Gynecologic Tumors, State-of-the-Art · Stratified by Stage, LN status, Histology, T volume,...

GCIG Education Symposium, November 2017, Vienna

f

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

Michael A Bookman MD

Chair, Ovarian Subcommittee, NRG Oncology

Director, Gynecologic Oncology Therapeutics

The Kaiser Permanente Medical Group

San Francisco, CA USA

Gynecologic Tumors, State-of-the-Art


Cervical Cancer: Global Mortality

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

Global Mortality from Cervical Cancer exceeds 250,000 per year


Cancer Evolution and Screening


High-Risk HPV Life Cycle

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


High-Risk HPV Antigen Expression

Doorbar J, et al. Vaccine 2012;30S:F55-70

Predominance of E6 and E7 with loss of capsid proteins (L1 and L2)


Cervical Cancer: Interventions

Prognostic factors• LVI, Stromal Invasion, Tumor Size, Hypoxia

• Histology, Demographics, PS

• Access to Resources (daily radiation)

• Patterns of Spread• Pelvis, Distant Sites, Combined

• Nodal vs Parenchymal vs Regional Extension

? Neoadjuvant

Chemotherapy

Clinical

Staging

? Fertility-Sparing or

Risk-Stratified Surgery

? Adjuvant

ChemoRx

? Vaginal

BrachyRT

Recurrence

Chemotherapy

+/- anti-VEGF

Cellular

Immunity

Vaccines

Immune

Checkpoint

Inhibition

Surgery Alone

Radiation

+/- Concurrent

Chemotherapy

? Dose-

Schedule


NCIC CTG CX.5: SHAPE

Plante M for NCIC CTG and GCIG-CCRN

A Randomized Trial Comparing Radical Hysterectomy and Pelvic Node

Dissection vs Simple Hysterectomy And Pelvic Node Dissection in Patients

with Low-Risk Early- Stage Cervical Cancer

I

II SIMPLE Hysterectomy*

RADICAL Hysterectomy*

R

*Includes PLD (optional SLN)

Low-Risk Cervical Cancer:

• Stage IA2-IB1 squamous or adeno

• T <2 cm, ≥3 mm intact cervical

stroma, <50% stromal invasion

• Grade 1-3

• No evidence of LN metastases (MRI)

Stratified by Centers (SLN yes/no), Stage, Histology, Grade

Post-operative adjuvant therapy permitted based on final pathology

Primary Endpoint: Pelvic Relapse-Free Survival (PRFS)

Non-inferiority design, p = 0.05, 80% power with one interim analysis

Open: 01-DEC-2012

Target: 700 pts


Cervix NACT: INTERLACE

McCormack M for CRUK-NCRI and GCIG-CCRN

Carboplatin AUC=2

Paclitaxel 80 mg/m2

(Weeks 1-6)

Standard CRT*

R

*40 to 50.4 Gy + weekly Cisplatin + ICBT

• Stage IB2-IVA squamous or adenocarcinoma

• Documented HIV negative

• Excludes lower 1/3 vaginal invasion

• Excludes LN metastases above aortic bifurcation

Stratified by Stage, LN status, Histology, T volume, Institution, IRMT (Yes/No)

Primary Endpoint: Overall Survival

p = 0.05, 80% power to detect a 10% increase in 5 year OS

Open: NOV-2012

Target: 630 pts

Standard CRT*


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


Cervix CRT: TACO

Ryu for KGOG-ASGO and GCIG-CCRN

Radiation Therapy with

Cisplatin 40 mg/m2

(Weekly x6)

Radiation Therapy with

Cisplatin 75 mg/m2

(Tri-Weekly x3)

R

• Stage IB2, IIB-IVA squamous

or adenocarcinoma

Primary Endpoint: Overall Survival

p = 0.05, 80% power to detect a 10% increase in 5 year OS, HR = 1.50

Open: MAR-2012

Target: 590 pts

GCIG/KGOG1027/TGCS2012: Randomized Phase III Clinical Trial

Comparing Weekly vs Tri-weekly Cisplatin-Based Concurrent

Chemoradiation in Locally-Advanced Cervical Cancer

ICBT

ICBT


ANZGOG GOG0274: OUTBACK

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

Carboplatin AUC=5

Paclitaxel 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

I

II

Concurrent Chemo-Radiation

Cisplatin 40 mg/m2/wk

+ Intracavitary Brachytherapy

Observation

Open: 03-JAN-2012

Closed: 28-JUN-2017 (5.5 y)

Accrual: 780 pts (increased to 900)


GOG 0240: Cervix (Advanced/Met)

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

Cisplatin 50 mg/m2 (d1 or d2)

Paclitaxel 135 or 175 mg/m2

Open: 06-APR-09

Closed: 03-JAN-12

Accrual: 427 (eligible)

I

II

+/- 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 Randomization

1. Chemotherapy

2. Bevacizumab

• Stage IV-B or recurrent with measurable disease

• No prior chemotherapy, allow prior adjuvant RT+/-Chemo

• Primary Objective: OS


GOG 0240: Cervix (Advanced/Met)

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

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36Months on Study

Progression-Free Survival

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36Months on Study

Overall Survival

Chemo + Bev (n = 227) Chemo + Bev (n = 227)

Chemo Alone(n = 225)

Chemo Alone(n = 225)

HR (+/- 97% CI) = 0.71 (0.54-0.95)

p = 0.0035 (1-sided)

Median: 17.0 vs 13.3 months

HR (+/- 95% CI) = 0.67 (0.54-0.82)

p = 0.0002 (2-sided)

Median: 8.2 vs 5.9 months

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


GOG0240: Fistula Complications

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


Activating Cellular Immunity

Modified from: Advaxis Immunotherapies

Lm-LLO isphagocytosed by APC

Some Lm-LLO escapes the phagolysosome and enters the cytosol

Proteasomal degradation of tLLO-TAA fusion protein into peptides for MHC class I Ag presentation

Some Lm-LLO is killed and degraded within the phagolysosome

Peptide-MHC APC complexes stimulate CD4+ (MHC II) and CD8+ (MHC I) T cells

Lm, Listeria monocytogenes

TAA, tumor-associated antigen

tLLO, truncated listeriolysin O

AXAL, Axalimogene Filolisbac


AXAL Adjuvant Monotherapy

Herzog T. for GOG-Foundation

GOG-3009 (Advaxis ADXS001-02)

Open: 03FEB2017

Target: 450 patients


Cervical Cancer: Anti-PD-L1

KEYNOTE-028 (NCT02054806) Phase IB Multicohort Frenel J-S, ASCO 2016

Total n = 24, Squamous n = 23


GOG3016: Anti-PD1 vs ChemoRx

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)

R

Open: SEP2017

Accrual: 436 pts

I

IIChemotherapy

Investigator’s Choice*

REGN2810

350 mg IV q3w (x8 cycles)

* Pemetrexed, topotecan, irinotecan,

Vinorelbine, gemcitabine


Cervical Cancer

• Universal multivalent HPV vaccination to prevent infection in children, with an

emphasis on high-risk populations in the developing world

• Development of low-resource strategies for HPV vaccination and screening

• Potential to activate the cellular immune response using novel E6/E7 vaccines

• Tailored management of early-stage disease, including minimized surgery

(SHAPE)

• Optimized management of high-risk disease, including adjuvant

chemotherapy, dose/schedule of cisplatin

• Prospective randomized evaluation of NACT (INTERLACE)

• 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)

• Evaluation of immune checkpoint inhibition in high-risk and advanced disease


Obesity Trends, US (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


Metformin Translational Window

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

IHC Molecular Markers (Pre- and Post-Rx)

pAMPK 60.3% pAKT 44.2% pS6 51.2%

p4EBP1 74.7% ER 65.7% PR (NC)

Mean Ki-67 Index

Pre-Rx: 39.5

Post-Rx: 27.7

(n = 20)

Pre-Rx Post-Rx

New Diagnosis BMI ≥30

Endometrioid Histology

Metformin

850 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)


GOG0286B: CP +/- Metformin

Bae-Jump V for NRG

Carboplatin AUC 5


Placebo (QDBID)

R

I

II

Carboplatin AUC 5


Metformin 850 mg (QDBID)Metformin 850 mg BID

Placebo BID

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

• Stg III-IVA (measurable) and Stg IVB or recurrent

• No metformin within 6 months

• No prior chemotherapy

Open: 17-Mar-2014

Closed: (ongoing)

Target: 540 pts (Phase II + III)

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)


Targeting Endometrial Cancer

Type I Type II

Median 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


GOG0210: Endometrial Cancer MSI

Billingsley CC, et al. SGO 2015

No Abnormality Sporadic Defect Probable Mutation

MMR IHC Staining

MLH1 Methylation

MSI Testing

Intact

Methylated

Negative

MLH1 Loss

Methylated

Positive

Some MMR Loss

non-Methylated

Positive

Molecular Risk Low Low High

Total N (%) 578 (62%) 253 (27%) 107 (11%)

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

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

• 38% of patients had abnormalities in MMR/MSI, 11% with probable mutations

• 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


Molecular Subtypes from TCGA

TCGA Network. Nature 497:67-73, 2013

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


Anti-PD1 and MSI

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 = 21

Non-Colorectal: MMR Deficient = 9 (endometrial = 2)


Endometrial FGFR2 Mutations

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

FGFR2

• Observed pattern of non-overlapping mutations: KRAS, β-Catenin,

FGFR2, and PIK3CA

• Many activating FGFR2 mutations are in the TK domain

• Challenging to specifically target FGFR2, due to overlap of TKI

activity with VEGFR2


GOG0249: VCB/C vs PXRT

Randall ME, et al. ASTRO 2017

• Stage I high-intermediate risk, Stage II, Stage I-II (serous or clear cell)

• LND not required, but performed in 89%

• Primary Objective: Improved RFS with VCB/C

Open: MAR-2009

Closed: FEB-2013

Target: 527 pts (eligible/treated)

• Stage 2 in 25%, Grade 3 in 21%, Serous in 15%, Clear Cell in 4.5%

• Overall event rate 18%, no difference in vaginal or distant failures. Pelvic

and PA LN failure more common in VCB/C (9% at 5 y vs 4%, HR 0.47)

I

IIPelvic RT (Median 45 Gy)

3D Conformal or IMRT

+/- Brachytherapy Boost

Brachytherapy (HDR or LDR)

Carboplatin AUC=6

Paclitaxel 175 mg/m2

q3w (x3 cycles)R


GOG0249: Relapse-Free Survival


Cumulative IncidencePelvic or PA LN Recurrence


GOG0249: Overall Survival


VCB/C was not superior to PXRT• Relatively good-prognosis population (18% event rate)

• Lower risk of Pelvic or PA LN recurrence with PXRT

• High level of LND (89%)

• Utilization of 3D Conformal Radiation or IMRT

• Only 3 cycles of chemotherapy


Endometrial Cancer

• Obesity can impact cancer risk and outcomes, and is a target for intervention

• Potential role for metformin, especially in obesity-associated cancers

• Implementation of universal endometrioid MMR/MSI screening

• At least 4 distinct clinical/molecular entities, beyond “Type I and Type II”

• Angiogenic pathways, including VEGFR2 and FGFR2, as potential targets

• Emergence of immune checkpoint inhibition as an important strategy, in

hypermutated subtypes, especially MSI-high

• Management of high-grade serous tumors remains challenging, with a need to

address drug resistance and the DNA damage response

• Overall clinical management and outcomes have improved, with access to

minimally invasive surgery, well-tolerated chemotherapy (carboplatin-paclitaxel),

and precision radiation therapy (3D conformal and IMRT)

• Optimal utilization and sequence of chemotherapy and radiation therapy has not

yet been established


Cancer Death Rates (US 1930-2012)

Cisplatin

Paclitaxel

Cytoreduction

IP Cisplatin

NACT

Bevacizumab

Key Endpoints:

• Improvements in median PFS, OS, and QOL

• Modest reduction in incidence and mortality

(RR-BSO and HRT)

• No impact on overall case-fatality ratio (or cure)


Molecular and Clinical Pathobiology

• Activation of B-RAF or K-RAS MEK

• Not Associated with High-Risk Families

• Precursor SBTLGSC

• 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)


Art and Mythology of Surgery


Adoption of NACT (US)

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

Stage III-C Stage IV

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)


Impact of Initial Disease Distribution

Hamilton CA, et al. Gynecol Oncol 122:521-6, 2011

• All patients achieved optimal (R0 microscopic) Cytoreduction

• Combined analysis GOG 114, 158, 172 intravenous chemo (n = 417)

Upper abdominal tumor burden correlated with inferior long-term clinical

outcomes, even though all patients achieved R0 status


Impact of Disease Scoring

Horowitz NS, et al. J Clin Oncol 10.1200/JCO.2014.56.3106

Data from GOG0182 FIGO Stage III-IV (n = 2,655)

Analyzed according to R0 (microscopic) or MR (macroscopic) residual, and

pre-operative DS (disease score)

• Achieving R0 generally associated with better outcomes

• Outcomes with R0 not improved with high PRE-operative DS

• Value of aggressive cytoreduction not resolved in extensive disease


Epithelial-Mesenchymal Transition

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

SCC15 AKT Activated

E-cadherin

Vimentin


Predicting Suboptimal Cytoreduction

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

Expression:

Suboptimal

Optimal

Prognosis

• Activation of key molecular pathways, including TGF-β and EMT, are

associated with invasive metastatic behavior and suboptimal outcomes

• Current molecular assays not sufficiently predictive to guide individual

surgical management

• Other strategies include functional imaging and decision-mode laparoscopy


Trial on Radical Upfront Surgical Therapy

Mahner S, Elser G, Fotopoulou C, et al. for TRUST

• Primary Endpoint: OS ITT population

• Secondary Endpoints PFS, resection rates, QOL, Fragility Index

• Strata: FIGO stage, Region, ECOG PS

• Site qualification process to ensure surgical quality

SC

P

C

P

C

P

C

P

C

P

C

P

C

P

C

P

C

P

C

P

C

P

C

PS

Bevacizumab 15mg/sq x 15

R

Bevacizumab 15mg/sq x 15

S surgery C PCarboplatin AUC5 Paclitaxel 175 mg/sq

Site Qualification

Accrual Status: 120/700 (May2017)


OV1741 (concept): NACT +/- ICS

Bregar A and Fleming G for NRG Oncology

• Epithelial ovarian, peritoneal, or fallopian carcinoma (EOPFC)

• Stage IIIC-IV and suitable for NACT with ICS

• Registered after CT with MRD, prior to planned ICS

• Permits minimally-invasive ICS

• Primary Endpoints: PFS and PRO/QoL

Status: Concept in planning

Target: Approximately 150 pts

Notes: Evaluating options for NCI support (DCP or CTEP)

CP (x3) CT-MRDCore Bx

CP = Carboplatin AUC 6 (D1), Paclitaxel 80 mg/m2 (D1,8,15)

CT-MRD = CT post-chemotherapy with minimal residual disease

ICS = Interval Cytoreductive Surgery (minimally invasive allowed)

CP (x3)ICS

CP (x3)No

ICS

R


NRG GY007: NACT +/- Ruxolitinib

Burger R, for NRG Oncology



• Phase I evaluating acute toxicity (C1) and cumulative tolerability

• Primary Endpoints: PFS and molecular targeting (stem cells, IL6)

Open: OCT 2016

Status: Ongoing Accrual (Phase I)

Target: Approximately 150 pts

CP (x3) ICS CP (x3) Observation

CP (x3)

+ Rux

CP (x3)

+ Rux

Rux Maint

(optional)ICS

Core Bx R 1:2

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


NRG GY015: NACT +/- Metformin

Yamada D, for NRG Oncology and U Chicago SPORE

Open: JUN 2014

Status: Ongoing Accrual (U Chicago SPORE)

Target: 76 pts

CP (x3) ICS CP (x3) Observation

CP (x3)

+ MET

CP (x3)

+ METMET MaintICS

Core Bx R 1:2



• No known diabetes or use of metformin

• Primary Endpoints: PFS and molecular/metabolic targeting

CP = Carboplatin AUC 6 (D1), Paclitaxel 80 mg/m2 (D1,8,15)

MET = Metformin 850 mg PO BID

ICS = Interval Cytoreductive Surgery


What About IP and Dose-Dense…

???

Chhatrapati Shivaji Terminus, Mumbai 2012


GOG0252: IP Therapy

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)

R

I

III

II

Carboplatin AUC=6 (IP)

Paclitaxel 80 mg/m2 (d1,8,15)

Bevacizumab (C2-6)

Bevacizumab

q21d x 16

Bevacizumab

q21d x 16

Bevacizumab

q21d x 16

IV Carbo

IP Carbo

IP Cisplatin

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer

• Optimal and Suboptimal Disease (through April 2011)

• Primary Endpoint: PFS (Analysis JAN 2016)

Open: 27-Jun-2009

Closed: 29-Oct-2011

Accrual: 1560 pts (max 250 suboptimal)


GOG0252: IP Therapy (PFS)

Walker J. for GOG, 2016

PFS ITT (All Eligible Patients)


GOG0252: IP Therapy (OS-Prelim)

Walker J. for GOG, 2016

• Current IV chemotherapy appears at least as

effective as modified IP chemotherapy

• Median OS exceeds historical data from GOG0172

OS ITT (All Eligible Patients)


iPocc: IP Carboplatin

Fujiwara K, for GOTIC and JGOG

• Stage II to IV ovarian, primary peritoneal, or fallopian

tube cancer (including suboptimal cytoreduction)

• Primary Endpoint: PFS

• Secondary Endpoints: OS, Toxicty, QoL, Cost/Benefit

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

Carboplatin AUC 6 IV, Day 1, Cycles 1-6

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

Carboplatin AUC 6 IP, Day 1, Cycles 1-6

R

Target: 655 pts (closed OCT2016)


Old Drugs, New Tricks (Maybe…)


GOG262 ACRIN6695: Dose-Dense

Chan JK, et al. NEJM, 2016


• Suboptimal residual disease (optional NACT-ICS)

• Primary Endpoint: PFS

• Early perfusion-based CT imaging (ACRIN 6695)

Carboplatin AUC=6

Paclitaxel 80 mg/m2 (d1,8,15)

+/- Bevacizumab (C2-6)$

I

II

Bevacizumab

q21d$

Bevacizumab

q21d$

Carboplatin AUC=6

Paclitaxel 175 mg/m2 (d1)

+/- Bevacizumab (C2-6) $

$ Use of Bevacizumab elected prior to randomization

R

Open: 27-SEP-2010

Closed: 08-FEB-2012 (ACRIN JUN-2013)

Target: 692 pts (randomized)


GOG262 ACRIN6695: Dose-Dense

Chan JK, et al. NEJM, 2016

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30 36

Pro

port

ion P

rogre

ssio

n-F

ree

Months on Study

Schedule ( n ) PFS

(+)

BEV

Three-Weekly

Dose-Dense Weekly

289

291

14.7

14.9

(-)

BEV

Three-Weekly

Dose-Dense Weekly

57

55

10.3

14.2

• 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


GOG262 ACRIN6695 Biomarkers

Ng C, et al. Clin Cancer Res 2017


GOG262 ACRIN6695 Biomarkers

Ng C, et al. Clin Cancer Res 2017

Blood Flow

Decreased

Blood Flow

Increased


MRC-UK ICON8: Dose-Dense

Clamp A, et al. ESMO 2017

IPS

IPS Chemo x6

DP

S

Bx Chemo x3 DPS Chemo x3

AS

SIG

NE

D

(Non-R

andom

ized)

RANDOMIZE

1:1:1

Carboplatin AUC=5 q3w

Paclitaxel 175 mg/m2 q3w1






• Presumptive Stage IC-IV

• Assigned to Immediate (IPS) or Delayed (DPS) Primary Surgery

• Stage III: Median PFS and OS

Open: JUN-2011

Closed: NOV-2014

Target: 1566 pts




Arm 1 Arm 2 Arm 3

StandardWeekly

paclitaxel

Weekly

carbo-paclitaxel

Total Patients N=522 N=523 N=521

Progressions 330 (63%) 335 (64%) 338 (65%)

Median PFS 17.9 months 20.6 months 21.1 months

Log rank (vs

Arm1)p=0.45 p=0.56

HR vs Arm 1

(97.5% CI)

0.92

(0.77, 1.09)

0.94

(0.79, 1.12)Restricted

means24.4 months 24.9 months 25.3 months

Primary Analysis PFS (ITT)


GOG3005: PARPi Primary Therapy

Coleman R, for GOG Foundation

x 6II Veliparib 400 mg

PO BID

Paclitaxel (standard or dose-dense)

Carboplatin AUC 6 (IV)*

Veliparib 150 mg PO BID

x 6I



Placebo PO BID

Placebo

PO BID

x 6II Placebo

PO BID



Veliparib 150 mg PO BID

• 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

Collaborative development with AbbVie (M13-694) including international

participation, seeking EMA and FDA regulatory approval

Open: JUL 2015

Closed: MAY 2017

Target: ~1100 pts (264 BRCA1/2 +)


PARPi: Therapy vs Maintenance

• Emerging data with maintenance and treatment is compelling, with an

immediate impact on regulatory approvals and PARPi utilization

• Should control of small-volume asymptomatic disease be our goal? Timing

and sequence has not been addressed in any prospective clinical trial…

• It is difficult to monitor ongoing response in a maintenance setting, with

normal CA125 and imaging (+/- secondary cytoreduction), and many patients

could actually receive ineffective therapy for a prolonged period of time

• Consider the importance of balancing treatment-related toxicity, risk of

symptomatic recurrence, and time off-therapy (in a non-curative setting)

• PRO, QoL, Quality-adjusted PFS, and TWIST provide guidance, but do not

establish optimal clinical benefit

• Uncertain how regulatory authorities will incorporate surrogates for OS, such

as TFST, TSST, etc.

• Long-term PARPi exposure is associated with emergence of resistance,

potentially limiting subsequent therapeutic benefit


CP Bevacizumab +/- Atezolizumab

Moore K and Pignata S, for GOG-F and ENGOT

YO39523/GOG-3015/ENGOT-ov39 • Previously untreated high-grade cancer

• Stage III macroscopic or Stage IV (allows election of NACT), Bx cohort

• Stratification PDL1 0 vs 1+, Stage, PS, NACT

• Co-Primary endpoints (PDL1+): OS HR 0.72 (81%, 0.046), PFS HR 0.7

Open: MAR 2017

Status: Ongoing Accrual

Target: 1300 pts

Carboplatin AUC=6 D1

Paclitaxel 175 mg/m2 D1

Bevacizumab 15 mg/kg D1

Atezolizumab 800 mg D1

R

Carboplatin AUC=6 D1

Paclitaxel 175 mg/m2 D1


Placebo IV D1

I

II

Bevacizumab 15 mg/kg

Placebo

(q3w x 16 cycles)


Atezolizumab 800 mg D1

(q3w x 16 cycles)


NRG GY009: PLD +/- Bev +/- Atezo

O’Cearbhaill RE, for NRG Oncology

• Recurrent high-grade, PFI < 6 months (most recent platinum)

• No more than 2 prior regimens (including primary therapy)

• RECIST measurable or evaluable disease with accessible tumor

• No prior anti-angiogenics for platinum-resistant recurrence

• Primary endpoints: Phase II PFS (selective) Phase III OS

Open: MAY 2017

Status: Ongoing safety lead-in (Phase I Working Group)

Target: 272 Phase II, Cumulative 488 Phase III

PLD 40 mg/m2 IV q4w

Bevacizumab 10 mg/kg IV q2w

Atezolizumab 800 mg IV q2w

PLD 40 mg/m2 IV q4w

Bevacizumab 10 mg/kg IV q2w

R

PLD 40 mg/m2 IV q4w

Atezolizumab 800 mg IV q2wI

II

III

HR PFS ≤ 0.783 (88% power)

HR OS* ≤ 0.625 (90% power)

*one-tail α 0.0115

(multiple comparisons)


NRG GY004: Olap +/- Cediranib

Liu J, for NRG Oncology

Cediranib 30 mg QD

Olaparib 200 mg BID

Platinum-based combo* (IV)

R

*Carboplatin + gemcitabine or paclitaxel or PLD

Olaparib 300 mg BID

• Recurrent HGSC with PFI > 6 months (most recent platinum)


• 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

Open: FEB 2016

Status: Ongoing Accrual

Target: 550 pts (135 BRCA1/2 +)


OV1719 (concept): Olap + Tremi

Adams S, for NRG Oncology

Preliminary data from pilot clinical trial at U New Mexico (INST1419)

Potential Mechanisms:

• Therapeutic synergy in immunocompetent

murine tumor model with BRCA1m OvCa

• PARPi-mediated immunogenicity through

increased expression of MHC1 and Fas

• Role of IFN-γ as mediator and predictive

marker (exploratory endpoint)

• Exploit anti-CTLA4 compared to PD-1

Olaparib 300mg PO twice daily. Tremelimumab IV

10mg/kg monthly x6 then every 3 m, up to 2 years


OV1719 (concept): Olap + Tremi

Adams S and Brady M, for NRG Oncology

• Recurrent HGSC with PFI > 6 months (following most recent platinum)


• RECIST measurable disease

• No prior PARPi therapy or immune checkpoint inhibitors

• Primary endpoint: PFS (pre-specified sequential analysis)

Status: Concept in planning

Target: 420 pts (126 BRCAm+, 168 HRD+, 126 HRD-)


FOCUS: CA4P (Fosbretabulin) VDA

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 GOG0186I


GOG-3011: FRα ADC

Moore K, et al. for GOG Foundation

• 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

R

I

IIChemotherapy

Investigator’s Choice*

IMGN853 6 mg/kg

IV q3w

* Paclitaxel, PLD, or topotecan

2 : 1


GOG-3017: Anetumab-Ravtansine

GOG Foundation

I

IIBAY94-9343 6.5 mg/kg q3w

PLD 30 mg/m2 q3w

BAY94-9343 6.5 mg/kg q3w

III PLD 50 mg/m2 q4w

R

• Ovarian Cancer, Recurrent < 6 m from most recent platinum-based therapy

• Human IgG1, disulfide linker, ravtansine cytotoxic (anti-tubulin)

• Confirmation of mesothelin expression by IHC (expected positive in 80%)

• RECIST measurable disease, excludes known BRCA1/2 mutations

• Stratification by prior bevacizumab, BRCA status, PFI duration

• Endpoints: PFS (3.6 m to 7.2 m) HR 0.50 with 90% power, split alpha 0.0125


Ovarian Cancer

• The mortality of advanced-stage HGSC has not changed, in spite of recent

advances in treatment and supportive care, with improved PFS-OS

• The role of primary aggressive cytoreductive surgery is being evaluated

(TRUST), but may have limited impact in patients with high disease burden

• Contemporary IV chemotherapy appears equivalent to modified IP

chemotherapy with either cisplatin or carboplatin

• Dose-dense weekly paclitaxel may have advantages in some populations, but

data from randomized trials are conflicting

• NACT with ICS offers a valuable platform for clinical research

• PARP inhibition has become widely utilized (as therapy and maintenance) with

questions about patient selection, timing, resistance, and combinations with

other agents, including immunotherapy and antiangiogenics

• The role of immune checkpoint inhibition in HGSC is unknown, but likely to be

complicated by multiple pathways of immunosuppression

• Novel approaches include antibody-drug-conjugates (ADC), vascular disruptive

agents (VDA), and agents that target the DNA damage response


Thank You!

Gynecologic Tumors, State-of-the-Art · Stratified by Stage, LN status, Histology, T volume,...

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Transcript of Gynecologic Tumors, State-of-the-Art · Stratified by Stage, LN status, Histology, T volume,...