Gynecologic Tumors, State-of-the-Art Michael A Bookman MD Chair, - - PowerPoint PPT Presentation

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Gynecologic Tumors, State-of-the-Art Michael A Bookman MD Chair, - - PowerPoint PPT Presentation

Nov 03, 2022 164 likes •860 views

f Bowtell DD, et al. Rethinking ovarian cancer II. Nature Reviews Cancer 15:668-79, 2015 Gynecologic Tumors, State-of-the-Art Michael A Bookman MD Chair, Ovarian Subcommittee, NRG Oncology Director, Gynecologic Oncology Therapeutics The Kaiser

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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

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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

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Cancer Evolution and Screening

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High-Risk HPV Life Cycle

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

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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)

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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

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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

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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*

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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

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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
  • r 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

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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)

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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
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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 12 24 36 Months on Study

Progression-Free Survival

0.0 0.2 0.4 0.6 0.8 1.0 12 24 36 Months 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

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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%) T

  • tal 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
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Activating Cellular Immunity

Modified from: Advaxis Immunotherapies

Lm-LLOis phagocytosed 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

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AXAL Adjuvant Monotherapy

Herzog T. for GOG-Foundation GOG-3009 (Advaxis ADXS001-02) Open: 03FEB2017 Target: 450 patients

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Cervical Cancer: Anti-PD-L1

KEYNOTE-028 (NCT02054806) Phase IB Multicohort Frenel J-S, ASCO 2016 Total n = 24, Squamous n = 23

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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 II Chemotherapy Investigator’s Choice* REGN2810 350 mg IV q3w (x8 cycles)

* Pemetrexed, topotecan, irinotecan, Vinorelbine, gemcitabine

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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

  • f fistula formation (in patients with prior radiation)
  • Evaluation of immune checkpoint inhibition in high-risk and advanced disease
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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

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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)
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GOG0286B: CP +/- Metformin

Bae-Jump V for NRG Carboplatin AUC 5 Paclitaxel 175 mg/m2 (3 h) Placebo (QDBID) R I II Carboplatin AUC 5 Paclitaxel 175 mg/m2 (3 h) Metformin 850 mg (QDBID) 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)

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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

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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

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Molecular Subtypes from TCGA

TCGA Network. Nature 497:67-73, 2013

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

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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)

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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

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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 II

Pelvic 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

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GOG0249: Relapse-Free Survival

Randall ME, et al. ASTRO 2017

Cumulative Incidence Pelvic or PA LN Recurrence

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GOG0249: Overall Survival

Randall ME, et al. ASTRO 2017

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
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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

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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)
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Molecular and Clinical Pathobiology

  • 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)
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Art and Mythology of Surgery

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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)

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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

  • utcomes, even though all patients achieved R0 status
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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
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Epithelial-Mesenchymal Transition

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

SCC15 AKT Activated E-cadherin Vimentin

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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
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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

S

C P C P C P C P C P C P C P C P C P C P C P C P

S

Bevacizumab 15mg/sq x 15

R

Bevacizumab 15mg/sq x 15 S surgery C P Carboplatin AUC5 Paclitaxel 175 mg/sq

Site Qualification Accrual Status: 120/700 (May2017)

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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-MRD Core 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

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NRG GY007: NACT +/- Ruxolitinib

Burger R, for NRG Oncology

  • Epithelial ovarian, peritoneal, or fallopian carcinoma (EOPFC)
  • Stage IIIC-IV and suitable for NACT with ICS
  • 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

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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) + MET MET Maint ICS Core Bx R 1:2

  • Epithelial ovarian, peritoneal, or fallopian carcinoma (EOPFC)
  • Stage IIIC-IV and suitable for NACT with ICS
  • 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

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What About IP and Dose-Dense…

???

Chhatrapati Shivaji Terminus, Mumbai 2012

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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)

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GOG0252: IP Therapy (PFS)

Walker J. for GOG, 2016

PFS ITT (All Eligible Patients)

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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)

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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)

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Old Drugs, New Tricks (Maybe…)

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GOG262 ACRIN6695: Dose-Dense

Chan JK, et al. NEJM, 2016

  • Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer
  • 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)

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GOG262 ACRIN6695: Dose-Dense

Chan JK, et al. NEJM, 2016

0.0 0.2 0.4 0.6 0.8 1.0 6 12 18 24 30 36

Proportion Progression-Free 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

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GOG262 ACRIN6695 Biomarkers

Ng C, et al. Clin Cancer Res 2017

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GOG262 ACRIN6695 Biomarkers

Ng C, et al. Clin Cancer Res 2017

Blood Flow Decreased Blood Flow Increased

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MRC-UK ICON8: Dose-Dense

Clamp A, et al. ESMO 2017 IPS IPS Chemo x6 DPS Bx Chemo x3 DPS Chemo x3

ASSIGNED (Non-Randomized) RANDOMIZE

1:1:1 Carboplatin AUC=5 q3w Paclitaxel 175 mg/m2 q3w

1

Carboplatin AUC=5 q3w Paclitaxel 80 mg/m2 q1w

2

Carboplatin AUC=2 q1w Paclitaxel 80 mg/m2 q1w

3

  • Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer
  • 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

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GCIG Education Symposium, November 2017, Vienna

MRC-UK ICON8: Dose-Dense

Clamp A, et al. ESMO 2017

Arm 1 Arm 2 Arm 3 Standard Weekly 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 means 24.4 months 24.9 months 25.3 months

Primary Analysis PFS (ITT)

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GCIG Education Symposium, November 2017, Vienna

MRC-UK ICON8: Dose-Dense

Clamp A, et al. ESMO 2017

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GCIG Education Symposium, November 2017, Vienna

GOG3005: PARPi Primary Therapy

Coleman R, for GOG Foundation

x 6 II Veliparib 400 mg PO BID Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Veliparib 150 mg PO BID x 6 I Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* Placebo PO BID Placebo PO BID x 6 II Placebo PO BID Paclitaxel (standard or dose-dense) Carboplatin AUC 6 (IV)* 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 +)

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GCIG Education Symposium, November 2017, Vienna

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

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GCIG Education Symposium, November 2017, Vienna

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 Bevacizumab 15 mg/kg D1 Placebo IV D1 I II Bevacizumab 15 mg/kg Placebo (q3w x 16 cycles) Bevacizumab 15 mg/kg D1 Atezolizumab 800 mg D1 (q3w x 16 cycles)

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GCIG Education Symposium, November 2017, Vienna

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 q2w I II III HR PFS ≤ 0.783 (88% power) HR OS* ≤ 0.625 (90% power) *one-tail α 0.0115 (multiple comparisons)

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GCIG Education Symposium, November 2017, Vienna

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)
  • No more than 3 prior 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

Open: FEB 2016 Status: Ongoing Accrual Target: 550 pts (135 BRCA1/2 +)

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GCIG Education Symposium, November 2017, Vienna

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

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GCIG Education Symposium, November 2017, Vienna

OV1719 (concept): Olap + Tremi

Adams S and Brady M, for NRG Oncology

  • Recurrent HGSC with PFI > 6 months (following most recent platinum)
  • No more than 3 prior regimens (including primary therapy)
  • 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-)

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GCIG Education Symposium, November 2017, Vienna

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 Data ORR 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

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GCIG Education Symposium, November 2017, Vienna

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 II Chemotherapy Investigator’s Choice* IMGN853 6 mg/kg IV q3w

* Paclitaxel, PLD, or topotecan 2 : 1

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GCIG Education Symposium, November 2017, Vienna

GOG-3017: Anetumab-Ravtansine

GOG Foundation I II BAY94-9343 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
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GCIG Education Symposium, November 2017, Vienna

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

  • ther 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

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Thank You!