Novel Targets And Strategies in Glioblastomas Patrick Y. Wen, M.D. - - PowerPoint PPT Presentation

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Novel Targets And Strategies in Glioblastomas Patrick Y. Wen, M.D. - - PowerPoint PPT Presentation

Jan 22, 2023 156 likes •1.03k views

Novel Targets And Strategies in Glioblastomas Patrick Y. Wen, M.D. Center For Neuro-Oncology Dana Farber/Brigham and Women s Cancer Center Division of Neuro-Oncology, Department of Neurology Brigham and Women s Hospital g p Harvard

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Novel Targets And Strategies in Glioblastomas

Patrick Y. Wen, M.D.

Center For Neuro-Oncology Dana Farber/Brigham and Women’s Cancer Center Division of Neuro-Oncology, Department of Neurology Brigham and Women’s Hospital g p Harvard Medical School

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DISCLOSURES DISCLOSURES

R h S t Ad i B d

  • Research Support

– Amgen – Astra Zeneca

  • Advisory Board

– Merck – Novartis Astra Zeneca – Boehringer Ingelheim – Esai E li i Novartis – Vascular Biogenic – NeOnc Inc – Exelixis – Genentech/Roche – Geron

  • Speaker

– Merck – Genentech/Roche – Medimmune – Merck N ti Genentech/Roche – Novartis – Sanofi-Aventis – Vascular Biogenics

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Treatment of High Grade Gliomas Treatment of High-Grade Gliomas

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Mil t i N O l Milestones in Neuro‐Oncology

A l Approvals

TMZ for TMZ up front for GBM Radiotherapy relapsed AA accelerated approval Gliadel wafer Lomustine Carmustine Avastin for recurrent GBM

1970 1980 1990 2000 2010

Levin criteria: Macdonald criteria: MRI + steroids; First US commercial MRI Brain Tumor Clinical Trial First US commercial CT RANO Criteria

Technology Advances

Levin criteria: CT scans ; WHO Pathology Criteria Endpoints Workshop ASCO Workshop

Technology Advances

AA=anaplastic astrocytoma; CT=computed tomography; GBM=glioblastoma multiforme; MRI=magnetic resonance imaging; RANO=Response Assessment in Neuro‐Oncology.

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Ang: CVX 060, Trebananib EGF: ABT-806, Cetuximab, Nimotuzumab, Panitumumab VEGF: Aflibercept VEGFR: Axitinib, Brivanib, Cabozantinib, Cediranib, Dasatinib, Foretinib, Lenvatinib, Nintedanib, Pazopanib, Pegdinetanib, Sorafenib, Sunitinib, Vandetanib Tie-2: Cabozantinib FGFR: Brivanib, Lenvatinib, Nintedanib CXCR4: Plerixafor

ECM Notch

HGF: Rilotumumab IL-2: Basiliximab, Daclizumab PDGFα: IMC-3G3, MEDI-575 PGF: RO5323441 VEGF: Bevacizumab, Ramucirumab CXCR4: Plerixafor

N

BLOOD VESSEL Smo PKC Notch

MK0752 RO4929097 c-KIT: Axitinib, Cabozantinib, Imatinib, Cilengitide Enzastaurin

INTEGRIN

Smo

Vismodegib LDE225

ICN

PLX3391, Sunitinib, Tandutinib CXCR4:Plerixafor EGFR: Afatinib, Dacomitinib, Erlotinib, Gefitinib, Lapatinib, Ri d i t (EGFR III)

Src

Bosutinib, Dasatinib, Nintedanib

HSP

Client Protein

Gli1/2 Ras PI3K Raf Akt PTEN

Rindopepimut (EGFRvIII) HGFR/c-Met: Cabozantinib, Onartuzumab PDGFR: Axitinib, Brivanib, Crenolinib, Dasatinib, Imatinib Lenvatinib P if i Tipifarnib Sorafenib Vitespen

HSP

MEK Akt mTOR

Imatinib, Lenvatinib, Nintedanib, Pazopanib, Sorafenib, Sunitinib, Tandutinib TGF: LY2157299 Everolimus, Sirolimus, Temsirolimus Perifosine, PX-866

Proteosome

Client Protein

ERK

Temsirolimus XL-765, GDC-0084 AZD8055, CC223 Bortezomib

NUCLEUS

DNA

HDAC

Panobinostat, Valproic Acid, Vorinostat

Veliparib

PARP Chk

Alexander, Lee et al. 2013

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SLIDE 7
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Outline

  • Issues
  • New therapies and targets
  • New approaches to trial design
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R f L k f P i T t d M l l Reasons for Lack of Progress in Targeted Molecular Therapies in Glioblastomas

  • Poor models
  • Blood-brain barrier

C i i f i ki

  • Co-activation of tyrosine kinases
  • Redundant signaling pathways

g g p y

  • Spatial and temporal heterogeneity
  • Failure to genetically enrich patient population
  • Stem cells

Stem cells

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Bypassing The Blood Brain Barrier Bypassing The Blood Brain Barrier

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B h N l 2012 78 1268 Benarroch Neurology 2012;78:1268

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Connolly et al, SNO 2012

Slide courtesy of May Han, Aveo

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Current Design Current Design

R

Surgery

Recurrent Tumor

PK PET MRI Blood biomarkers PK PET MRI Blood biomarkers

Therapy Therapy

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SLIDE 14
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Convection‐Enhanced Delivery Convection‐Enhanced Delivery

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Low density Lipoprotein Receptor Related Protein (LRP 1)

Angiopep

TPA (tissue plasminogen activator)

(LRP‐1)

2-Macroglobulin (MW ~ 700 kDa) RAP

  • Transports small and large

molecules (> 40 ligands)

Thyroglobulin

molecules (> 40 ligands)

  • One of the most expressed

receptor at the surface of the

Lactoferrin

receptor at the surface of the BBB

  • Expressed on cancer cells

ß

p

  • Expressed also in liver, lung and
  • varian tissues

Cell Membrane

LRP-1: ~600kDa

(515,  85)

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ANG1005

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ANG1005 ANG1005

Low density y lipoprotein receptor related protein (LRP1)

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ANG1005

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ANG1005 ANG1005

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ANG1005

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ANG1005

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ANG1005

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SLIDE 24
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2013; 19(6):1567‐1576

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Science 2011;344:1727

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Pulse Dosing

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Vivanco et al. Cancer Discovery 2012;2:458‐71

Vivanco et al. Cancer Discovery 2012;2: 458‐271

GBM Lung Cancer

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Vivanco et al. Cancer Discovery 2012

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Vivanco et al. Cancer Discovery 2012

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Are we delivering the drugs appropriately?

  • Continuous dosing versus pulse dosing

Ad i i t t t d d b f ft h th

  • Administer targeted drug before or after chemotherapy
  • NSCLC

– Solit et al CCR 2005;11:1983 – Riely JCO 2009:27;264

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Targeted Molecular Therapies Targeted Molecular Therapies

The Cancer Genome Atlas Research Network. Nature. 2008;455:1061-1068;

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Stum et al. Cancer Cell 2012;22:425‐437

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Failure To Genotype Patients

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Sequencing Epigenetic Analysis

Set of activated Combinations of kinases and pathways appropriate drugs Ivy Foundation Early Phase Clinical Trials Consortium DF/HCC DF/HCC MSKCC UCLA UCSF UCSF MDACC U Utah

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New Targets

  • PI3K

PI3K

  • FGFR/TACC
  • BRAF
  • CDK4

CDK4

  • WeeI
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PI3 Kinase Inhibitors

Growth Factors, etc

Ras Raf

PI3K inhibitor

XL765

Mek Erk

XL765 XL147 BKM120 PX866

Proliferation

Erk

GDC0084

Proliferation

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BKM120 BKM120

  • Oral pan-class I phosphatidylinositol-3-kinase (PI3K)

inhibitor belonging to the 2,6-dimorpholino pyrimidine g g , p py derivative family

  • Inhibits p110α, p110β, p110δ and p110γ

p , p β, p p γ

  • Cross the blood-brain barrier (brain/blood ratio 2)

T k ll d il

  • Taken orally once daily
  • Inhibits the growth of U87MG and GBM explants in vivo

39

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Ivy Foundation Early Phase Clinical Trials Consortium A Phase II study of BKM120 for patients with recurrent glioblastoma and activated PI3K pathway

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BKM 120 T i l BKM 120 Trial

Patient Eligibility

  • Activation of PI3K pathway:
  • Activation of PI3K pathway:

– PIK3CA/PIK3R1 mutation or – PTEN mutation, loss of PET by FISH, or PTEN IHC negative g Goal

  • 30 PTEN loss
  • 20 PIK3CA/PIK3R1 mutants

44

20 PIK3CA/PIK3R1 mutants

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Next Steps Next Steps

  • Isoform specific Inhibitors

– ? Beta specific isoforms better for PTEN loss ? Beta specific isoforms better for PTEN loss – ? Alpha specific isoforms for PI3Ca mutants

  • Combinations

BKM120 +RT+TMZ – BKM120 +RT+TMZ – BKM120 + LDE225 (SMO inhibitor) – BKM120 + INC 280 (MET inhibitor)

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Science 2012

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Phase II Trial of BGJ398 (FGFR inhibitor) Phase II Trial of BGJ398 (FGFR inhibitor)

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TCGA TCGA

The Cancer Genome Atlas Research Network. Nature. 2008;455:1061-1068;

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PD-0332991 (CDK 4/6 inhibitor) Michaud et al: Cancer Res 2010;70:3228

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Michaud et al: Cancer Res 2010;70:3228 Michaud et al: Cancer Res 2010;70:3228

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LY2835219 (CDK4/6 Inhibitor) Sanche Martine et al Sanchez Martinez et al

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h i l Sanchez‐Martinez et al

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BRAF and/or MEK inhibitors for BRAFV600E mutated gliomas? mutated gliomas?

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Flaherty et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600E Mutations Melanoma with BRAF V600E Mutations NEJM 2012; 2012 Nov;367(18):1694-703

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A Phase II, Open-label Study in Patients with BRAF V600EMutated Rare Cancers with Several Histologies to V Mutated Rare Cancers with Several Histologies to Investigate the Clinical Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib

Dabrafenib Trametanib

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Histologies

  • Anaplastic Thyroid Carcinoma

Histologies

  • Biliary Tract Cancer
  • Diffuse Large B Cell Lymphoma
  • GIST
  • Hairy Cell Leukemia

Hi h G d Gli (GBM A l i PXA A l i

  • High Grade Glioma (GBM, Anaplastic PXA, Anaplastic

ganglioglioma)

  • Low-Grade Gliomas (PXA Ganglioglioma Pilocytic

Low-Grade Gliomas (PXA, Ganglioglioma, Pilocytic Astrocytoma)

  • Multiple Myeloma

p y

  • NSGCT/NGGCT
  • Small Intestine Adenocarcinoma
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Plummer: Clin Cancer Res 2010;16(18); 4527–31 Plummer: Clin Cancer Res 2010;16(18); 4527 31

Double strand break Single strand break Homologous

Non- homologous

Homologous Recombinati

  • n

homologous end joining (NHEJ)

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Plummer: Clin Cancer Res 2010;16(18); 4527–31

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I i C t t i it f TMZ d RT Increasing Cytotoxicity of TMZ and RT

  • PARP Inhibitors

– ABT 888 (ABTC; RTOG) ABT 888 (ABTC; RTOG)

  • Wee1 Inhibitor

– MK1775

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W 1 Wee1

MK1775

G2 Arrest

G2 progression and mitotic and mitotic catastrophe

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Glioma Initiating Cells

Wen PY, Kesari S. N Engl J Med 2008;359:492-507

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Glioma Initiating Cells

Wen PY, Kesari S. N Engl J Med 2008;359:492-507

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BKM120+LDE225 In vivo data: orthotopic xenograft

f PTEN d fi i

  • f PTEN‐deficient tumor

Mariella Gruber-Olipitz et al. Nature Med. In Press

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LDE225+BKM120

MA

Combo

man NUM Hum

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M h i Many choices; limited resources

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Challenges Challenges

  • Phase II trials often not predictive of positive outcome in

se s o e

  • p ed c ve o pos

ve ou co e phase III studies – Imatinib mesylate and hydroxyurea y y y – Enzastaurin – Cediranib Cediranib – Cintredekin Besudotox (IL13-PE38QQR) Cilengitide – Cilengitide

  • More drugs and more combinations

i i d

  • Limited resources
  • Need more efficient trial designs
  • Need better response criteria, endpoints and more efficient

trials and design

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SLIDE 63
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New Clinical Trial Designs New Clinical Trial Designs

  • Improve efficiency

Improve efficiency

  • Rapid elimination of ineffective regimens
  • Test multiple combinations simultaneously

Test multiple combinations simultaneously

  • Shorter path to definitive testing
  • D

i

  • Designs
  • “Pick the Winner”
  • S

l i i f h / i l

  • Seamless integration of phase II/III trials
  • Sequential Accrual Design for Phase I/II studies
  • Factorial Design
  • Adaptive Randomization

p

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Adaptive Randomization Strategies Adaptive Randomization Strategies

  • Multiple arm study
  • Multiple arm study
  • Allocation of patients based on Bayesian probability of treatment

efficacy efficacy

  • Treatment arms with success are more likely to accrue patients
  • Treatment arms with poor results are dropped alternative arms

Treatment arms with poor results are dropped, alternative arms added, and accrual continues until clear evidence of superior treatment(s) emerge

A + B A C

Ad ti R d i d “B i ” D i

A + C A + B + C

Winner

Adaptive Randomized “Bayesian” Design

Courtesy of Mark Gilbert, MD.

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Trippa et al (JCO 2012; 30:3258-3263)

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Trippa et al (JCO 2012;30:3258 3263) Trippa et al (JCO 2012;30:3258-3263)

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Trippa et al (JCO 2012;30:3258-3263) pp ( ; )

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Ideally we can have trials that evaluate multiple drugs efficiently and identify predictive biomarkers p

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Wh t M l l S b ? What Molecular Subgroups?

  • EGFR amplification (45%) or mutation (20%)
  • PTEN loss (40%) / PIK3Ca or PIK3R1 mutations
  • PTEN loss (40%) / PIK3Ca or PIK3R1 mutations

(15%)

  • CDK4/6 amp (18%); P16/15 loss (50%)
  • MDM2 amplification (15%) (with intact p53

MDM2 amplification (15%) (with intact p53

  • PDGFR amplification (13%)
  • Other less common subgroups
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Predictive or Prognostic Biomarkers

Predictive Prognostic Prognostic

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EGFR PI3K MDM2 CDK4/6 n + + + + 1 (1%) + + + ‐ 3 (3%) + + ‐ + 3 (3%) 11 (12%) + + ‐ ‐ 11 (12%) + ‐ + + 4 (4%) + ‐ + ‐ 0 (0%) 0 (0%) + ‐ ‐ + 1 (1%) + ‐ ‐ ‐ 18 (20%)

TCGA (all)

Courtesy of ‐ + + + 2 (2%) ‐ + + ‐ 1 (1%) 0 (0%) Brian Alexander ‐ + ‐ + 0 (0%) ‐ + ‐ ‐ 17 (19%) ‐ ‐ + + 1 (1%) ( %) ‐ ‐ + ‐ 1 (1%) ‐ ‐ ‐ + 4 (4%) ‐ ‐ ‐ ‐ 24 (26%) 41 (18) 38 (17) 13 (1) 16 (4) 91

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How to prioritize overlapping classification

  • Adaptive design with equal or weighted

randomization will allow each subgroup to be randomization will allow each subgroup to be evaluated

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Biomarkers Biomarkers

EGFR amplification/ i Pik3Ca/PIK3R1 mutations/ PTEN l CDK4/6 amplification/P16 l mutation loss loss + + + + + + + + + + + + +

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Recurrent GBM

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Red: EGFR Amplification Green: PDGFRA Amplification

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PNAS 2013;110:4013 ;

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Recurrent GBM

Reoperation and Genotype

RANDOMIZE 3‐5 weeks EGFR Amplified 40%; MDM2 Amplified 14% PIK3Ca/R1 mutations 15% CDK4 amplification 16%; 40%; mutations 20% 14% 15%

  • r loss of

PTEN 40% 16%; P16 and 15 deletion 50% 40% 50%

Drug A or A+B Drug C Drug E or Drug G or A+B

  • r C+D

E+F G+H

Survival

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S i l St d Surgical Study

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Possible Studies

  • PI3K + MEK
  • EGFR/mTOR inhibitor + Arsenic Trioxide
  • etc
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PNAS 2013; 110:4339‐4344

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Iwanami et al:

Cell Cycle 2013:12:10, 1473–1474

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U87 H GBM U87 Human GBM

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We are slowly making progress! We are slowly making progress!

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Thank You!