Transcript Glioblastoma * Novel Insights and Therapies

RENATO V. LA ROCCA, MD, FACP
CANCER MEDICINE, NEURO ONCOLOGY
NORTON CANCER INSTITUTE
LOUISVILLE, KENTUCKY
Renato V. La Rocca, MD,
FACP
Advisory Boards 2014 -2016
Genentech
MGI Pharma/Eisai
Sanofi Aventis
Novocure
Celgene
Arbor Pharmaceuticals
Speakers Bureaus 2014-2016
Merck
MGI Pharma/Eisai
Sanofi Aventis
Celgene
38% of adult brain tumors
 80% of malignant brain tumors (~15,000
incident cases/year in the USA)
 6.5 new cases/100,000 persons annually in
the US
 10th leading cause of cancer death overall
in the US
 tumors rarely metastasize but are locally
invasive and associated with significant
morbidity.

Prostate
1 in 6
Lung & bronchus
1 in 13
Colon & rectum
1 in 19
Urinary bladder
1 in 26
Non-Hodgkin lymphoma
1 in 48
Melanoma
1 in 35
Leukemia
1 in 63
Stomach
1 in 92
Brain
1 in 151
Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.6.1
Statistical Research and Applications Branch, NCI, 2012. http://srab.cancer.gov/devcan
Incidence Rates by State 2008-2012
Brain and ONS
5
Established
• Older age
• Male gender
• Caucasian race
• Higher SES
• Genetic syndromes
• Family history
• Genetic susceptibility
• Ionizing irradiation
*one or more
epidemiologic studies
Proposed (partial list)*
• Body weight / stature
• Handedness
• Allergic conditions
• Head trauma
• Dental x-rays
• Cell phone use
• Pesticides/ farming
• Diet (nitrosamines)
• Smoking/ alcohol
Study of 1433 intra-cranial meningioma cases,
diagnosed between May 1, 2006 and April 28, 2011
compared to 1350 controls matched by age, sex
and geography.
Increased risk of meningioma is associated with
Panorex films taken at a young age or on a yearly or
greater frequency with persons reporting receiving
such films under the age of 10 years at 4.9 times
(95%CI: 1.8-13.2) increased risk of meningioma.
EB Claus, et al. Cancer. 2012 Sep 15; 118(18): 4530–4537.
Glioblastoma Multiforme
Glioblastoma
•Invasive
•Hypoxic
•Phenotypically heterogeneous
•Resistant to therapy
Courtesy of M. Prados, MD
Glioblastoma – An infiltrative Tumor
Courtesy of M. Prados, MD
Ratio of tumor cells
to total cells
1:1
Percentage of tumor
Cell population
92%
1:10
6%
1:100
1.8%
1:1000
0.2%
Adapted from Wilson CB. Clin Neurosurg. 1992;38:32.


Current Therapies

STUPP Regimen

Antiangiogenesis Agents (Bevacizumab)

Novocure TTF
Novel Therapies


Vaccines

CDX -110 (Rindopepimut)

ICT-107
Immunotherapy

Nivolumab


Current Therapies

STUPP Regimen

Antiangiogenesis Agents (Bevacizumab)

Novocure TTF
Novel Therapies


Vaccines

CDX -110 (Rindopepimut)

ICT-107
Immunotherapy

Nivolumab
From August 2000 until March 2002, 573 patients from 85 institutions
in 15 countries were randomly assigned to receive radiotherapy (286
patients) or radiotherapy plus temozolomide (287 patients).
Focal RT 6 weeks to tumor volume + 2-3 cm margin
Stupp, Roger, et al. N Engl J Med 2005; 352:987-996
Current Therapies- STUPP Regimen
At a median follow-up of 28 months, 480 patients (84 percent) had died. The median
survival benefit was 2.5 months; the median survival was 14.6 months with radiotherapy
plus temozolomide and 12.1 months with radiotherapy alone. These data indicate a 37
percent relative reduction in the risk of death for patients treated with radiotherapy plus
temozolomide, as compared with those who received radiotherapy alone.
Current Therapies- STUPP Regimen
MGMT promoter in GBM tissue was analyzed as a predictor of benefits from TMZ
treatment. Overall, patients with a silenced MGMT gene had a significantly longer
survival. Patients with a methylated MGMT gene had a 2-year survival rate of 22% in
those who had received radiation alone and 46% in those who had received radiation
and TMZ.


Current Therapies

STUPP Regimen

Antiangiogenesis Agents (Bevacizumab)

Novocure TTF
Novel Therapies


Vaccines

CDX -110 (Rindopepimut)

ICT-107
Immunotherapy

Nivolumab
Current Therapies- Antiangiogenic
Bevacizumab
Microvascular proliferation is a diagnostic hallmark for GBM
The vasculature of GBM is both structurally and functionally
abnormal:

Increased permeability, blood flow and transport properties
resulting in vasogenic cerebral edema

Increased interstitial pressure and hypoxia
The major proangiogenic mediator in GBM is VEGF, which is
expressed by infiltrating inflammatory cells, platelets and
perhaps most importantly, glioma cells, especially those
surrounding zones of necrosis
Hypoxia is an important inducer of VEGF expression by
glioma cells
Chi AS et al. The Oncologist 2009;14:621-636
Current Therapies- Antiangiogenic
Bevacizumab
Potential Mechanisms of Action
of Antiangiogenic Agents

Direct anti tumor effect (cancer stem cells, other)

Disruption of the angiogenic cascade

Potentially decrease vascular leakage resulting in:

Decreased peritumoral edema

Improved blood flow efficiency, resulting in improved oxygen and
drug delivery

Inhibition of additional blood vessel formation (for example, through
blocking VEGF and decreasing hypoxia)
Jain RK. Science 2005;307:58-62
Current Therapies- Antiangiogenic
Bevacizumab
Bevacizumab:
A
therapeutic antibody that inhibits VEGF
 Administered
 Approved
intravenously
in the USA for the treatment of :
 Metastatic
colorectal cancer (first-and second-line)
 Metastatic
or locally advanced non-squamous non-small
cell lung cancer in combination with carboplatin and
paclitaxel
 Advanced
 Recurrent
renal cell carcinoma
glioblastoma as a single agent (May 2009)
Bevacizumab

Has an impact on progression free survival in the
recurrent setting

Not proven to be of benefit when given at time of
initial diagnosis

It allows the patient to be on less steroids
(traditionally decadron) which in turn results in less
steroid-related toxicities which over the long term,
have a significant impact on outcome
Bevacizumab

Administered intravenously on either a biweekly or
once every three week schedule

Usually requires a port

Potential toxicities:

Hypertension

Decreased wound healing

Proteinuria

Fatigue

Increased risk of bleeding

Increased risk of clotting
A Phase 2 Study of Bevacizumab Plus Temozolomide
During and After Radiation Therapy for Patients with
Newly Diagnosed Glioblastoma Multiforme (GBM)
70 patients with newly diagnosed GBM,
compared with a UCLA control cohort who did
not receive bevacizumab up front
Results:
Group that received bevacizumab
 Progression-free
survival: 13.6 months
 Overall survival: 19.6 months
Control Cohort
 Progression-free survival: 7.6 months
 Overall survival: 21.1 months
Lai et al/ J Clin Oncol 29:142-148, 2010
What agent has efficacy in GBM
following progression with
Bevacizumab?
One hundred patients, aged 36–84 years (median 62 years) with
recurrent glioblastoma (GBM), were treated previously with surgery,
concurrent radiotherapy and temozolomide and postradiotherapy
temozolomide followed by single-agent bevacizumab (BEV) at either
first (60 patients) or second recurrence (40 patients). Patients were
then treated following progression on BEV only with BEV and
carboplatin (75 patients), cyclophosphamide (15 patients) or BCNU
(ten patients; BEV+).
Following 2 months of BEV+, 60 patients (60%) demonstrated
progressive disease and discontinued therapy. Forty patients (40%)
had neuroradiographic stable disease. Survival ranged from 1 to 12
months (median: 4 months). Median and 6-month progression free
survival was 2.5 months and 5%, respectively.
Chamberlain M. Expert Review of Neurotherapeutics 2012, 12:929-936
2004 - Yoram Palti et al – documented with cancer cell
lines in vitro that alternating electric fields at frequencies
between 100 and 300 kHz can:
 Disrupt the formation of the mitotic spindle during
metaphase (tubulin subunits being very polar
molecules)

Result in dielectrophoretic movement of polar or
charged molecules and organelles during
anaphase and telophase, thereby disrupting normal
cytokinesis and leading to apoptosis
Kirson et al. Cancer Res 2004;64:3288-3295
Gutin and Wong ASCO 2012
Noninvasive Application of
Alternating Electric Fields
(NovoTTF-100A)
 No
systemic toxicity when applied to
various animals and in particular, no
significant heating, nor effect (at the
frequency range of 100-300 kHz) on
excitable tissues such as brain, muscle
or heart
Gutin and Wong ASCO 2012
25
To date, TTF therapy has been shown to:

Effectively inhibit cancer cell growth in various cell lines in
vitro (with an optimal frequency in the range of 100 and 300
kHz, dependent on cell type and inversely related to cell
size – for example – glioma cells – 200 kHz)

The antimitotic effect on cell lines was enhanced by
sequentially applying more than one field direction to the
cells

The combination of TTF therapy and chemotherapy
appears to have additive (temozolomide), and in some
instances synergistic (paclitaxel) effects.
Novocure (Haifa, Israel) developed a portable
device for use in humans:

Initially applied to humans in a small feasibility trial in 2003

Conducted a pilot trial in Switzerland in patients with
recurrent GBM:

PFS at 6 months of 50%

Median OS 14.4 months

Most patients developed grade 1-2 contact dermatitis
beneath the transducer arrays on the scalp

Gutin and Wong ASCO 2012
Kirson ED et al. Proc Natl Acad Sci USA 2007;104:10152-10157
TTFields with TMZ
Novocure EF-14
In the intent-to-treat population, patients treated with TTFields plus TMZ showed a statistically
significant increase in PFS, the primary endpoint, compared to TMZ alone (median PFS 7.1 months
versus 4.0 months)
In the per-protocol population, patients treated with TTFields plus TMZ demonstrated a statistically
significant increase in OS compared to TMZ alone (median OS 20.5 months versus 15.6 months)
JAMA. 2015;314(23):2535-2543. doi:10.1001/jama.2015.16669.


Current Therapies

STUPP Regimen

Antiangiogenesis Agents (Bevacizumab)

Novocure TTF
Novel Therapies


Vaccines

CDX -110 (Rindopepimut)

ICT-107
Immunotherapy

Nivolumab


Current Therapies

STUPP Regimen

Antiangiogenesis Agents (Bevacizumab)

Novocure TTF
Novel Therapies


Vaccines

CDX -110 (Rindopepimut)

ICT-107
Immunotherapy

Nivolumab
Background:

Epidermal growth factor variant III (EGFRvIII) is a
consistent tumor-specific mutation present in 25-30%
of newly diagnosed GBMs

Occurs most frequently in de novo GBM and rarely in
GBMs progressing from lower grade tumors

EGFRvIII expression typically occurs in the presence of
wild type EGFR overexpression

Given that it is not expressed on normal cells, it is an
effective target for immunotherapy
Babu R and Adamson DC. Core Evidence 2012;7:93-103
Background:

EGFVRvIII contains an inframe deletion of 801 base pairs from
the extracellular domain resulting in the fusion of two distant
portions of the molecule and creating an antigenic junction
with a novel glycine residue

The mutation encodes an active tyrosine kinase resulting in:
a) Enhanced tumorgenicity
b) Increased migration
c) Augmented chemo- and radiation resistance
Sampson et al. Semin Immunol 20:267-275, 2008
Babu R and Adamson DC. Core Evidence 2012;7:93-103

An EGFRvIII-specific 14-mer peptide vaccine coupled to
keyhole limpet hemocyanin (KLH) targeting the EGFRvIII
fusion junction is efficacious in syngeneic murine models

In human phase 2 trials these vaccines can induce potent
T- and B-cell immunity and lead to unexpectedly long PFS
and overall survival times as compared to historical
controls)

The vaccines were successful in eliminating tumor cells
expressing EGFRvIII without significant toxicity

Compound elicits both humeral and cellular immune
responses in preclinical and clinical studies

However, recurrence was characterized by the
development of EGFRvIII negative tumors
Sampson et al. Semin Immunol 20:267-275, 2008
Heimberger and Sampson Expert Opin Biol Ther 9:087-1098, 2009
• Tumor-specific oncogene ideally suited for immune targeting
• Expressed in 31% of primary glioblastoma, but not in normal tissue
• In-frame deletion of exons 2-7 results in constitutively active protein
with unique amino acid sequence at the fusion junction
• Epitope is in the extracellular domain; accessible to antibodies and
highly immunogenic
The ReACT study: a randomized, Phase
2 trial of RINTEGA in combination with
bevacizumab (Avastin®) in patients
with recurrent EGFRvIII-positive
glioblastoma.
The ReACT study: a randomized, Phase
2 trial of RINTEGA in combination with
bevacizumab (Avastin®) in patients
with recurrent EGFRvIII-positive
glioblastoma.
The ReACT study: a randomized,
Phase 2 trial of RINTEGA in
combination with bevacizumab
(Avastin®) in patients with recurrent
EGFRvIII-positive glioblastoma.
A Phase 3 study called ACT IV was conducted in newly diagnosed
EGFRvIII-positive glioblastoma patients. The 745-patient study was a
randomized, double-blind, controlled study of RINTEGA plus granulocytemacrophage colony-stimulating factor (GM-CSF) added to standard of
care temozolomide.
The ACT IV study was discontinued in March 2016 based on the
recommendation of the independent Data Safety and Monitoring Board
that the study was unlikely to meet its primary overall survival endpoint in
patients with minimal residual disease as both the RINTEGA arm and the
control arm were performing on par with each other.
In the ACT IV study, RINTEGA performed consistently with prior Phase 2
studies but the control arm significantly outperformed expectations
(median OS: RINTEGA 20.4 months vs. control 21.1 months).


Current Therapies

STUPP Regimen

Antiangiogenesis Agents (Bevacizumab)

Novocure TTF
Novel Therapies


Vaccines

CDX -110 (Rindopepimut)

ICT-107
Immunotherapy

Nivolumab
ICT-107 Vaccine
ICT-107 is an autologous vaccine consisting of the patient’s
dendritic cells pulsed with 6 synthetic peptide epitopes
targeting the GBM tumor and tumor-stem cell associated
antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100 and IL-13Rα2.

Targeting multiple antigens increases the probability of
effective treatment, by blocking tumor escape mechanisms
associated with single antigen targeting.

Dendritic cells reprogrammed with the antigen targets train
immune system t-cells to recognize the cancer cells and target
them for destruction.

One advantage is the ability to manufacture large amounts of
activated dendritic cells, allowing enough activated dendritic
cells via injection to overcome immune suppression of the
activated t cells.
ICT-107 Phase 1 Trial
(Newly diagnosed patients):

Results:






Median Progression Free Survival – 16.9 months
Two year PFS rate – 43.75%
Two Year Overall Survival Rate – 80.2%
Median Overall Survival – not reached
Expression of 4 ICT-107 targeted antigens in the pre-vaccine
tumors correlates with improved survival as measured by PFS
and OS
Immune responders showed a trend towards a better survival
Phuphanich S et al. ASCO 2011, abstract 2042
ICT-107 Phase III Trial
(Newly diagnosed patients):
The phase 3 registrational trial of ICT-107 in patients with newly diagnosed
glioblastoma is designed as a randomized, double-blind, placebocontrolled study of a target number of 414 HLA-A2+ subjects.
The primary endpoint in the trial is overall survival (OS). Secondary
endpoints include progression-free survival (PFS) and safety, as well as
overall survival in the two pre-specified MGMT subgroups.

First Patient worldwide on this study was treated at Norton Cancer
Institute in June of this year.

ICT-107 has been granted orphan drug designation in the US and
Europe.


Current Therapies

STUPP Regimen

Antiangiogenesis Agents (Bevacizumab)

Novocure TTF
Novel Therapies


Vaccines

CDX -110 (Rindopepimut)

ICT-107
Immunotherapy

Nivolumab
The Immune System
In order to protect an individual, the immune system:
1.
detects the presence of an infection or
malignant cells,1
2.
carries out effector functions to contain or to
eliminate the affected cells,1
3.
performs self-regulation to minimize collateral
damage to healthy cells in the body,1 and
4.
generates immunological memory so that
subsequent exposures
to the same antigen are dealt with efficiently.1
1. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004
46

Absence of lymphatic architecture within the brain


It has now been shown that antigens drain into the
CSF through Virchow-Robin spaces to cervical and
nasal lymph nodes
The blood-brain barrier (BBB) – now considered less
relevant

Lymphocytes have been shown to penetrate the BBB

BBB composition varies in different brain regions

Microglia, and macrophages can act as effective
APCs within the CNS to initiate T-cell responses
Babu R and Adamson DC. Core Evidence 2012;7:93-103

GBM cells express and secrete various immunosuppressive
factors including:

TGF-b (inhibition of T and NK cell cytotoxicity)

IL-10

PGE2

Gangliosides (induction of T-cell apoptosis)

B7-H1 and CD70 (induction of T-cell apoptosis)

CCL2 (attract Treg cells to the GBM microenvironment))
•
2000- Dana Farber scientists publish paper announcing existence of a protein on
normal cells called PD-L1. The researchers found it entwines with a T cell co-receptor
(PD-1) deterring the T cell from attacking the cell.
•
2001- Freeman, et al. discover and publish a surprising finding- PD-L1 appears on
many cancer cells. This meant that the cancer cells had hijacked the mechanism from
normal cells in order to evade immune system attack. Pharmaceutical companies
quickly seized on the finding, developing antibodies that can block PD-1, PD-L1, or
PD-L2.
http://www.dana-farber.org/Newsroom/Publications/Hope-Blossoms.aspx
Three checkpoint inhibitors have received rapid approval from the U.S. Food and Drug
Administration for cancer, including ipilimumab (Yervoy®), atezolizumab (Tecentriq®),
pembrolizumab (Keytruda®), and nivolumab (Opdivo®).
Yervoy
Tecentriq
PDL-1 antibody
Keytruda
Opdivo
Melanoma
Bladder
Metastatic Melanoma
Metastatic Melanoma
*Hepatocellular
* Lung
Non Small Cell Lung Cancer
Non Small Cell Lung Cancer
*Lung
*Kidney
Head and Neck Cancer
Renal Cell Carcinoma
*CRC
*Breast
*Renal
Classical Hodgkin
Lymphoma
*Lymphoma
*Breast
*GBM
*Sarcoma
*Multiple Myeloma
*Bladder and Kidney
*Prostate
*Lymphoma
*CRC/ Esophageal/ Gastric
*Urothelial
*Ovarian
*Lymphoma
* Gastric and CRC and
Esophageal
*Head and Neck
*Hepatocellular
*Hepatocellular
* Not yet approved for this indication, clinical trials currently active
Glioblastoma –
Novel Therapies- Immunotherapy
There is preclinical evidence to support testing checkpoint inhibitors against
primary high grade glioma:.
Immune checkpoint receptors such as PD-L1/B7-H1/CD274, a
transmembrane receptor ligand and negative regulator of T cell
signaling, have been reported to be upregulated in gliomas.
Currently three trials with Nivolumab in Glioblastoma therapy:
NCI trial NRG BN002- Ipilimumab and/or Nivolumab in Combination
with Temozolomide
Checkmate 498 Trial: Nivolumab + RT vs. TMZ +RT in unmethylated
newly diagnosed GBM
Checkmate 548 Trial: Nivolumab + TMZ vs. Placebo + TMZ as
concomitant therapy with RT in methylated newly diagnosed GBM
Jacobs JF, Idema AJ, Bol KF et al. 2009 NeuroOncol; 11
Wilmotte R, Burkhardt K, Kindler V, et al. Neuro Report 2005, 16

STUPP protocol became standard of care in 2005.
At the 5 year analysis of the phase III study that
started the new treatment regimen for
Glioblastoma, the benefits of adjuvant TMZ + RT
have had a lasting effect.
Treatment
Median Survival
5 year
RT
12.1 mos
1.9%
RT+TMZ
14.6 mos
9.8%
RT+TMZ+Bev
19 mos
?
RT+TMZ+Bev+?
?
?
The Multi-Disciplinary Team Approach:
Essential for Optimal Care
Neurosurgeon
Neuro-Oncologist
Optimal
Management of the
High-Grade Glioma
Patient
NeuroPathologist
Radiation Oncologist
The Conquest of
Cancer
1. Knowledge of the molecular phenotype of the
cancer
2. Knowledge of the pharmacogenomics of the
patient
3. Knowledge of the angiogenic profile/status of
the cancer
4. Knowledge of the immunocompetence of the
patient
5. Understanding of the comorbities of the patient
The Conquest of
Cancer
1. Knowledge of the molecular footprint of the tumor
1.
2.
Susceptibility to one or a combination of targeted
therapies
Needs to be in real time and with the understanding of
possible metastatic site heterogeneity
The Conquest of
Cancer
2. Knowledge of the pharmacogenomics of the patient
1.
2.
Verification that the therapeutic molecule will achieve
therapeutic concentrations and will be appropriately
metabolized
Knowledge of drug/drug interactions during
administration of the therapeutic agent
The Conquest of
Cancer
3. Knowledge of the angiogenic profile/status of the
tumors
1.
Determine that in fact the appropriate targeted agent,
metabolized appropriately, can effectively arrive at its
target at every site
The Conquest of
Cancer
4. Knowledge of the immunocompetence of the patient
1.
A perfect vaccine may not work in every patient in light
of a different level of immune competency, which in turn
can be impact by:
1.
2.
Age
Exposure to prior immunosuppressive/immune destroying
agents
The Conquest of
Cancer
5.
Understanding of the co-morbidities of the patient and
integrating that knowledge into the care plan
(e.g., the perfect treatment, in the perfect context
(pharmocogenomics, etc) that arrives to target (appropriate
angiogenic profile), but exacerbates two of the four comorbidities that the patient has, thus not conferring a survival
benefit)