheckpointInhibition


7

Meta Analysis: Impact of CTRT by Stage

Meta Analysis Collab. J Clin Oncol 26:5802-5812, 2008

Clear benefit associated with Chemo-RT, but need for improved outcomes in high-risk disease


8

Carboplatin AUC=5Paclitaxel 155 mg/m2 (3 h) x4

• Stage I-B1 PLN(+), I-B2, II, IIIB, IVA• GOG PS 0-2, HIV (-)• Squamous, Adenocarcinoma, or Adenosquamous• EBRT Dose (45 - 50.4 Gy)• Primary Endpoint: Overall Survival

R

Open: 03-JAN-12Closed: (ongoing)Accrual: 780 pts (increased to 900)

I

II

ANZGOG GOG0274: Cervix OUTBACK

Mileshkin L (ANZGOG), Moore K (GOG), et al. In progress

Concurrent Chemo-RadiationCisplatin 40 mg/m2/wk+ Intracavitary Brachytherapy

Observation


9

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24Months on Study

Prog

ress

ion-

Free

Sur

viva

l .Cervix Biologic Phase II

227-C Bevacizumab Monk 5/46 (10.9%)

227-D Erlotinib Schilder 0/25 (0%)

Cumulative historical phase II data

Suggestion of improved PFS and RR from bevacizumab


10

Cisplatin 50 mg/m2 (d1 or d2)Paclitaxel 135 or 175 mg/m2

• Stage IV-B or recurrent with measurable disease• No prior chemotherapy, allow prior adjuvant RT+/-Chemo• Primary Objective: OS

Open: 06-APR-09Closed: 03-JAN-12Accrual: 427 (eligible)

III

GOG 0240: Cervix (Metastatic)

Tewari KS, et al. NEJM 2014; 370:734-43

+/- Bevacizumab 15 mg/kg

Paclitaxel 175 mg/m2 (3 h)Topotecan 0.75 mg/m2 (d1,2,3)III

IV+/- Bevacizumab 15 mg/kg

DSMB Review JAN-2012: No evidence of superiority for non-Cisplatin regimen

Bifactorial Randomization1. Chemotherapy2. Bevacizumab


11

GOG 0240: Cervix (Metastatic)

Tewari KS, et al. NEJM 2014; 370:734-43

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36

Pro

gres

sion

-Fre

e S

urvi

val

Months on Study

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36O

vera

ll S

urvi

val

Months on Study

HR OS (+/- 97% CI) = 0.71 (0.54-0.95)p = 0.0035 (1-sided)

Median OS: 17.0 vs 13.3 months

HR OS (+/- 97% CI) = 0.71 (0.54-0.95)p = 0.0035 (1-sided)

Median OS: 17.0 vs 13.3 months

HR PFS (+/- 95% CI) = 0.67 (0.54-0.82)p = 0.0002 (2-sided)

Median PFS: 8.2 vs 5.9 months

HR PFS (+/- 95% CI) = 0.67 (0.54-0.82)p = 0.0002 (2-sided)

Median PFS: 8.2 vs 5.9 months

Chemo + Bev (n = 227)

Chemo + Bev (n = 227)

Chemo Alone(n = 225)

Chemo Alone(n = 225)

FDA approved indication for bevacizumab with chemotherapy 14-AUG-2014


12

GOG 0240: Risk of Fistula Formation

Willmott LJ, et al. IGCS 2015

Chemo+Bev(n=218)

Chemo(n=222)

GI-vaginal fistula 18 ( 8.2%) 2 (0.9%)

GU-vaginal fistula 4 ( 1.8%) 3 (1.4%)

GI fistula (other) 1 ( 0.5%) 0 ( 0%)

Total Fistula 23 (10.5%) 5 (2.3%)

Perforation / Peritonitis 8 ( 3.6%) 0 ( 0%)

• Fistula risk increased with bevacizumab, particularly after prior radiation• Patient treatment decisions need to be individualized


13

Activating the Cellular Immune Response

Modified from: Advaxis Immunotherapies

Lm‐LLO isphagocytosed by APC

Some Lm‐LLO escapes the phagolysosome and enters the cytosol

tLLO‐TAA fusion protein is degraded by proteasomes into peptides for presentation to the MHC class I pathway

Some Lm‐LLO is killed and degraded within the phagolysosome

Peptide‐MHC complexes on the APC simulate CD4+ (MHC II) and CD8+ (MHC I) T cells

Lm, Listeria monocytogenesTAA, tumor-associated antigentLLO, truncated listeriolysin O

AXAL, Axalimogene Filolisbac


14

AXAL Adjuvant Monotherapy

Herzog T. for GOG-Foundation

GOG-3009 (Advaxis ADXS001-02)Open: 03FEB2017Target: 450 patients


15

GOG-3016: Anti-PD1 vs Chemotherapy

GOG Foundation (under development)

• Fully human hinge-stabilized IgG4P, binds to human PD-1 ECD• Cervical Cancer, progression or recurrence < 6 m from prior

platinum-based therapy (platinum-refractory)• Stratification by histology, geographic region, prior bevacizumab• Endpoints: OS (Primary), PFS and ORR (Secondary)

Open: JUL2017 (projected)Accrual: 436 pts

I

IIChemotherapyInvestigator’s Choice*

REGN2810350 mg IV q3w (x8 cycles)

* Pemetrexed, topotecan, irinotecan,Vinorelbine, gemcitabine


16

Summary: Cervical Cancer• Multivalent HPV vaccination to prevent infection in children, with an

emphasis on high-risk populations in the developing world

• Tailored multidisciplinary management of early-stage disease

• Integration of adjuvant chemotherapy in high-risk disease

• Improved PFS and OS following incorporation of bevacizumab with chemotherapy for metastatic or recurrent disease, but with an increased risk of fistula formation (in patients with prior radiation)

• Activation of the cellular immune response using novel vaccines

• Emergence of Immune checkpoint inhibition as an important strategy, in view of HPV-associated target antigens


17

Obesity Trends, US Adults (BMI ≥30)

Source: CDC Behavioral Risk Factor Surveillance System.

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

1985 1990 1995 2000 2005 2006


18

Metformin Translational Window Study

Schuler KM, et al. SGO 2014 (Abstract 8)

New Diagnosis BMI ≥30Endometrioid Histology

Metformin850 mg QD

Definitive Surgery(within 7-28 d)

• Tissue microarrays pre- and post-metformin• Immunohistochemistry Ki-67, pAMPK, mTOR, pAKT, pS6, ER/PR• Metabolomics panel (serum and tissue)

Mean Ki-67 IndexPre-Rx: 39.5Post-Rx: 27.7

(n = 20)

Pre-Rx Post-Rx

IHC Molecular Markers (Pre- and Post-Rx)pAMPK 60.3% pAKT 44.2% pS6 51.2%p4EBP1 74.7% ER 65.7% PR (NC)


19

Carboplatin AUC 5Paclitaxel 175 mg/m2 (3 h)Placebo (QDBID)

• Stg III-IVA (measurable) and Stg IVB or recurrent• Integrated Phase II (PFS) Phase III (OS)

240 pts phase II (60 events, PFS HR 0.76)540 pts phase III (OS HR 0.76)

Open: 17-Mar-2014Closed: (ongoing)Accrual: 540 (Phase II + III)

I

II

GOG286B: Chemotherapy +/- Metformin

Bae-Jump V, et al. for GOG

Carboplatin AUC 5Paclitaxel 175 mg/m2 (3 h)Metformin 850 mg (QDBID)

Metformin 850 mg BID

Placebo BID

Q21d x 6 cycles Maintenance (CR, PR, SD)


20

Targeting Endometrial Cancer

Type I Type IIMedian Age 50 - 60 60 - 70

Estrogen Related Common Uncommon

Obesity Common Variable

Background Hyperplastic Atrophic

Precursor EIN EGD, EIC

Histology Endometrioid Serous, Clear Cell

Molecular Alterations MLH/MSI, PTEN, K-RAS, FGFR2, -Catenin p53, 17p del, HER2/neu

Detection Early-Stage Advanced-Stage

Familial Risk HNPCC BRCA (serous)

Spread LN, Distal LN, Peritoneal


21

Targeting Endometrial Cancers (I & II)

Gene Abnormality Prevalence of AbnormalityType I Type II

PIK3CA Amp 2-14% 46%PIK3CA Mut 26-36% 26-36%KRAS Mut 13-26% 0-10%TP53 Mut 5-10% 80-90%MLH1 Meth/Mut 20-35% 0-10%MSI Meth/Mut 20-45% 0-5%ER, PR Exp 70-73% 19-24%HER2/ERBB2 Amp/Exp Rare 18-80%PTEN Mut/Del/Meth 35-55% 0-11%Stathmin Exp 15% 64%CDKN2A Mut/Meth/Exp 10% 10-40%-Catenin Mut 25-38% 0-5%

Modified from: Salvesen HB, et al. Lancet Oncol 2012; 13: e353–61


22

Clinical History

• OCT 2013: 56 year-old G0/P0, post-MP bleeding, office EMB unsuccessful due to cervical stenosis

• MAR 2014: Hysteroscopy, D&C, HTA ablation. Pathology: endometrioid cancer, FIGO Grade II

• APR 2014: LAVH, BSO, pelvic and PA LN dissection• Endometrioid cancer FIGO grade II, 3.2 cm, myometrial invasion 10%,

LVI (-), no cervical involvement, margins (-), 10 pelvic LN (-)

Primary TumorLymphocytic

Infiltrate Isolated PA LN


23

Mismatch Repair Gene ExpresionImmunohistochemistry performed:• ER positive (80%), PR positive (80%), PMS2 positive• p53 negative (5%, sporadic), IMP-3 negative• MSH2 and MSH6 abnormal (loss of staining)

H&E

MSH2

PMS2

MSH6


24

Endometrial Cancer: MMR, MSI, and LS

Approximately 9% of women with endometrioid cancer at age <50 carry mutations in DNA mismatch repair (MMR) genes

Umar A, et al. J Natl Cancer Inst 2004;96:261-8

MSH2-SeqVar

MSH2-Del

MLH1-SeqVar

MLH1-Del

MSH6PMS2


25

GOG210: Endometrial Ca and MSI

No Abnormality Sporadic Defect Probable MutationMMR IHC StainingMLH1 Methylation

MSI Testing

IntactMethylatedNegative

MLH1 LossMethylated

Positive

Some MMR Lossnon-Methylated

PositiveMolecular Risk Low Low High

Total N (%) 578 (62%) 253 (27%) 107 (11%)Family Hx N (%) 52/578 (9%) 26/253 (10%) 21/107 (20%)

Billingsley CC, et al. SGO 2015

• Only 20% of high-risk patients had a positive family history• Germline HNPCC-LS mutations confirmed 18/47 high-risk patients (38%)• Overall predicted frequency of HNPCC-LS = 3.75%

Recommend adoption of universal molecular tumor screening:IHC and methylation MSI testing Genomic Validation

A Molecular Staging Study of Endometrial Carcinoma (PI: WT Creasman)


26

Targeting Endometrial Cancer: TCGA

TCGA Network. Nature 497:67-73, 2013

POLE UltraMutated MSI Hypermutated Copy-Number Low Copy-Number High


27

Anti-PD1 and MMR Deficiency

Le DT, et al. N Engl J Med 2015;372:2509-20

• Pembrolizumab 10 mg/kg IV every 14 days• Treatment-refractory progressive metastatic cancer (n):

Colorectal: MMR Deficient = 11, MMR Proficient = 21Non-Colorectal: MMR Deficient = 9 (endometrial = 2)


28

OSPFS

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24

Pro

porti

on P

FS o

r OS

Months on Study

GOG Endometrial Biologic Phase II229-C Gefitinib PI: Leslie 1/26 (3.8%)229-D Lapatinib PI: Leslie 1/30 (3.3%)181-B Trastuzumab PI: Fleming 0/17 FISH+229-E Bevacizumab PI: Aghajanian 8/53 (15.1%)

No evidence of clinical benefit targeting EGFR or HER2; possible benefit with bevacizumab


29

GOG 086-P: Randomized Phase II

Carboplatin AUC=6Paclitaxel 175 mg/m2

Bevacizumab 15 mg/kg

• Adenocarcinoma• Measurable Stage III or IV-A, IV-B, or recurrent, without prior chemotherapy• Prior radiation permitted• 1 Objective: 35% decrease in HR (1.53) of progression or death rate (PFS)• Comparison with historical reference population from GOG0209 Phase III

Open: 14-Sep-2009Closed: 09-Jan-2012Accrual: 334 (Evaluable)

I

Aghajanian C, et al. ASCO Annual Mtg 2015

Carboplatin AUC=6Ixabepilone 30 mg/m2

Bevacizumab 15 mg/kgIII

Carboplatin AUC=6Paclitaxel 175 mg/m2

Temserolimus 25 mg D1,8II

MaintenanceBevacizumab

MaintenanceBevacizumab

MaintenanceTemserolimus


30

GOG 086-P: Randomized Phase II

Aghajanian C, et al. ASCO Annual Mtg 2015

Comparison to Historical Reference:PFS HR (92.2% CI)

Arm 1 0.805 (0.633-1.023)Arm 2 1.222 (0.961-1.554)Arm 3 0.871 (0.685-1.107)

Trend for PFS improvement in both arms with bevacizumab (1 and 3)


31

Pathway Mutations in Endometrial Ca

Byron SA, et al. PLoS ONE 7: e30801, 2012

FGFR2

• Interesting pattern of non-overlapping mutations, including KRAS, -Catenin, FGFR2• Challenging to specifically target FGFR2, due to TKI overlap with VEGFR2


32

Summary: Endometrial Cancer• Obesity can impact cancer risk and clinical outcomes across subtypes

• Potential role for metformin in obesity-associated cancers

• Importance of screening for MMR deficits (MSI, Lynch Syndrome)

• Not just “Type I and II”, but at least 4 distinct clinical and molecular entities (TCGA) have been established

• Angiogenic pathways, including FGFR2, of interest as potential targets

• Emergence of immune checkpoint inhibition as an important strategy, in hypermutated subtypes, including POLE and MSI-high

• Management of high-grade serous tumors remains challenging, with a need to address drug resistance and the DNA damage response


33

Molecular and Clinical Pathobiology

Modified from: Singer et al., Am J Surg Pathol 29:218-24, 2005


34

• Activation of B-RAF or K-RAS MEK• Not Associated with High-Risk Families• Precursor SBT LGSC• ER+/PR+, low mitotic rate• Intact p53 and DNA Repair: Genomic Stability• Low-Elevated or Normal CA125• Frequently early-stage (FIGO I)


• Uniform loss of p53• Frequent loss 17q21 (BRCA1), 13q12 (BRCA2),

13q14 (RB1)• Associated with High-Risk Families• DNA Repair Defect (HRD): Genomic Instability• CA125• Advanced-stage (FIGO III-IV)




35

AGO ROBOT: Borderline-LMP PFS

Sehouli J for AGO Study Group, . Intl J Gynecol Cancer 22:Supp 3;E81, 2012

Years

Pro

porti

on P

rogr

essi

on-F

ree

FIGO HR 95%CI p N EI 782 72II vs I 2.49 (1.44, 4.29) 0.0010 72 16III vs I 2.48 (1.51, 4.08) 0.0003 96 20

FIGO IIIFIGO II

FIGO I


36

SBT-LMP: Invasive Implants

102

66

40

34

6

AllPatients

Stage I

Stage II+

Non-InvasiveImplants

InvasiveImplants

1 Pelvic Recurrence(invasive)

2 Died, unrelated

5 Died, tumor-related1 Alive, progression

0.0

0.2

0.4

0.6

0.8

1.0

0 100 200

Pro

porti

on S

urvi

ving

Months on Study

Non-Invasive

Invasive

Prat and de Nictolis, Am J Surg Pathol 26:1111-28, 2002


37

SBT-LMP: Invasive Implants

Hannibal CG et al. Gynecol Oncol 134:267-73, 2014

Implants (n) Incidence (n=1024)

Relative Survival Deathsp

5 Y 10 Y 15 Y Obs Exp O:ENon-Invasive 114 11.1% 95% 90% 83% 35 13.6 2.6 <0.0001

Invasive 19 1.9% 75% 60% 37% 13 2.0 6.5 <0.0001

Nationwide study of borderline tumors in Denmark (1978-2002) with centralized pathology review and outcomes compared to the general population


38

AGO ROBOT: OS Post-Recurrence

Sehouli J for AGO Study Group, . Intl J Gynecol Cancer 22:Supp 3;E81, 2012

Carcinoma vs BOT: HR (95% CI) = 26 (2.3-209)Log rank test: p<0.0001

Years

Pro

porti

on S

urvi

ving

Carcinoma

BOT


39

SBT LGSC

Tsang YT, et al. J Pathol 231:449-56, 2013


40

SBT-LGSC: High-Grade Transformation

210

3

3

AllCases

SBT + HG Serous

LGMP + HG Serous

Dehari R, et al. Am J Surg Pathol 2007;31:1007–1012

K-RAS(+)B-RAF(wt)p53 (wt)

K-RAS(+)B-RAF(wt)p53 (wt)

K-RAS(wt)B-RAF(wt)p53 (wt)

When SBT-LGSC recurs with high-grade transformation, it retains the molecular phenotype of the original SBT(K-RAS activation with wild-type TP53), distinct from HGSC


41

GOG0182: Outcomes in LGSC vs HGSC

Fader AN, et al. Obstet Gynecol 2013, 122:225-32

LGSC(n=189)

HGSC(n=1763) P

Age Med (Range) 56.5 (46.6 - 64.3) 59.3 (51.6 - 67.3) <.001

BMI Med (Range) 26.6 (23.4 - 30.3) 25.2 (22.2 - 29.6) y .007

PS 012

49.2 %46.04.8

48.8 %44.07.2

.444

FIGO Stage IIIIV

87.3 %12.7

84.3 %15.7 .284

Residual Micro0.1-1.0 cm

>1 cm

24.9 %51.323.8

20.3 %47.528.4

.106

CA125 Med (Range) 119.1 (51.8 - 323.9) 246.7 (101.8 - 719.8) <.001

Ascites Present 63.1 75.7 <.001


42

GOG0182 LGSC: Residual Disease


Long-term outcomes in advanced-stage LGSC correlate with extent of residual disease following primary cytoreduction


43

GOG0182: LGSC and HGSC


When analyzed by extent of residual disease, long-term outcomes in advanced-stage LGSC appear similar to HGSC.


44

LGSC: Hormonal Maintenance

Gershenson DM, et al. ASCO 2016

Stage II-IVLGSC

Primary Cytoreductive

Surgery

Platinum-BasedChemotherapy

Surveillance(n = 134)

HormonalMaintenance

Therapy*(n = 70)

• Retrospective experience, 1981 to 2013• Primary outcome: PFS• 204 patients eligible from 544 with LGSC• Median Age 47.6 years

Residual Disease(Post-Chemo)

Hormonal RxN (%)

SurveillanceN (%)

NED 27 (39.1) 121 (91.7)

Persistent Disease 42 (60.9) 11 (8.3)

Missing 1 2

* Letrozole 54%Tamoxifen 29%Anastrozole 3%

Leuprolide 7%Other 7%


45

LGSC: Hormonal Maintenance

Gershenson DM, et al. ASCO 2016

Multivariate Analysis HR PFS (95% CI) P-Value

Treatment Group (Surv vs HMT) 0.23 (0.11, 0.51) < .001

Primary Site (Ovary vs Peritoneal) 0.45 (0.27, 0.76) .003

Residual Disease (Gross vs Micro) 0.49 (0.28, 0.87) .02

Disease Status (Persistent vs NED) 0.42 (0.18, 0.96) .04


46

LGSC: BRAF and KRAS Genomics

Tsang YT, et al. J Pathol 231:449-56, 2013

SBT-LMP LGSC HGSCBRAF 20-40% <5% RareKRAS 40% 30-40% 0-14%


47

• BRAF mutations common in SBT-LMP, but uncommon in LGSC• KRAS G12V mutation associated with decreased survival• Direct targeting of mutated KRAS not currently feasible


48

GOG0239: LGSC Selumetinib Phase II

AZD6244 100 mg PO bid x28d• Low-Grade Serous Carcinoma• Histologic Confirmation• No Restriction on Prior Therapy• PS 0-1• Two-stage accrual design• RECIST Measurable Disease

Open: Dec 2007Closed: Nov 2009Accrual: 52 pts (2 stages)

Farley J, et al. Int J Gynecol Can 21:S3(LBA), 2011

Inhibitor of mitogen-activatedprotein kinases (MEK)(RAS-RAF-MEK-ERK pathway)


49

GOG0239: LGSC Selumetinib Phase II

Farley J, et al. Int J Gynecol Can 21:S3(LBA), 2011

RECIST n (%)

Complete Response 1 ( 1.9%)

Partial Response 7 (13.5%)

Stable Disease 34 (65.4%)

Increasing Disease 8 (15.4%)

Indeterminate 2 ( 3.8%)

n CR+PR (%)Total 34 7 (20.6%)

BRAFNo 32 7 (21.9%)Yes 2 0 ( 0.0%)

KRASNo 20 5 (25.0%)Yes 14 2 (14.3%)

BRAF - or -

KRAS

No 18 5 (27.8%)

Yes 16 2 (12.5%)

Total Population (52) Mutation Cohort (34)


50

• Recurrent LGSC (allows prior LGSC, micropapillary, or SBT-LMP)• Measurable disease RECIST 1.1• At least one prior platinum-based chemotherapy regimen • Stratify by Region (US vs UK), PS, prior treatment, planned treatment• Primary Endpoint: 50% improvement PFS (8 to 12 m), 80% power, p 2.5%

Trametinib 2 mg PO(Daily x28d)II

I Reference/Control(Physician’s Choice)*

Crossover to Trametinib

Open: 27-FEB-2014Closed: 29-JUN-2016 (US sites, ongoing in UK)Accrual: Target 250 pts

GOG0281: Trametinib Phase II/III

Gershensen DM, et al. for NRG Oncology

PD

* Treatment Options:Letrozole 2.5 mg PO QDTamoxifen 20 mg PO BIDPaclitaxel 80 mg/m2/wkPLD 40-50 mg/m2 q28DTopotecan 4.0 mg/m2/wk


51

Open: JUN-2013Closed: APR-2016Accrual: Target 360 pts

MILO ENGOT ov11: Binimetinib Phase III• Recurrent LGSC• RECIST-Measurable disease• At least one prior platinum-based regimen • Stratify by PFI and number of prior regimens• Primary Endpoint: PFS

Binimetinib 45 mg PO(BID x28d)II

IReference/Control(Physician’s Choice)*

* Treatment Options:Paclitaxel 80 mg/m2 (weekly)PLD 40 mg/m2 Q28DTopotecan 1.25 mg/m2 daily x5

1:2

Closed 01APR2016 following planned interim analysis of HR (PFS) which crossed the predefined futility boundary


52

Open: SEP-2013Closed: MAY-2016Accrual: 65 pts

• Recurrent LGSC• RECIST-Measurable disease• Double-blind, randomized phase II • Primary Endpoint: ORR

Pimasertib 60 mg PO QD(and Pimasertib Placebo QD)SAR245409 70 mg PO QD

II

IPimasertib 60 mg PO BIDSAR245409 Placebo QD

Combined MEKi and PI3Ki

Closed 01MAY2016 following planned interim futility analysis of ORREarly discontinuation (<8 wk) in 29% of patientsCentral pathology review with 30% not LGSC

Receptor TK

RAS

PTEN RAF

MEK

ERK

PI3K

AKT

FOXO

mTORC1

Crosstalk

Cell proliferation angiogenesis

Cell growth,metabolismCell survival


53

Summary: SBT and LGSC• The molecular and clinical biology of LGSC is distinct from HGSC

• SBT with invasive implants is probably best categorized as LGSC

• Overall mortality in advanced-stage LGSC is similar to HGSC

• Primary hormonal maintenance may delay recurrence (retrospective)

• SBT-LGSC can recur with high-grade features, retaining the molecular profile of LGSC (KRAS+ and TP53 wt)

• Targeting the RAS/RAFMEK/ERK pathway has modest activity; although combined network targeting is limited by toxicity

• The role of immune checkpoint inhibition in LGSC is unknown, but neoantigen production and mutational burden are low


54

Molecular and Clinical Pathobiology

Modified from: Singer et al., Am J Surg Pathol 29:218-24, 2005


55








56

Cancer Death Rates: (US 1930-2012)

CisplatinCisplatin

PaclitaxelPaclitaxel

CytoreductionCytoreduction

IP CisplatinIP Cisplatin

NACTNACT

BevacizumabBevacizumab• Improvements in median PFS, OS, and QOL• Modest reduction in incidence and mortality

(RR-BSO and HRT)• No impact on overall case : fatality (or cure)


57

• Improvements in median PFS, OS, and QOL• Modest reduction in incidence and mortality

(RR-BSO and HRT)• No impact on overall case : fatality (or cure)


58

APR-246: Restoring p53 Function

Basu B, et al. for EUTROC

• p53 tumor suppressor induces cycle arrest, senescence and/or apoptosis, in response to cellular stress

• TP53 mutations correlate with chemoresistance and outcomes across diverse tumors

• APR-246 is a small molecule pro-drug that stabilizes mutant p53 into wild-type conformation via active MQ

• APR-246 also depletes glutathione, inhibits thioredoxin reductase, increases ROS levels and ER stress


59

FRα Antibody Drug Conjugate (ADC)

Moore K, et al. for GOG Foundation (GOG-3011)

• FRα (FOLR1) over-expressed on >80% of HGSC• Mirvetuximab Soravtansine (IMGN853) consists of humanized anti-FRα

with a cleavable disulfide linker and the cytotoxic maytansinoid DM4• Phase III trial for platinum-resistant recurrent disease (PFI < 6m)• Primary Endpoint: PFS (BIRC) n = 333 patients

I

IIChemotherapyInvestigator’s Choice*

IMGN853 6 mg/kgIV q3w

* Paclitaxel, PLD, or topotecan

2 : 1


60

What About IP Chemotherapy…

Chhatrapati Shivaji Terminus, Mumbai 2012

???


61

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer• Optimal and Suboptimal Disease (through April 2011)• Primary Endpoint: PFS (Analysis JAN 2016)

GOG0252: IP Therapy

Open: 27-Jun-2009Closed: 29-Oct-2011Accrual: 1560 pts (max 250 suboptimal)

Walker J. for GOG, SGO 2016

Carboplatin AUC=6 (IV)Paclitaxel 80 mg/m2 IV (d1,8,15)Bevacizumab (C2-6)

Cisplatin 75 mg/m2 (IP)Paclitaxel 135 mg/m2 (d1, 3h)Paclitaxel 60 mg/m2 (d8, IP)Bevacizumab (C2-6)

I

III

IICarboplatin AUC=6 (IP)Paclitaxel 80 mg/m2 (d1,8,15)Bevacizumab (C2-6)

Bevacizumabq21d x 16



IV Carbo

IP Carbo

IP Cisplatin


62

GOG0252: IP vs IV (PFS)

Walker J. for GOG, 2016

ITT (All Eligible Patients)


63

GOG0252: IP vs IV (OS)

Walker J. for GOG, 2016

ITT (All Eligible Patients)

PRELIMINARY• Current IV chemotherapy appears at least as effective

as modified IP chemotherapy• Median OS exceeds historical data from GOG0172


64

• Current IV chemotherapy appears at least as effective as modified IP chemotherapy

• Median OS exceeds historical data from GOG0172


65

Stage II to IVovarian, primary peritoneal, or fallopian tube

cancerIncluding

suboptimal Cases

• Accrual: 655 pts (closed OCT2016)

• Primary Endpoint: PFS

• Secondary Endpoints: OS, Toxicity, QOL, Cost/Benefit

Paclitaxel 80 mg/m2/1h IV, weekly, Cycles 1-6Carboplatin AUC 6 IV, Day 1, Cycles 1-6

Paclitaxel 80 mg/m2/1h IV, weekly, Cycles 1-6Carboplatin AUC 6 IP, Day 1, Cycles 1-6

RANDOMIZE

iPocc Trial


66

Old Drugs with New Tricks


67

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer• Suboptimal residual disease (optional NACT-ICS)• Primary Endpoint: PFS• Early perfusion-based CT imaging (ACRIN 6695)

GOG0262 / ACRIN6695: Dose-Dense

Open: 27-SEP-2010Closed: 08-FEB-2012 (ACRIN JUN-2013)Target Accrual: 692 pts (randomized)

Carboplatin AUC=6Paclitaxel 80 mg/m2 (d1,8,15)+/- Bevacizumab (C2-6)$

I

II

Bevacizumabq21d$

Bevacizumabq21d$

Carboplatin AUC=6Paclitaxel 175 mg/m2 (d1)+/- Bevacizumab (C2-6) $

$ Use of Bevacizumab to be elected prior to randomization

Chan JK, et al. NEJM, 2016


68

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30 36

Pro

porti

on P

rogr

essi

on-F

ree

Months on Study

GOG0262 / ACRIN6695: Dose-Dense

Chan JK, et al. NEJM, 2016

Schedule ( n ) PFS

(+) BEV

Three-WeeklyDose-Dense Weekly

289291

14.714.9

(-) BEV

Three-WeeklyDose-Dense Weekly

5755

10.314.2


69

• In the absence of bevacizumab, weekly scheduling of paclitaxel was associated with improved PFS

• The overall effect size that was similar to incorporation of bevacizumab in three-weekly therapy


70

GOG0262 / ACRIN6695 Biomarkers

Ng C, et al. Clin Cancer Res 2017


71

GOG0262 / ACRIN6695 Biomarkers

Ng C, et al. Clin Cancer Res 2017

Blood FlowDecreased

Blood FlowIncreased


72

VDA: CA4P (Fosbretabulin)

Monk BJ, et al. IGCS 2016 A0502

CA4P (VDA)

Study Complete

CA4P + Bev + PCC n=178

Bev + PCC n=178

ORR Data, PFS DataORR Data Trigger

Part 2 Trigger Part 2

Bev + PCC n=40

CA4P + Bev + PCC n=40

Untreated

1d CA4P

3d CA4P

Phase II/III trial extending experience from GOG0186IPlatinum-resistant disease (PFI <6 m)


73

What About Neoadjuvant Therapy…

Meyer L, et al. J Clin Oncol 34:3854-3863, 2016

Within NCCN, NACT use increased from 16% to 34% in stage IIIC (P trend < .001), and from 41% to 62% in stage IV (P trend < .001)

Stage III-C Stage IV


74

Epithelial-Mesenchymal Transition (EMT)

SCC15 AKT Activated

E-cadherin

Vimentin

From: Larue and Bellacosa. Oncogene 24:7443–7454, 2005


75

Predicting Suboptimal Cytoreduction

Expression:SuboptimalOptimal

Prognosis

Reister M, et al. J Natl Cancer Inst 2014;106 doi:10.1093/jnci/dju048


76

• Activation of key molecular pathways, including TGF-β and EMT, are associated with invasive metastatic behavior

• Current assays not sufficiently predictive to guide individual surgical management

• Other strategies include functional imaging and decision-mode laparscopy


77

• Epithelial ovarian, peritoneal, or fallopian carcinoma (EOPFC)• Stage IIIC-IV and suitable for NACT-ICS• Initial Phase I (acute toxicity and cumulative tolerability)• Maintenance ruxolitinib permitted in patients tolerating concurrent therapy• Primary Endpoints: PFS and molecular targeting (stem cells and IL6)

CP (x3) ICS CP (x3) Observation

CP (x3)+ Rux

CP (x3)+ Rux

Rux Maint(optional)ICS

Core Bx R

CP = Carboplatin AUC 5 or 6 (D1), Paclitaxel 80 mg/m2 (D1,8,15)Rux = Ruxolitinib 10-15 mg PO BID (pending Phase 1)ICS = Interval Cytoreductive Surgery

1:2

Burger R, for NRG Oncology

NRG-GY007: NACT +/- Ruxolitinib

Open: 10-OCT-2016Closed: (ongoing phase I)Accrual:


78

PARP Inhibition…Who? What? Where? When? Why?

CSI: Chemotherapy Substance Investigation

gBRCA1/2musBRCA1/2muBRCAwtHRDLOH

OlaparibRucaparibNiraparibVeliparib(and friends)

TreatmentMaintenanceFront-LineRecurrencePlatinum SensitivePlatinum Resistant

PFSOSPRO


79

GOG3005: PARPi Primary Therapy & Maint• High-grade extrauterine serous tumors, Stage I-C, II, III, IV• Election for NACT-ICS and scheduling of paclitaxel (no IP therapy)• Primary endpoint PFS: (1) Entire Population, (2) BRCA1/2 Population• Stratifications: Stage, Residual Disease, NACT-ICS, Region, gBRCA status

x 6II Veliparib 400 mgPO BID

Paclitaxel (standard or dose-dense)Carboplatin AUC 6 (IV)*

Veliparib 150 mg PO BID

x 6IPaclitaxel (standard or dose-dense)Carboplatin AUC 6 (IV)*

Placebo PO BIDPlaceboPO BID

Collaborative development with AbbVie (M13-694) including international participation, seeking EMA and FDA regulatory approval

Coleman R, for GOG Foundation

Open: JUL 2015Closed: (to complete MAY 2017) Target Accrual: ~1100 pts (264 BRCA1/2 +)

x 6II PlaceboPO BID

Paclitaxel (standard or dose-dense)Carboplatin AUC 6 (IV)*

Veliparib 150 mg PO BID

1:1:1


80

NRG-GY004: PARPi +/- Cediranib• Recurrent HGSC with PFI >6 months (following most recent platinum)• No more than 3 prior treatment regimens (including primary therapy)• RECIST measurable or evaluable disease with accessible tumor• No prior PARPi therapy, prior bevacizumab permitted• Stratify for BRCA status, number of prior treatment regimens• Primary endpoint: PFS 85% Power with HR 0.625

Cediranib 30 mg QDOlaparib 200 mg BID

Platinum-based combo* (IV)

R

*Carboplatin + gemcitabine or paclitaxel or PLD

Olaparib 300 mg BID

Open: FEB 2016Closed: (to complete 2017)Target Accrual: 550 pts (135 BRCA1/2 +) Liu J, for GOG


81

PFS in gBRCAmut and non-gBRCAmutcohortsPrimary Endpoint

• Overall survival (OS)• Patient-reported outcomes (PRO)• Chemotherapy-free interval (CFI)• Safety and tolerability

Key Secondary Endpoints

• PFS2• Evaluation of QTc

ENGOT-OV16 / NOVAPhase 3 Randomized Double-Blind Trial of Maintenance with Niraparib Versus Placebo

in Patients with Platinum Sensitive Ovarian Cancer

gBRCAmut (N=203)

Niraparib N=138

PlaceboN=65

Non‐gBRCAmut (N=350)

Niraparib N=234

PlaceboN=116

2:1 Randomization 2:1 Randomization

Platinum‐Sensitive Recurrent High Grade SerousOvarian Cancer (N=553)

N=47 N=46N=4 N=12Ongoing Therapy

Mirza M, et al, ESMO 2016


82

ENGOT-OV16 / NOVA


0

25

50

75

100

0 2 4 6 8 10 12 14 16 18 20 22 24Time Since Randomization (months)

Prog

ress

ion–

free

Sur

viva

l (%

)

NiraparibPlacebo

Progression-free Survival: gBRCAmut

Arm (n) Median (m)Niraparib 138 21.0Placebo 65 5.5

HR (95% CI) 0.27 (0.173, 0.410) p <0.0001


83

0

25

50

75

100

Prog

ress

ion–

free

Sur

viva

l (%

) NiraparibPlacebo


ENGOT-OV16 / NOVA


Progression-free Survival: Non-gBRCAmut and HRDpos


HR (95% CI) 0.38 (0.243, 0.586) p <0.0001


84

0

25

50

75

100

Prog

ress

ion–

free

Sur

viva

l (%

) NiraparibPlacebo


ENGOT-OV16 / NOVA


Progression-free Survival: Non-gBRCAmut


HR (95% CI) 0.45 (0.338, 0.607) p <0.0001


85

ENGOT-OV16 / NOVA


Progression-free Survival: Exploratory Subgroups Non-gBRCAmut

0

25

50

75

100

Time Since Randomization (months)

Prog

ress

ion–

free

Sur

viva

l (%

)

0 2 4 6 8 10 12 14 16 18 20 22 24

NiraparibPlacebo

0

25

50

75

100


Prog

ress

ion–

free

Sur

viva

l (%

)

0 2 4 6 8 10 12 14 16 18 20 22 24

NiraparibPlacebo

0

25

50

75

100


Prog

ress

ion–

free

Sur

viva

l (%

)

NiraparibPlacebo

0 2 4 6 8 10 12 14 16 18 20 22 24

HRD-positive HRD-negative

sBRCAmut

BRCAwt

HR (95% CI) 0.27 (0.081, 0.903) p <0.0248 HR (95% CI) 0.58 (0.361, 0.922) p <0.0226

HR (95% CI) 0.38 (0.231, 0.628) p <0.0001


86

ENGOT-OV16 / NOVA


Treatment-emergent Grade 3/4 Adverse EventsOccurring in ≥5% of Patients

Niraparib(N=367)

Placebo(N=179)

Thrombocytopeniaa 124 (33.8%) 1 (0.6%)

Anemiab 93 (25.3%) 0

Neutropeniac 72 (19.6%) 3 (1.7%)

Fatigued 30 (8.2%) 1 (0.6%)

Hypertension 30 (8.2%) 4 (2.2%)

MDS/AML occurred in 5 of 367 (1.4%) in patients who received niraparib and 2 of 179 (1.1%) in patients who received placebo.


87

FDA 27-MAR-2017: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.


88

Summary: HGSC• The molecular and clinical biology of HGSC is distinct from LGSC

• The case-fatality ratio in advanced-stage HGSC has not changed, in spite of recent advances in treatment and supportive care

• Restoring tumor suppressor function of mutated p53 might be feasible

• Contemporary IV chemotherapy appears equivalent to modified IP chemotherapy with either cisplatin or carboplatin

• Fractionated weekly paclitaxel, with carboplatin, improves outcomes in the absence of bevacizumab

• Vascular disrupting agents, combined with bevacizumab, are under evaluation

• NACT with ICS offers a valuable platform for clinical research

• PARP inhibition has become widely utilized in the setting of recurrent disease, with questions about patient selection, timing, resistance, and combinations with other agents, including immunotherapy

• The role of immune checkpoint inhibition in HGSC is unknown, but likely to be complicated by multiple pathways of immunosuppression


89

Thank you!

Chiricahua National Monument, Arizona, NOV 2016

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