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Molecular Therapeutics for Ovarian Cancer:

Targeting the Tumor Microenvironment

Robert L. Coleman, MD

Professor & Executive Director, Cancer Network Research

Dept. Gynecologic Oncology & Reproductive Medicine

M.D. Anderson Cancer Center, Houston

Research

Grants

Abbvie, AstraZeneca Pharmaceuticals LP, Clovis

Oncology, Esperance, Genentech/Roche, Janssen

Biotech Inc, Merck, V-Foundation, Gateway Foundation

Advisory

Committee

Abbvie, AstraZeneca Pharmaceuticals LP, Bayer

HealthCare Pharmaceuticals, Clovis Oncology,

Roche/Genentech, Esperance, Janssen Biotech Inc,

Merck

Disclosures

The Tumor Microenvironment (TME) in Oncogenesis

Quail Nat Med 2013

TME: Angiogenesis as a Target

Pericyte Tumor

Endothelium

Tumor Cell

Stroma and Immune Cells


Study Agent Setting HR-PFS (95% CI)

HR-OS (95% CI)

GOG 218 Bevacizumab Front-line/Maintenance 0.72 (0.63-0.82) 0.89 (0.75-1.04)

ICON7 Bevacizumab Front-line/Maintenance 0.81 (0.70-0.94) 0.99 (0.85-1.14)

AGO-OVAR12 Nintedanib Front-line/Maintenance 0.84 (0.72-0.98) Neg

AGO-OVAR16 Pazopanib Primary Maintenance 0.77 (0.64-0.91) 0.99 (0.75-1.32)

AURELIA Bevacizumab Recurrence, Platinum-resistant, 1-2 priors 0.48 (0.38-0.60) 0.85 (0.66-1.08)

TRINOVA-1 Trebananib Recurrence, Platinum-resistant/sensitive,

1-3 priors 0.66 (0.57-0.77) 0.86 (0.69-1.08)

OCEANS Bevacizumab Recurrent, Platinum-sensitive, 1 prior 0.53 (0.41-0.70) 0.96 (0.76-1.21)

ICON6 Cediranib Recurrent, Platinum-sensitive, 1 prior 0.57 (0.44-0.74) 0.76 (0.55-1.05)

GOG0213 Bevacizumab Recurrent, Platinum-sensitive, 1 prior 0.61 (0.52-0.72) 0.82 (0.68-0.99)

Angiogenesis Therapy: The “Banana Effect”

GOG-218 ICON-7

AURELIA GOG-213

OVAR-12

OCEANS

Angiogenesis “Escape”

Bottsford-Miller, Coleman and Sood, J Clin Oncol 2012

Adaptive resistance to anti-VEGF drugs

Bevacizumab + paclitaxel started

Bevacizumab + paclitaxel started

Disease Progression

Adaptive resistance to anti-VEGF drugs

Phenotypic Diversity Of

Macrophage Populations

Dalton, Coleman, Sood, Clin Cancer Res 2017

Targeting Immune Microenvironment

VEGF-Resistance Model Macrophage Trafficking Macrophage VEGFR Expression

Addition of CSF1-R inhibitor to adaptive resistant tumors treated with Pac/Bev Dalton, Clin Cancer Res 2017

REDIRECT: Randomized Phase II

• Loss of VEFGR-1, 3 expression

• CSF-1R expressing

macrophages

• Emactuzumab is a CSF-1R

inhibitor

“Next-Gen” Angiogenesis Therapy

• Reverse epigenetic regulatory and

response transcriptions factors

(EZH2, VASH1, Dll4/Notch, etc)

• Alter EMT and MET processes

• Alternative growth signaling (FAK,

Paxillin, Ephrins)

• Abrogate immune response

(TAM’s, CAF, PD-1/PD-L1, etc)

E2F1

E2F3

VEGF

VEGFR-2

Transcription Factors

EZH2

Angiogenesis

VASH1

EZH2

Lu, Cancer Cell 2010

E2F1

E2F3

VEGF

VEGFR-2

Transcription Factors

EZH2

Angiogenesis

VASH1

EZH2

EZH2 Targeting: Tazametostat

Tazemetostat

C. Dulaney et al. / Seminars in Cell & Developmental Biology 63 (2017) 144–153

PARP as a Therapeutic Target

DNA Damage Response: PARP

Nature 2005

BRCA +/+

BRCA -/-

BRCA +/- 1000x

Olaparib: Objective Response – BRCA-mt

Chemotherapy

T

T T

Matulonis U… Coleman RL. Ann Oncol 2016

Griffiths RW et al. Int J Gynecol Cancer. 2011;21:58-65.

PARPi Phase III Maintenance Trials – Ovary

PFS (inv Review – Primary) Rucaparib Placebo HR P

tBRCA 16.8 5.4 0.23 P<0.0001

tBRCA + HRD 13.6 5.4 0.32 P<0.0001

ITT 10.8 5.4 0.37 P<0.0001

PFS (BICR – Primary) Niraparib Placebo HR P

tBRCA 21.0 5.5 0.26 P<0.0001

tBRCA + HRD - - -

All non-gBRCA (sBRCA+ HRD + HRC) 9.3 3.9 0.45 P<0.001

ITT (FDA analysis) 11.3 4.7 0.42 Not Given

PFS (Inv Review - Primary) Olaparib Placebo HR P

gBRCA 19.1 5.5 0.30 P<0.0001

Treatment Paradigm for Use of PARP Inhibitors

Under investigation

FDA approved

y

Symptoms

Diagnosis

Chemo #1

Staging/debulking

Evaluation ? SLL

Progression

Chemo #2

Chemo #3

Supportive care

Death

Secondary surgery?

Chemo #4+

Maintenance M Concomitant Concomitant

M

What’s Next? • Enhancement therapy

• Resistance therapy

• Contextual synthetic lethality (inducing HRD in HR compliant tumors)

What’s Next? • Enhancement therapy

– Chemotherapy (DNA-damaging agents); GOG-3005 – Immune checkpoint inhibitors (CTLA-4, PD-1, PD-L1) – Radiation therapy

• Resistance therapy – P53 targeted agents (AZD-1775, COTI-2, selinexor) – CDK inhibitors (ribociclib, palbociclib, roniciclib) – HDAC – HSP90 – MEK

• Contextual synthetic lethality (inducing HRD in HR compliant tumors) – Hypoxia inducement (anti-angiogenesis, EZH2) – PI3K pathway inhibitors – ATR/ATM, CDK inhibitors

Targeting The Stroma (CAFs)

Quail Nat Med 2013


• Reactive stromal cells play an integral role in cancer cell survival

• An adaptive response to PARPi and anti-angiogenesis therapy

• Reliable therapeutic targets are few

• Glutamine pathway provides a unique energy source for CAFs

Yang, Cell Met 2016


• Synthetic lethal targeting glutamine synthetase in CAFs and glutaminase in cancer cells

• Selective inhibitors (CB-839, IACS-6274) are in phase I/II trials

• Synergy with chemotherapy may be due to reduced interstitial pressure and reprogramming immune surveillance

Yang, Cell Met 2016

Re-educating the Tumor Microenvironment

Quail Nat Med 2013

Metastatic Organ “Tropism”

Mechanism of dissemination: • Direct extension • Ascites • Vasculature

Metastatic Organ Tropism

Pradeep, Cancer Cell 2014

Metastatic Organ Tropism

Pradeep, Cancer Cell 2014

Similar Effect Seen with MM-121 • Anti-ErbB3 antibody

ErbB3-Targeting: Seribantumab

Liu, J Clin Oncol 2016

ITT Biomarker Positive

Re-educating the Tumor Microenvironment

Quail Nat Med 2013

Tumor

Ipilimumab* Tremelimumab

CTLA-4 PD-1/PD-L1

Priming phase Effector phase

Nivolumab* Pembrolizumab*

Atezolizumab* Avelumab

Durvalumab

Ribas A. N Engl J Med. 2012;366(26):2517-2519.

Immunotherapy

Nivolumab1 Pembrolizumab2 Avelumab3 Atezolizumab4 Durvalumab5

N 20 26 124 12 20*

Prior therapies ≥4

in 55% of cases

≥5

in 38.5%

≥3

In 65.3%

≥6

In 58%

4*

Median

PD-L1+

prevalence

80%

(IC 2/3)

100%

(≥1% TC)

77%

(≥1% TC)

83%

(IC 2/3)

73%

(>5% TC)

ORR (95% CI) 15% 11.5% 9.7% 25% Not reported

mPFS, months 3.5 Not reached 2.6 2.9 Not reported

mOS, months 20 Not reached 10.8 11.3 (IC2);

17.4 (IC3) Not reported

* Includes ovarian cancer (n = 15), triple-negative breast cancer (n = 2), cervical cancer (n = 2), and uterine leiomyosarcoma patients (n = 1)

CI, confidence interval; IC, immune cell; ORR, overall response rate; mOS, median overall survival; mPFS, median progression-free survival; TC, tumor cell;

TRAE, treatment-related adverse event, Tx, treatment

1. Hamanishi J, et al. J Clin Oncol. 2015;33(34):4015-4022. 2. Varga A, et al. J Clin Oncol. 2015;33(suppl): Abstract 5510. 3. Disis ML, et al. J

Clin Oncol. 2016;34(suppl): Abstract 5533. 4. Infante JR, et al. Ann Oncol. 2016;27(suppl_6): Abstract 871P. 5. Lee J-M, et al. J Clin Oncol.

2016;34(suppl): Abstract 3015.

Immune Checkpoint Inhibitors in Ovarian Cancer: Overview

Alexandrov Nature 2013

Neoantigen Repertoire by Tumor Primary

Alexandrov Nature 2013

Neoantigen Repertoire by Tumor Primary

BRCA/HRD Ovarian Cancer

MSI/POLE Uterine Cancer

FDA Regulatory Actions: Pembrolizumab GYN

MSI-H

Cervix

Enhancement Strategies: IO+PARPi

PSR OC

2L+

gBRCAm

PARPi and IO naïve Durvalumab 1.5 g IV q4w

4 week run-in

Tumor assessments

Optional biopsies

• Primary endpoints: DCR at 12 weeks, safety

• Secondary endpoints: DCR at 28 weeks, ORR, DoR, PFS, OS, PD-L1 expression

• Exploratory endpoints: TILs

8 weeks 8 weeks

Target DCR

at 12 weeks:

90%*

N=31

*Target based on olaparib monotherapy efficacy

Olaparib 300 mg po bid

MEDIOLA TOPACIO

ATHENA

• Statistical Design (PFS) (a= 0.0166)

• A vs B

• A vs D

• B vs D

• Step down procedure

• tBRCA, if positive

• tBRCA + LOH-H, if positive

• ITT

Front. Genet., 2012 3:124

Cytoplasmic and Nuclear Exosomes

Hanahan, Cell (2011)

• Tumor microenvironment is a dynamic and adaptive functional structure providing regulatory support for tumor survival, growth, spread and the EMT-MET process

• Each element, tumor, vasculature, lymphatics, stroma, immune cells, nerves, exosomes, etc., provides treatment opportunity

• Functional non-invasive and invasive real-time surveillance strategies are necessary to optimize treatment

• Clinical trials designed for adaptive response need to keep pace with emerging information of tumor biology

The Challenge…

Thank You!

[email protected]

Photography

molecular therapeutics for ovarian cancer: targeting the ... 1_ robert coleman.pdfmolecular...

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