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GlioblastomaNewer Advances
Dr. Vibhay Pareek
Introduction to Glioblastoma
3
CNS and the Blood-Brain Barrier• CNS includes the brain and spinal cord[1]
– Brain is major control network for every physiological, motor, and thought process[4]
• CNS cell types include[2] – Neurons: Structural and
functional cells of the CNS– Glial cells: Perform neuronal
support and immune functions
Blood-brain barrier
Blood-brain barrier (BBB) protects the brain and maintains
a stable brain environment[3]
Astrocyte Oligodendrocytes
Microglial cell
Capillary
Neurons
CNS, central nervous system.
1. SEER Training Modules- Anatomy and Function Areas of the Brain and CNS. Available at: http://training.seer.cancer.gov/brain/tumors/anatomy/. Accessed December 17, 2015.
2. SEER Training Modules- Neurons and Glial Cells. Available at: http://training.seer.cancer.gov/brain/tumors/anatomy/neurons.html. Accessed December 17, 2015.
3. Yilmaz A et al. J Antimicrob Chemother. 2011. doi:10.1093/jac/dkr492.4. Krucik G. Healthline: Brain. Available at
http://www.healthline.com/human-body-maps/brain#seoBlock. Accessed December 17, 2015.
5. Allen NJ. Nature. 2009;457(7230):675-677.
Adapted from Allen NJ 2009.[5]
4
Primary CNS Tumors• CNS tumors arise from CNS cells and are categorized according to the cell
type/tissue from which they originate[1]
• Gliomas arise from glial cells and neuronal precursors, and constitute 80% of all malignant primary brain and CNS tumors[2]
CNS, central nervous system; NOS, Not Otherwise Specificed1. DeAngelis LM. N Engl J Med. 2001;344(2):114-123.2. Ostrom QT et al. Neuro Oncol. 2013;15(Suppl 2):ii1-ii56.
3. Brain Tumor Information. Available at http://www.braintumor.org/brain-tumor-information/. Accessed December 17, 2015.
Brain metastases are more common than primary brain tumors[3]
Benign (63%)[2,3] Malignant (37%)[3]
Primary CNS Tumors (28%–40%)[3]
Other (20%)[2]
Glioblastoma (54%)
Meningioma
Tumors of the Pituitary
Vestibular Schwannoma
Hernangioma
Craniopharyngioma
Ependymal Tumors
Lymphoma
Embryonal Tumors
Meningioma
Germ Cell Tumors
Diffuse Astrocytoma
NOS Malignant Glioma
Ependymal Tumors
Oligodendroglioma
Anaplastic Astrocytoma
Pilocytic Astrocytoma
Oligoastrocytic Tumors
Gliomas (80%)[2]
Brain Mets (60%–72%)[3]
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2. DeAngelis LM. N Engl J Med. 2001;344(2):114-123.3. Louis DN et al. Acta Neuropathol. 2007;114(2):97-109.4. Burkhard C et al. J Neurosurg. 2003;98(6):1170-1174.5. NCCN Guidelines®. Central Nervous System Cancers. V1.2015. 6. Kleihues P, Ohgaki H. Neuro Oncol. 1999;1(1):44-51.
• Brain tumors are typically graded according to cellular origin and aggressiveness [1]
• WHO classification combines tumor type with degree of malignancy[1-3]
World Health Organization (WHO) Grades of CNS Tumors
• Low proliferative potential• Potentially curable with surgical resection aloneGrade I[3]
• Infiltrative properties• Tendency to recur and progress to malignancy
despite low-level proliferationGrade II[3]
Includes malignant astrocytomas• Histological evidence of malignancy• Often recur as higher grade tumors
Grade III[3,5,6]
Includes glioblastoma and variants*• Cytologically malignant• Rapid pre- and postoperative disease evolution
Grade IV[3]Hig
h-gr
ade
L
ow-g
rade >10[4]
>5[3]
3[3]
1[1]
mOS (yrs)
* Gliosarcoma, giant cell glioblastoma, and small cell glioblastoma.[1]
CNS, central nervous system; mOS, median Overall Survival1. Wen PY, Kesari S. N Engl J Med. 2008;359(5):492-507.
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Incidence and Mortality of Brain and Other Nervous System Cancer
2012 Worldwide Brain and CNS Cancer Statistics*Global[1] EU[1] Asia[1] US FR DE JP
New cases 256,213 43,136 131,452 22,850†[2] 4,770[4] 7,120[4] 5,700†[5]
Glioblastoma NA NA NA 11,140[3] 2,200[3] 3,740[3] 2,700[3]
Incidence rate‡ 3.4 6.9 3.0 5.3[1] 5.1[1] 5.3[1] 2.8[1]
Deaths 189,382 32,960 95,732 15,320†[2] 3,290[4] 5,660[4] 2,100†[5]
Mortality rate‡ 2.5 4.9 2.2 3.3[1] 3.2[1] 3.5[1] 1.0[1]
• CNS cancers are the 13th most commonly diagnosed cancer worldwide[1]
– Glioblastoma accounts for 54% of new glioma and 45% of primary malignant tumors[6]
* Estimated 2012 unless otherwise noted.† Estimated 2015.‡ Estimated ASRs (W) per 100,000. Both sexes, all ages.
3. Decision Resources: Glioblastoma Multiforme. September 2013.4. Ferlay J et al. Eur J Cancer. 2013;49(6):1374-1403. 5. National Cancer Center. Available at:
http://ganjoho.jp/en/public/statistics/short_pred.html. Accessed December 21, 2015. 6. Ostrom QT et al. Neuro Oncol. 2013;15:ii1-ii56.
ASR, age standardized rate; CNS, central nervous system; W, world.
1. GLOBOCAN 2012: Population Fact Sheets. Available at: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed December 21, 2015.
2. American Cancer Society. Cancer Facts and Figures 2015. Available at: http://www.cancer.org/acs/groups/content/ @research/documents/webcontent/acspc-044552.pdf. Accessed December 21, 2015.
7
2012
2013
2014
2015
2016
2017
2018
2019
2020
2021
2022
02,0004,0006,0008,000
10,00012,00014,00016,000
USFranceGermanyJapan
Regional Incidence Trends for Glioblastoma• Number of newly diagnosed cases of glioblastoma is expected to
increase in the US, France, Germany, and Japan[1]
Projections for 2012–2022
2.01.31.01.0
Growth (%/yr)
1. Decision Resources: Glioblastoma Multiforme. September 2013.
8
Glioblastoma 5-Year Survival Rates by Region
4.7%
US[1]
2.7%
Europe[2]
6.3%
Japan[3]
• Grade IV glioblastoma has the poorest prognosis of all primary brain tumors[4]
– Overall 5-year survival worldwide <3%[4]
1. Ostrom QT et al. Neuro Oncol. 2013;15:ii1-ii56.2. Sant M et al. Int J Cancer. 2012;131(1):173-185. 3. Nomura K et al. Int J Clin Oncol. 2000;5(6):355-360.4. Roche Glioblastoma Backgrounder. Available at:
http://www.roche.com/backgrounder_glioblastoma__concise_guide.pdf. Accessed December 17, 2015.
9
• Etiology of brain tumors is not well understood[1]
– Ionizing radiation is the only established environmental risk factor[1,2]
Risk Factors for Glioblastoma
Non-ionizing radiation
Ionizing radiation
Genetically inherited
syndromes
Family history
Male gender
Urban residence
Age
Caucasian origin
Glioblastoma Risk
Factors[1-3]
1. Grossman SA et al. Cancer Invest. 1999;17(5):299-308. 2. Neglia JP et al. J Natl Cancer Inst. 2006;98(21):1528-1537.3. Deorah S et al. Neurosurg Focus 2006;20(4):E1.
10
Prognostic Factors for Glioblastoma
Younger ageSingle most
powerful predictor of outcome[1]
Methylated MGMT
status[1,2]
Higher KPS score[1]
Tumor resectability (size, location, and number)[3,4]
Factors associated with better prognosis
1. Hegi ME et al. N Engl J Med. 2005;352:997-1003.2. Arvold ND et al. Clin Interv Aging. 2014;9:357-367.3. Kawano H et al. Br J Neurosurg. 2014;14:1-7. 4. NCCN Guidelines®. Central Nervous System Cancers. V1.2015.
KPS, Karnosfsky performance status ; MGMT, O6-methylguanine DNA methyltransferase.
11
Prognostic Factors for Glioblastoma: Age
Survival Rates by Age Group[2]
Age Group (yrs)
1-Year Survival, %
5-Year Survival, %
0-19 57.2 19.220-44 66.5 16.945-54 52.7 5.955-64 40.7 3.865-74 23.7 1.775+ 9.2 0.8
Glioblastoma incidence
0
20–44
10
20
30
40
45–54 55–64 65–74 75+Age Groups
Age
-Adj
uste
d In
cide
nce
Rat
e pe
r 100
,000
Incidence Rate by Age Group[2]
• Elderly* patients represent ~50% of newly diagnosed glioblastoma[1]
– Virtually all elderly glioblastoma tumors are primary and characterized by genetic differences[1]
• Glioblastoma incidence: increases with age[1,2]
• Glioblastoma survival rates: decrease with age[1,2]
1. Arvold ND et al. Clin Interv Aging. 2014;9:357-367.2. Ostrom QT. Neuro Oncology. 2013;15(Suppl 2):ii1-ii56.* Definition of “elderly” varies, with most randomized trials including
patients aged 60, 65, or 70 years and older.[1]
12
• Potential of prognostic biomarkers in identifying specific patient populations has not yet been fully realized[6]
• MGMT methylation status is the only biomarker with predictive implications on treatment outcomes identified to date[6]
Select Biomarkers in Glioblastoma
Biomarker Prognostic Indication Favorable Poor
MGMT methylation[1]
• Methylated in 30%–60% of cases• Methylated MGMT increases response to chemotherapy• Unmethylated MGMT decreases response to
chemotherapy
IDH1/2 mutations[2,3]• More common in lower grade glial tumors• IDH1/2 mutation occurs in approximately 3.7% of primary
GBMs versus 73.3% in secondary GBM
EGFR amplification[4,5] Observed in ~50% of primary glioblastomas
EGFRvIII mutation[4]• EGFR-amplified cells often contain EGFRvIII mutation,
which confers constitutive activity• 30% glioblastoma tumors express EGFRvIII
Prognostic Association
1. Preusser M et al. Ann Neurol. 2011;70(1):9-21. 2. Nobusawa S et al. Clin Cancer Res. 2009;15(19):6002-6007.3. Yan H et al. N Engl J Med. 2009;360(8):765-773.4. Johnson H et al. Mol Cell Proteomics. 2012;11(12):1724-1740.5. Stupp R et al. Ann Oncol. 2014;25(Suppl 3):iii93-iii101.6. McNamara MG et al. Cancers. 2013;5(3):1103-1119.
EGFR, epidermal growth factor receptor; IDH1/2, isocitrate dehydrogenase 1/2; MGMT, O6-methylguanine DNA methyltransferase.
13
• Glioblastomas are highly heterogeneous at the molecular level[1]
• Four transcriptional subclasses have recently been defined based on tumor expression profiles[2]
Toward a Molecular Signature: The Cancer Genome Atlas Histological Subtypes of Glioblastoma
Classical
EGFR amplification/mutations
Significantly decreased mortality
Mesenchymal
High expression of tumor necrosis factor pathway
genes
Significantly decreased mortality
Neural
Neuronal marker expression
Efficacy suggested
Proneural
IDH1 mutations
No difference in survival
Transcriptional profile includes:[2]
Response to intensive treatment*:[2]
• Classifying glioblastoma tumors according to expression profiles may help predict response to certain treatments and assess patient prognosis[2]
1. Olar A, Aldape KD. J Pathol. 2014;232(2):165-177.2. Verhaak RG et al. Cancer Cell. 2010;17(1):98-110.
* Concurrent chemotherapy and radiation or more than four cycles of chemotherapy.EGFR, epidermal growth factor receptor; IDH1, isocitrate dehydrogenase.
14
Summary of Treatment Approaches and Unmet Needs
NATURE AND PREVALENCE OF
TUMORS
• Glioblastomas are the most common and most aggressive primary brain cancer[1]
• Lower-grade gliomas (WHO grade II and III gliomas) eventually progress into grade IV within 5–10 years[2]
BLOOD-BRAIN BARRIER
• Physical, metabolic, and immunological privilege status of the brain limits therapeutic potential[3]
BIOMARKERS• Potential of prognostic/predictive biomarkers in
identifying specific patient populations has not been fully realized[4]
1. Olar A, Aldape KD. J Pathol. 2014;232(2):165-177.2. Zong H et al. Expert Rev Mol Diagn. 2012;12(4): 383-394.3. Wei X et al. Acta Pharmaceutica Sinica B. 2014;4(3):193-201.4. McNamara MG et al. Cancers. 2013;5(3):1103-1119. WHO, World Health Organization
Treatment Guidelinesin Glioblastoma
16
• Time between onset of symptoms and diagnosis of glioblastoma is often short[1]
– Headaches, memory loss, and motor weakness are among the most common presenting symptoms[1]
• Early diagnosis and treatment do not improve disease outcomes[2]
Glioblastoma Presentation
Glioblastoma presenting symptoms
General[1]
(Related to increased ICP)• Headaches• Slowed cognitive function• Seizures• Nausea/vomiting• Personality changes
Focal[2]
(Related to tumor location)• Aphasia• Hemiparesis• Sensory/visual loss
1. Chang SM. JAMA. 2005;293(5):557-564.2. Omuro A, DeAngelis LM. JAMA. 2013;310(17):1842-1850. ICP, intracranial pressure.
17
• MRI: Preferred imaging modality for high-grade glioma diagnosis and treatment-planning[3]
– BBB disruption results in enhancement on contrast MRI[4]
• Challenging to distinguish between grade III and IV glioma by MRI
• No lab studies can currently suggest or confirm diagnosis of glioblastoma[2]
– Tissue diagnosis is mandatory[6]
Glioblastoma Workup and Diagnosis
1. Uddin ABMS. Medscape, Neurologic manifestations of glioblastoma multiforme workup. Available at: http://emedicine.medscape.com/article/1156220-workup#showall. Accessed December 17, 2015.
2. Bruce JN. Medscape. Glioblastoma multiforme workup. Available at: http://emedicine.medscape.com/article/283252-workup#showall. Accessed December 17, 2015.
3. Omuro A, DeAngelis LM. JAMA. 2013;310(17):1842-1850. 4. DiStefano AL et al. Biomed Res Int. 2014;2014:154350.5. Pope WB, Hessel C. AJNR Am J Neuroradiol. 2011;32(5)794-797.6. Stupp R et al. Ann Oncol. 2014;25(Suppl 3):iii93-iii101.
T1-weighted MRI*Contrast-enhanced[1]
Irregular margins may make defining
exact tumor size challenging[2]
T2-weighted/ FLAIR MRI*†
Not contrast-enhanced[1,2]
May result in improved definition of tumor volume[5]
* MRI images of same glioblastoma tumor.[1]
† Image shows T2 MRI.BBB, blood-brain barrier; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.
18
• There are no curative therapies for glioblastoma[1]
– Glioblastoma recurrence rate is nearly 100%• Treatment goals are focused on preserving PS/QOL, neurological function, and
extending survival[2]
– NCCN recommends glioblastoma patients receive palliative care from diagnosis[3]
Goals of Therapy for Glioblastoma
Surgery[4]
• Pathological diagnosis• Alleviate mass effect• Increase survival
(mainly GTR)• Facilitate adjuvant
therapy• Decrease
corticosteroid need
Radiotherapy[5]
• Increase survival after surgery in newly diagnosed patients
Chemotherapy[6]
• Extend survival• Potentially increase
therapeutic effect of RT[1]
1. Rulseh AM et al. World J Surg Oncol. 2012;10:220.1-6.2. Henriksson R et al. J Neurooncol. 2011;104(3):639-646.3. NCCN Guidelines®. Central Nervous System Cancers. V1.2015. 4. Sanai N, Berger MS. Neurosurgery. 2008;62(4):753-766.5. Valduvieco I et al. Clin Transl Oncol. 2013;15(4):278-282.6. Stupp R et al. J Clin Oncol. 2007;25(26):4127-4136.
GTR, gross total resection; NCCN, National Comprehensive Cancer Network; PS, performance status; QOL, quality of life; RT, radiotherapy.
Guidelines for Standard of Care
Diagnosis GBMCraniotomyMaximal Surgical resection or Biopsy
FitKPS>60
UnfitKPS<60
Age <70
Age >70
Radiotherapy short course or Temozolamide or BSC: steroids, anticonvulsants etc.
Radiotherapy 60Gy/30#/6weeks+ concurrent Temozolamide 75mg/m2
Followed by 6 cycles adjuvant Temozolamide 150 mg/m /day for 5d every 28d
Methylated
Unmethylated
1. NCCN Guidelines®. Central Nervous System Cancers. V2.2014. 2. Stupp R et al. Ann Oncol. 2014;25(Suppl 3):iii93-iii101.3. Weller M et al. Lancet Oncol. 2014;15(9):e395-e403
KPS 60 - Ambulatory and capable of most self-care but requires occasional assistance. Unable to carry out any work activities. KPS 50 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. Requires considerable assistance and frequent medical care
Temozolamide
Radiotherapy 60Gy/30#/6weeks
20
• Virtually all patients relapse and there is no defined SOC[1,2]
• Clinical trial enrollment is suggested by ESMO and always recommended by NCCN[1]
Treatment of Recurrent Glioblastoma
Good PS [1,3]
Poor PS
Re-resection† ± / + BCNU†
Surgery to alleviate mass
effect‡
BSCChemotherapy
TMZNU
PCVBEV ± IRI
± NU ± TMZ ± Carb
CP Carb Erlotinib Imatinib
Re-irradiation TTFBevacizumab use in glioblastoma is increasingly widespread[1]*
2A 4C
2A 2B1A
2B
2A 3C
2B
2C
2B 4C 3
BSC
NCCN
ESMO
Both
1. NCCN Guidelines®. Central Nervous System Cancers. V1.2015. 2. Decision resources. Glioblastoma Multiforme. 2013.3. Stupp R et al. Ann Oncol. 2014;25(Suppl 3):iii93-iii101.4. Wick W et al. J Clin Oncol. 2010;28(12):e188-e189.
IFNβ-based regimens are also used in Japan[4]
BCNU, carmustine; BEV, bevacizumab; BSC, best supportive care; Carb, carboplatin; CP, cisplatin; EMA, European Medicines Agency; ESMO, European Society of Medical Oncology; IFNβ, interferon beta; IRI, irinotecan; NCCN, National Comprehensive Cancer Network; NU, nitrosourea; PCV, vincristine; PS, performance status; SOC, standard of care; TMZ, temozolomide; TTF, tumor treating fields.
* BEV is used in parts of EU despite not having received EMA approval[4]; † For local recurrent disease, the NCCN Guidelines recommend re-resection, when feasible[1]; ‡ Recommended by NCCN for recurrent disease with diffuse/multiple tumors.[1]
21
• All patients should receive BSC[1]
• Neurological function is closely monitored and lab tests are performed according to treatment regimen[2]
• MRI scans are routinely performed– Early detection of recurrence is desirable[1]
– Management of recurrent tumors is guided by patient condition and extent of disease[1]
Follow-Up/Monitoring
NCCN[1]
• Serial scans starting at 2–6 weeks after RT to titrate corticosteroid dose
• Then every 2–4 months for 2–3 years to monitor for recurrence
ESMO[2]
• Scans every 3–4 months unless otherwise clinically indicated
Monitoring MRI scans
1. NCCN Guidelines®. Central Nervous System Cancers. V1.2015. 2. Stupp R et al. Ann Oncol. 2014;25(Suppl 3):iii93-iii101.
BSC, best supportive care; ESMO, European Society for Medical Oncology; MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; RT, radiotherapy.
22
• Treatment-induced changes in brain permeability introduce challenges in detecting response to therapy and disease recurrence by MRI[1]
Challenges in Response Assessment: Pseudoprogression and Pseudoresponse
PseudoprogressionApparent increase of tumor lesion
on imaging that is not due to actual tumor growth[1-3]
PseudoresponseApparent decrease of tumor lesion
on imaging that does not reflect true tumor reduction[1]
Often occurs with antiangiogenic agents such as bevacizumab[1]
Observed in 5%–31% patients* after RT/chemotherapy[2]
• “Pseudoprogression” has also been observed after treatment with immunotherapies, but is often followed by tumor regression[4,5]
– Apparent increases in tumor lesions in these cases may be a result of immune-cell infiltration of the tumor[4]
* More common in MGMT-methylated patients.[2]
MGMT, O6-methylguanine DNA methyltransferase; MRI, magnetic resonance imaging; RT, radiotherapy.
1. Hygino da Cruz LC et al. AJNR Am J Neuroradiol. 2011;32(11):1978-1985.
2. Stuplich M et al. J Clin Oncol. 2012;30(31):e180-183.3. Brandsma D et al. Lancet Oncol. 2008;9(5):453-461.4. Wolchok JD et al. Clin Cancer Res. 2009;15(23)7412-7420.5. Lipson EJ. Oncoimmunology. 2013;2(4):e23661.
23
iRANO Criteria for Glioblastoma Assessment
RANO Criteria[1,2] CR PR SD PD*
T1 enhancing disease None ≥ 50% < 50% if ↓ but
< 25% if ↑ ≥ 25% ↑
T2/FLAIR Stable/improved Stable/improved Stable/improved Worsened
New lesion None None None Present
Corticosteroid use None Stable or ↓ Stable or ↓ NA†
Clinical status Stable/improved
Stable/improved
Stable/improved Declined
iRANO[2]
• Further guidance on confirmation scans
• New lesions are incorporated into total lesion area
• Further guidance on considerations for corticosteroid use
* Progression occurs when any one of these criteria are present[1]; † Increase in corticosteroids alone will not determine PD without persistent clinical deterioration.[1]
1. Wen PY et al. J Clin Oncol. 2010;28(11):1963-1972. 2. Okada H et al. Lancet Oncol. 2015;16(15):e534-e542.
CR, complete response; FLAIR, fluid-attenuated inversion recovery; iRANO, Immunotherapy RANO; NA, not available; PD, progressive disease; PR, partial response; RANO, Response Assessment in Neuro-Oncology; SD, stable disease.
24
Summary of and Challenges in Glioblastoma Treatment
Diagnosis • Early diagnosis and treatment do not improve outcomes for glioblastoma, precluding the utility of screening efforts[1]
Biomarkers• Although molecular characterization is specified in guidelines
for glioblastoma (eg, MGMT status), biomarkers have not yet translated into making clinical decisions[2]
Treatment• SOC for glioblastoma is MSR/Biopsy→RT/TMZ→TMZ[3,4]
• PS is the main criterion in deciding to administer SOC[3,4]
Recurrence • Virtually all glioblastomas recur, and there is nodefined SOC for this setting[3,5]
MGMT, O6-methylguanine DNA methyltransferase; MSR, maximal surgical resection.; PS, performance status; RT, radiotherapy; SOC, standard of care; TMZ, temozolomide.
1. Omuro A. JAMA. 2013;310(17):1842-1850. 2. Jackson CM et al. Clin Cancer Res. 2014;20(14):3651-3659.3. NCCN Guidelines®. Central Nervous System Cancers. V1.2015. 4. Stupp R et al. Ann Oncol. 2014;25(Suppl 3):iii93-iii101.5. Decision resources. Glioblastoma multifigure. 2013.
Treatment Options for Glioblastoma
Module 3
26
• RT with concurrent and adjuvant temozolomide is SOC for newly diagnosed patients[1-3]
Current Treatment Options for Newly Diagnosed Glioblastoma
Newly Diagnosed• Surgery (MSR or biopsy) ± carmustine wafer
− 5-ALA dye*• Radiation• Systemic chemotherapy
− Temozolomide• Clinical trials (NCCN)• Bevacizumab (Japan only†)
* Approved in Europe, Japan, and Canada.[4]
† As part of SOC.[3]
5-ALA, aminolevulinic acid; MSR, maximal safe resection; NCCN, National Comprehensive Cancer Network; RT, radiotherapy; SOC, standard of care.
1. NCCN Guidelines. Central Nervous System Cancers. V1. 20152. Stupp R et al. Ann Oncol. 2014;25(Suppl3):iii93-iii101.3. Takano S et al. Onco Targets Ther. 2014;7:1551-1562.4. Roberts DW et al. Neurosurg Clin N Am. 2012;23(3):271-377.
27
• Adjuvant radiotherapy has long been a mainstay of glioblastoma therapy[1]
– RT is administered to T1-enhanced tumor region + 2–3-cm margin on T2 or FLAIR abnormality[2]
• Key randomized clinical trials demonstrated mOS benefit of 5 mo for RT in newly diagnosed patients:
Radiotherapy
Trial Setting N Experimental Arms Control Arms mOS
NCI (1978)[3] 1L, Anaplastic gliomas 303
RT
BSC
36 wks
14 wksRT + IV BCNU 34.5 wksIV BCNU 18.5 wks
Scandinavian Glioblastoma Study Group[4]
1L 118RT+ bleomycin
BSC10.8 mo
5.2 moRT 10.8 mo
1L, first line; BCNU, 3-bis (2-chloroethyl 1)-1-nitrosourea (carmustine); BSC, best supportive care; EBRT, external beam radiation therapy; IFRT, involved-field radiation therapy; FLAIR, fluid-attenuated inversion recovery; IV, intravenous; MGMT, O6-methylguanine DNA methyltransferase; mOS, median overall survival; NCI, National Cancer Institute; PS, performance score; RT radiotherapy.
1. Brandes AA et al. J Clin Oncol. 2009;(8):1275-12792. Dhermain F. Chin J Cancer. 2014;33(1):16-24.3. Walker MD et al. J Neurosurg. 1978;49(3):333-343.4. Kristiansen K et al. Cancer. 1981;47(4):649-652.5. NCCN Guidelines. Central Nervous System Cancers. V1. 2015.6. Malmstrom A et al. Lancet Oncol. 2012;13(9):916-926.
• Fractionated EBRT and IFRT: Most commonly used RT modalities[5]
• Hypofractionated radiotherapy: Often preferred in elderly/poor PS patients, especially when lacking MGMT promoter methylation[6]
28
Chemotherapy: Carmustine Wafer (BCNU) • Biodegradable polymer wafers loaded with nitrosourea carmustine (BCNU) are
implanted into the surgical cavity at the time of initial resection[1]
• A key phase III trial demonstrated survival benefit* for BCNU wafers in newly diagnosed malignant glioma patients (N=240)[2,3]
* P=0.03.[2]
BCNU, 3-bis (2-chloroethyl 1)-1-nitrosourea (carmustine); CI, confidence interval; Gliadel, poly [carboxyphenoxy-propane/sebacic acid] anhydride wafers containing 3.85% carmustine; HR, hazard ratio; NS, not significant; OS, overall survival; PBO, placebo.
100
90
80
70
60
50
40
30
20
10
00 6 12 14 16 18 22 24
Months From Implant Surgery
Sur
viva
l Rat
e (%
)
42 20108
BCNU
Placebo
• At 3-year follow-up, glioblastoma patients who received BCNU had 22% reduced risk of death (NS)[3]
• Survival benefit of BCNU wafer for glioblastoma remains unclear[2,3]
• Implanting wafers may impact clinical trial enrollment[4]
1. Valtonen S et al. Neurosurgery. 1997;41(1):44-49.2. Westphal M et al. Neuro Oncol. 2003;5(2):79-88.3. Westphal M et al. Acta Neurochir (Wein). 2006;148(3):269-275.4. NCCN Guidelines. Central Nervous System Cancers. V1. 2015.
Median OS (mo)BCNU
(n=101) 13.5 HR (95% CI):0.76 (0.55–1.05)
P=0.10PBO (n=106) 11.4
Glioblastoma Subgroup (n=207)[2]
Minimum follow-up:
12 mo
29
Chemotherapy: Temozolomide (TMZ)
TMZ is an alkylating agent prodrug• Alkylating agents bind to DNA, impairing
replication/transcription and ultimately leading to cell death[1]
• TMZ is able to cross the BBB and is spontaneously converted into the active metabolite in the CNS[2]
• TMZ is a standard treatment for newly diagnosed glioblastoma[3]
− Administered daily concomitantly with RT and as maintenance thereafter*[3]
− Available in oral and IV formulation[4]
* Alternative TMZ dosing regimens have not demonstrated improved efficacy, but continue to be investigated (see Module 4 for further details).
Tumorcell
TMZ
ReplicationTranscription
1. Fu D et al. Nat Rev Cancer. 2012;12(2):104-120.2. Agarwala SS, Kirkwood JM. Oncologist. 2000;5(2):144-151.3. NCCN Guidelines. Central Nervous System Cancers. V1. 2015.4. TEMODAR [package insert]. Whitehouse Station, NJ:
Merck & Co, Inc; 2014. 5. Wesolowski JR et al. Am J Neuroradiol. 2010;31(8):1383-1384.
BBB, blood-brain barrier; CNS, central nervous system; DNA, deoxynucleic acid; IV, intravenous; RT, radiotherapy; TMZ, temozolomide.
Adapted from Wesolowski et al 2010.[5]
30
TMZ in Glioblastoma: Phase III EORTC/NCIC Trial
Daily TMZ + RT→ 6 cycles TMZ
Key Inclusion Criteria[1]
• 18–70 years old• Newly diagnosed
glioblastoma• WHO PS<2
R
RT alone
N=573
• ~2 month increase in mOS[1]
• 2-yr survival: 26.5% vs 10.4%[1]
• 5-yr survival: 10% vs 2%[2]
00 6 12 18 24 30 36 42
102030405060708090
100
Months
Prob
abili
ty o
f Ove
rall
Surv
ival
(%)
RT + TMZRT
The widespread use of TMZ in glioblastoma is based on the EORTC/NCIC trial
1. Stupp R et al. N Engl Med. 2005;352(10):987-996.2. Stupp R et al. Lancet Oncol. 2009;10(5):459-466.
CI, confidence interval; EORTC, European Organization for Research and Treatment of Cancer; HR, hazard ratio; mOS, median OS; NCIC, National Cancer Institute of Canada; OS, overall survival; PS, performance status; R, randomization; RT, radiotherapy; TMZ, temozolomide; WHO, World Health Organization.
Median OS (mo)[1]
RT+TMZ(n=287) 14.6 HR (95% CI):
0.63 (0.52–0.75)P<0.001RT
(n=286) 12.1
31
• Alkylating agents, such as TMZ, cause cell death by binding to DNA[1,2]
• The MGMT protein can reverse alkylation*[1]
• MGMT methylation leads to loss of MGMT protein and thus, ineffective DNA repair[1]
‒ TMZ remains effective• Unmethylated MGMT retains
MGMT protein synthesis and therefore, DNA repair[1]
‒ TMZ ineffective
MGMT Methylation Status in Glioblastoma: Predictive Biomarker for TMZ
100 EORTC/NCIC Trial[2]
80
60
40
20
00 6 12 18 24 30 36 42
Months
Prob
abili
ty o
f OS
(%)
MethylatedMGMT
promoter
UnmethylatedMGMT
promoter P<0.001
1. Esteller M et al. N Engl J Med. 2000;343(19):1350-1354.2. Hegi ME et al. N Engl J Med. 2005;352(10):997-1003.
* If alkylation is at the O6 position of guanine.[1]
EORTC, European Organisation for Research and Treatment of Cancer; MGMT, O-methylguanine DNA methyltransferase; OS, overall survival; NCIC, National Cancer Institute of Canada; TMZ, temozolomide.
32
• Non-invasive medical device that applies tumor-treating fields (TTF) via electrodes placed on the scalp, shown to have antimitotic activity[1,2]
• Phase III trial in newly diagnosed glioblastoma was terminated at interim analysis due to early success[3]
– Control arm pts are now crossing over to receive SOC + TTF[3]
TTF for Newly Diagnosed Glioblastoma
1. Vymazal J, Wong ET. Semin Oncol. 2014;41(Suppl6):S14-24.2. Stupp R et al. Eur J Cancer. 2012;48(14):2192-2202.3. PR Newswire. Novocure EF-14 PhIII. www.prnewswire.com/
news-releases/novocure-announces-the-ef-14-phase-iii-clinical-trial-of-tumor-treating-fields-in-patients-with-newly-diagnosed-glioblastoma-has-been-terminated-at-the-interim-analysis-due-to-early-success-282808841.html. Accessed December 17, 2015.
Trial[4] Study Arms N mPFS[3] mOS[3] 2-yr Survival[3]
EF-14NCT00916409Phase III
SOC + TTF*vs
SOC
315[3]
(interim analysis)
7.1 vs 4 mo
HR=0.63; P=0.001
19.6 vs 16.6 mo
HR=0.75; P=0.034
43% vs 29%
HR, hazard ratio; mOS, median overall survival; mPFS, median progression-free survival; SOC, standard of care; TTF, tumor-treating fields.
* Administered as 4 insulated electrode arrays placed on scalp.[4]
33
• Virtually all patients eventually relapse[1]
• There is no standard of care for relapsed patients[2]
Overview of Current Treatment Options for Recurrent Glioblastoma
• Chemotherapy− Temozolomide− Nitrosoureas− PCV− Cyclophosphamide− Cisplatin/Carboplatin
• Targeted therapies− Bevacizumab* ±
chemotherapy− Erlotinib/Imatinib†
• Re-resection ± carmustine wafer
• Alternating electric field therapy
• Re-irradiation‡
• Clinical trials (NCCN and ESMO/EANO)
BEV, Bevacizumab; EANO, European Association for Neuro-Oncology; ESMO, European Society for Medical Oncology; EMA, European Medicines Agency; FDA, Food and Drug Administration; NCCN, National Comprehensive Cancer Network; PCV, procarbazine/lomustine/vincristine.
1. Felsberg J et al. Int J Cancer. 2011;129(3):659-670.2. Gil-Gil MJ et al. Clin Med Insights Oncol. 2013;7:123-135.3. NCCN Guidelines. Central Nervous System Cancers. V1. 20154. Stupp R et al. Ann Oncol. 2014;25(Suppl3):iii93-iii101.
* Currently approved by FDA but not EMA. BEV + chemo considered if BEV monotherapy fails (NCCN); BEV ± Irinotecan is Category 3C in ESMO.
† Recommended in ESMO guidelines (Category 2C) but not in NCCN guidelines.‡ Data are lacking on re-irradiation of recurrent glioblastomas, and its use is controversial.
Recurrent Disease[3,4]
34
• Even before the 2009 accelerated approval in US, bevacizumab has been used for management of recurrent glioblastoma in US and parts of Europe[1]
• In Japan, BEV use has been increasing since its approval[2]
• Despite PFS benefit, no significant effect of bevacizumab on mOS has been reported in phase III trials[3,4]
Bevacizumab: Registrational Trial Data
Trial Study Arms Ph Study Setting N ORR, % mPFS, mo mOS, mo
BRAIN[5]BEV
II Recurrent glioblastoma 167
28 4.2 9.2BEV + irinotecan 38 5.6 8.7
NCI[6] BEV II Recurrent glioblastoma 48 35 16 wks 31 wks
JO22506[7] BEV IIRecurrent
glioblastoma (Japan)
31 28 3.3 10.5
AVAglio[3] BEV + RT + TMZ vsPlacebo + RT + TMZ III Newly diagnosed
glioblastoma 921 NA 10.6 vs 6.2* 16.8 vs 16.7†
* Statistically significant. † Not statistically significant (P=0.10).
BEV, bevacizumab; mOS, median overall survival; mPFS, median PFS; NA, not applicable; NCI, National Cancer Institute; ORR, objective response rate; PFS, progression-free survival; Ph, phase; RT, radiotherapy; TMZ, temozolomide.1. Wick W et al. J Clin Oncol. 2010;28(12):e188-189.
2. CancerMPact® Japan, 2013. April 2014, v1.1. 3. Chinot OL et al. N Engl J Med. 2014;370(8):709-722.4. Gilbert MR et al. N Engl J Med. 2014;370(8):699-708.5. Friedman HS et al. J Clin Oncol. 2009;27(28):4733-4740. 6. Kreisl TN et al. J Clin Oncol. 2009;25(5):740-745. 7. Nagane M et al. Jpn J Clin Oncol. 2012;42(10):887-895.
35
• The FDA conferred accelerated approval for bevacizumab (2009) based on nonrandomized phase II trials[1]
– Approval based on durable objective responses observed in two single-arm trials, AVF3708g and NCI 06-C-0064E.
Regulatory Approval of Bevacizumab
3. ESMO Oncology News. Available at http://www.esmo.org/Oncology-News/European-Medicines-Agency-Adopts-a-Final-Negative-Opinion-for-an-Extension-of-Indications-for-Bevacizumab. Accessed December 17, 2015
4. ESMO Oncology News. Available at http://www.esmo.org/Oncology-News/European-Medicines-Agency-Recommends-to-Refuse-a-Change-to-the-Marketing-Authorisation-for-Bevacizumab. Accessed December 17, 2015.
5. Roche Media Release, 2013. Available at http://www.roche.com/media/media_releases/med-cor-2013-06-17.htm Accessed December 17, 2015.
• The EMA rejected regulatory approval for bevacizumab in 2009 and 2014[2,3]
– Doubtful of ORR and PFS as endpoints and wary of lack of OS benefit[4]
• ORR is highly variable in independent assessments[2]
• Anti-angiogenic agents affect brain permeability and therefore imaging responses[2]
• The Japanese MHLW approved bevacizumab for both lines of therapy[5]
– Approval in the newly diagnosed setting was based on improved mPFS results in the AVAglio study[5]
EMA, European Medicines Agency; FDA, Food and Drug Administration; MHLW, Ministry of Health/Labor/and Welfare; ORR, objective response rate; OS, overall survival; mPFS, median progression-free survival; PFS, progression-free survival.
1. Cohen MH et al. Oncologist. 2009;14(11):1131-1138.2. Wick W et al. J Clin Oncol. 2010;28(12):e188-e189.
36
• Despite PFS improvement, no OS benefit observed in either trial[1,2]
• Due to discrepancy in QOL, it has been proposed that the investigators of these studies should share their raw data with the US FDA[5]
Conflicting Quality of Life Outcomes From RTOG 0825 Trial and AVAGlio
Trial N Primary Endpoint(s) Key Efficacy Data Key Safety Data
RTOG 0825NCT00884741[1,3] 637 OS, PFS
BEV vs PBO• mOS: 15.7 vs 16.1 mo• mPFS*: 10.7 vs 7.3
• Increased AE profile in BEV group• Increased symptom burden,
worse QOL, declined neurocognition in BEV group
AVAglioNCT00943826[2,4] 921 OS, PFS
BEV vs PBO• mOS: 16.8 vs 16.7 mo• mPFS†: 10.6 vs 6.2 mo
• More frequent grade >3 AE in BEV group
• QOL and PS maintained longer in BEV group
1. Gilbert MR et al. N Engl J Med. 2014;370(8):699-708.2. Chinot OL et al. N Engl J Med. 2014;370(8):709-722.3. Clinicaltrials.gov. NCT00884741 4. Clinicaltrials.gov. NCT009438265. Fine HA. N Engl J Med. 2014;370(8):764-765.
* Did not meet prespecified cutoff for outcome benefit (P=0.007).† Statistically significant (P<0.001).
Phase III RTOG 0825 and AVAglio trials compared SOC + BEV vs placebo in newly diagnosed glioblastoma patients[1,2]
AE, adverse event; BEV, bevacizumab; OS, overall survival; mPFS, median progression-free survival; PBO, placebo; PFS, progression-free survival; PS, performance status; QOL, quality of life; RTOG, Radiation Therapy Oncology Group; SOC, standard of care.
37
• Recently reported results from a randomized trial evaluating BEV ± lomustine demonstrated potentially meaningful OS benefit for the combination[1]:Prespecified criteria for further phase III studies were met for the combination[2]
Bevacizumab in Combination With Lomustine: BELOB and EORTC 26101
Trial[1] Experimental Arms Ph Study Setting N ORR, % 6-mo PFS, % 9-mo OS, %
BELOBNTR1929
LomustineII Recurrent
glioblastoma 1485 13 43
BEV 38 16 38 Lomustine* + BEV 34 41 59
1. Taal W et al. Lancet Oncol. 2014;15(9):943-953.2. Taal W et al. Presentation at SNO 2014. AT-55.3. Clinicaltrials.gov : NCT01290939.4. Wick W. et al SNO 2015 Abstract
1L, first line; 2L, second line; BEV, bevacizumab; EORTC, European Organisation for Research and Treatment of Cancer; NTR, Netherlands Trial Register; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
* 90 mg/m2 dose, determined after interim safety analysis.
• EORTC 26101: Phase III Trial Exploring the Combination of Bevacizumab and Lomustine vs Lomustine in Patients With First Recurrence of Glioblastoma3,4
Trial Experimental Arms Study design Ph N Primary Endpoint mPFS* mOS**
EORTC 26101 NCT01290939
Lomustine ± BEV Recurrent III 433 OS
1.54 mos (LOM; n=149) vs.
4.17 mos (BEV+LOM; n=288)
mOS 8.64 mos (LOM; n=149) vs.
9.10 mos (BEV+LOM;
n=288) * Locally assess PFS was longer with the addition of BEV to LOM: HR 0.49 (95% CI 0.39, 0.61) P< .0001
** With 329 OS events (75.3%) OS was not superior in the combination therapy arm (HR: 0.95, CI: 0.74-1.21, p=0.650)
Toxicity was in the expected range with more events in the combination arm being also longer on treatment
38
Key Adverse Events by Class of Therapy
VEGF-Targeted Agents[4-9]
• Hypertension and diarrhea occur in all VEGF/VEGFR inhibitors
• Other AEs include gastrointestinal AEs (diarrhea, nausea, vomiting), dermatologic AEs (HFS), and fatigue
• Bevacizumab has a black box warning in the US for GI perforation and serious bleeding[9]
Alkylating Agents(TMZ, BCNU)[2-3]
• Alopecia• Fatigue• Nausea/vomiting• Thrombocytopenia• Neutropenia
RT[1]
• Hair loss• Nausea• Fatigue• Increased ICP• Other AEs include
memory loss and radiation necrosis
• Adverse events associated with TMZ are generally milder than other alkylating agents[2]
AE, adverse event; BCNU, carmustine; GI, gastrointestinal; HFS, hand-foot syndrome; ICP, intracranial pressure; RT, radiotherapy; TMZ, temozolomide; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.
1. Lawrence YR et al. Br J Cancer. 2011;104(9):1365-1371.2. Chang L et al. Onco Targets Ther. 2014;7:235-244.3. Reithmeier T et al. BMC Cancer. 2010;10:30.
4. Eisen T et al. J Natl Cancer Inst. 2012;104(2):93-113. 5. SUTENT [package insert]. New York, NY: Pfizer Labs; 2014. 6. VOTRIENT [package insert]. Middlesex, UK: GlaxoSmithKline; 2014.7. NEXAVAR [package insert]. Berlin, Germany: Bayer HealthCare
Pharmaceuticals Inc; 2013. 8. INLYTA [package insert]. New York, NY: Pfizer Labs; 2013. 9. AVASTIN [package insert]. San Francisco, CA: Genentech, Inc; 2013.
39
Summary of Currently Available Agents Approved for Glioblastoma
Agent[1-4] MOA[1,3,5] Line[1,2] Admin[1,2,6-9] Guideline Recommendation[1-4]
Temozolomide Alkylating agent ND, R PO/IV NCCN, ESMO
Carmustine (wafer) Alkylating agent ND, R Implant NCCN, ESMO
Carmustine (systemic) Alkylating agent R IV NCCN, ESMO*
Lomustine Alkylating agent R PO NCCN, ESMO
Bevacizumab VEGF inhibitorND
IVJapan only
R NCCN, JapanTTF device Anti-mitotic R Electrodes NCCN†, Japan‡
* Single agent nitrosourea therapy.[2]
† Not all panelists recommended TTF.[1]‡ TTF has been made available on a restricted case basis for compassionate use in Japan.[4]
Admin, administration; ESMO, European Society for Medical Oncology; IV, intravenous; NCCN, National Comprehensive Cancer Network; MOA, mechanism of action; ND, newly diagnosed; PO, by mouth; R, recurrent; TTF, tumor-treating fields; VEGF, vascular endothelial growth factor.
1. NCCN Guidelines ®. Central Nervous System Cancers. V1. 2015.2. Stupp R et al. Ann Oncol. 2014;25(Suppl3):iii93-iii101.3. Roche Press Release, June 17, 2013. Available at:
http://www.roche.com/media/store/releases/med-cor-2013-06-17.htm. Accessed February 25, 2015.
4. Muragaki Y et al. Presentation at SNO 2014. NT-25.5. Decision Resources: Glioblastoma Multiforme. September 2013.6. TEMODAR [package insert]. Whitehouse Station, NJ: Merck & Co, Inc;
2014. 7. BiCNU [package insert]. Princeton, NJ: Bristol-Myers Squibb Company;
2011.8. CeeNU [package insert]. Princeton, NJ: Bristol-Myers Squibb
Company; 2012.9. AVASTIN [package insert]. South San Francisco, CA: Genentech, Inc;
2014.
40
Additional Recommended Agents for Glioblastoma
Agent[1,2] MOA[2-4] Line[1,2] Admin[3,4] Guideline Rec[1,2] Key Efficacy[2,4-6]
Cyclophosphamide Alkylating agent R PO NCCN Modest mPFS increase
PCVProcarbazine Alkylating
agents RPO
NCCN, ESMO Comparable efficacy with TMZLomustine PO
Vincristine IV
Carboplatin DNA crosslinking agents
R IV NCCNModest activity
Cisplatin R IV NCCN
Bevacizumab VEGF inhibitor R IV ESMO Steroid-sparing effect†
Irinotecan Topoisomerase inhibitor R IV NCCN, ESMO Modest mPFS
increase (+BEV)†
Erlotinib EGFR inhibitor R PO ESMO Anti-tumor efficacy not shown‡Imatinib PDGFR inhibitor R PO ESMO
Admin, administration; bev, bevacizumab; DNA, deoxynucleic acid; EGFR, epidermal growth factor receptor; ESMO, European Society for Medical Oncology; IV, intravenous; mPFS, median progression-free survival; NCCN, National Comprehensive Cancer Network; PCV, procarbazine/ lomustine/vincristine; PDGFR, platelet-derived growth factor receptor; PO, by mouth; R, recurrent; rec, recommendation; RR, response rate; TKI, tyrosine kinase inhibitor; TMZ, temozolomide,
VEGF, vascular endothelial growth factor. 1. NCCN Guidelines®. Central Nervous System Cancers. V1. 20152. Stupp R et al. Ann Oncol. 2014;25(Suppl3):iii93-iii101.3. Decision Resources: Glioblastoma Multiforme. September 2013.4. Chamberlain MC, Tsao-Wei DD. Cancer. 2004; 100(6):1213-20.5. Roci E et al. Med Arch. 2014;68(2):140-143.6. Friedman HS et al. J Clin Oncol. 2009;27(28):4733-4740.
* As single agents in recurrent high grade gliomas[5]; † In a study of bevacizumab±irinotecan, there was a trend toward stabilization/decrease in steroid use, in patients taking corticosteroids at baseline[6]; ‡ In unselected patient populations.[2]
41
Limitations of Current Therapies
BBB, blood-brain barrier; mOS, median overall survival; mPFS, median progression-free survival; RR, response rate; tx, treatment.
1. Patel MA et al. Cancers. 2014;6(4):1953-1985. 2. SEER Stat Fact Sheets: Brain and Other Neurons System
Cancer. Available at: http://seer.cancer.gov/statfacts/html/brain.htmlAccessed December 17, 2015.
Treatment Outcomes
• Over the past 4 decades, treatment advances have only modestly impacted overall patient survival[1,2]
• Recurrence rate remains ~100%[3]
• Prognosis for patients with relapsed glioblastoma remains extremely poor[4]
− RR <4%–16% − mPFS ~2.3 months− mOS 3–9 months
Challenges and Unmet Needs
• Imaging challenges due to tx-related changes in brain permeability[5]
• Fewer tx options for elderly population despite higher incidence[6]
• Drug delivery past the BBB[7]
• Neurotoxicity of treatments[7]
3. NCCN Guidelines. Central Nervous System Cancers. V1. 2015.4. Gil-Gil MJ et al. Clin Med Insights Oncol. 2013;7:123-135. 5. Hygino da Cruz LC et al. AJNR Am J Neuroradiol.
2011;32(11):1978-1985.6. Arvold ND, Reardon DA. Clin Interv Aging. 2014;9:357-367.7. Chamberlain MC. Neurosurg Focus. 2006;20(4):E19.
Investigational Agents for Glioblastoma
Module 4
43
Investigational Agents:Chemotherapies (cont’d)
VAL-083 (DelMar) is a novel alkylating agent under phase I/II development for recurrent glioblastoma[1,2]
• Unaffected by MGMT methylation status in vitro[1]
Has orphan drug designation in US (2012) and Europe (2013) for gliomas[3]
Preliminary results of phase I/II dose escalation trial in newly diagnosed pts*[2] have recently been reported[4]:
• Safety: Well-tolerated; MTD not yet reached• Efficacy: Improved clinical signs in 3 pts reaching SD or PR†
1. Steino A et al. Mol Cancer Ther. 2013;12(11 suppl):B252.2. Clinicaltrials.gov. NCT01478178.3. DelMar Press Release. Available at:
http://www.delmarpharma.com/DelMarPharmaVAL-083EUORPHANDRUG130107.pdf. Accessed February 17, 2015.
4. Shih KC et al. Poster presentation at ASCO 2014. 2093.
AE, adverse event; MGMT, O6-methylguanine DNA methyltransferase; MTD, maximum tolerated dose; PR, partial response; SD, stable disease; TMZ, temozolomide.
* Also enrolling patients previously treated with surgery and/or radiation who have failed on both TMZ and bevacizumab.[4]
† Maximum response of 28 cycles (84 weeks) prior to discontinuing due to unrelated AE.[4]
44
Although approved in 1L and 2L settings, OS benefit has not been observed[1]
Investigational Agents: Antiangiogenics
Other Antiangiogenic Agents• TKIs targeting the VEGFR pathway have
shown limited or no clinical benefit in glioblastoma, with some trials demonstrating high toxicity rates[1,2]
• VEGF-targeting next-generation antibody pegdinetanib is in phase II development for glioblastoma[3]
Adapted from Oudard S et al 2012.[4]
PI3K
mTOR
AKT
Angiogenesis
VEGFR
VEGF
Tumorcell
Bevacizumab*
*Bevacizumab is further discussed in Module 3
1. Wilson TA et al. Surg Neurol Int. 2014;5:64.2. Reardon DA, Wen PY. Oncologist. 2006;11(2):152-164.3. Evans JB, Syed BA. Nat Rev Drug Discov. 2014;13(6):413-4144. Oudard S et al. Cancer Treat Rev. 2012;38(8):981-987.
1L, first line; 2L, second line; AKT, protein kinase B; mAb, monoclonal antibody; mTOR, mammalian target of rapamycin; OS, overall survival; PI3K, phosphoinositide-3 kinase; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.
Roche
45
• DNA-histone H1 complex*
• Radioactive Iodine
Early Phase Targeted Agents for Glioblastoma: Cytotoxic Antibody Conjugates• Antibody-drug conjugates are designed to deliver cytotoxic drug activity
specifically to tumor cells[1]
• LRP-1†
• Anti-MT agent paclitaxel
• EGFR or mut EGFRvIII
• Anti-MT agent MMAF
131I-chTNT-1/B MAb[2]
ANG-1005[3]
ABT414[4]
Adapted from http://www.seattlegenetics.com/adc_technology.
1 ADC bindsto target
ADC receptor complex is
internalized
2
Apoptosis4
Cytotoxic agent is released
3
1. Seattle Genetics. Advancing ADC technology. Available at: http://www.seattlegenetics.com/adc_technology. Accessed December 17, 2015
2. Shapiro WR et al. J Clin Oncol. 2010;28:15s. Abstract 2039.3. Drappatz J et al. Poster presentation at ASCO 2010. 2009.4. Gan HK et al. Poster presentation at ASCO 2014. 2021.
* DNA-histone H1 complex is exposed in tumor necrotic core[2].† LRP1 is expressed in BBB endothelium and in tumor cells[3].
ADC, antibody-drug conjugate; EGFR, epidermal growth factor receptor; EGFRvIII, EGFR variant III; LRP-1, low-density lipoprotein receptor-related protein 1; MMAF, monomethyl auristatin F; MT, microtubule.; mut, mutated.
Peregrine
Angiochem
AbbVie
46
Early Phase Targeted Agents for Glioblastoma: Cytotoxic Antibody Conjugates (cont’d)
Study N Efficacy Safety Status
131I-chTNT-1/B MAb[1-3]
Phase II
Dose-confirmatory in pts at 1st relapse
41 • mOS: 9.3 mo• 2-yr OS: 19%
Grade 3/4 AE in 22% patients
• Orphan drug status, FDA and EMA
• Fast-track status, FDA
• No currently ongoing trials*
ANG1005[4,5]
Phase I (NCT00539344)
Safety and preliminary efficacy in recurrent glioblastoma and AG pts
63 2 CR and 2 PR in glioblastoma pts
• Well-tolerated• No CNS toxicity• Minimal systemic
toxicity
• Orphan drug status, FDA[6]
• Fast-track status, FDA[6]
• Phase II trial currently ongoing[4]
ABT414[4,7]†
Phase I +TMZ(NCT01800695)
Safety and preliminary efficacy in newly diagnosed or recurrent pts
21 1 CR and 3 PR in TMZ-refractory pts
MMAF-induced corneal epithelial microcysts
• Orphan drug status, FDA and EMA
• Trial still ongoing
1. Peregrine Press Release. 2012. http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=725023 Accesed December 21, 2015
2. Peregrine Press Release. 2011. http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=579150 Accesed December 21, 2015
3. Shapiro WR et al. J Clin Oncol. 2011;29. Abstract 2035.4. Clinicaltrials.gov.5. Drappatz J et al. Poster presentation at ASCO 2010. Abstract 2009.6. Angiochem. Angiochem’s ANG1005 received orphan drug designation from FDA for
the treatment of glioblastoma multiform. http://angiochem.com/angiochem%E2%80%99s-ang1005-received-orphan-drug-designation-fda-treatment-glioblastoma-multiform. Accessed February 15, 2015.
7. Gan HK et al. Poster presentation at ASCO 2014. 2021.
AE, adverse events; AG, angioblastoma; CNS, central nervous system; CR, complete response; EMA, European Medicines Agency; FDA, Food and Drug Administration; mAb, monoclonal antibody; MMAF, monomethyl auristatin F; mOS, median OS; OS, overall survival; TMZ, temozolomide.
* Plans for phase III trial have been approved by FDA as of 2012.[5]
† Phase II trial is planned.[1]
47
Phase III Failures of Targeted Agents Highlight Need for New Treatment Modalities
Agent MOA Patient Population Results (Primary Endpoint)
Enzastaurin[1] Serine/threonine kinase inhibitor
Recurrent Terminated following interim futility analysis (no PFS benefit)
Cediranib[2] (REGAL trial) VEGF Inhibitor Recurrent No PFS, OS benefit demonstrated
Imatinib[3] TKI Recurrent No PFS benefit demonstratedCintredekin besudotox (IL13-PE38)[4]
Cytotoxin Recurrent No OS benefit demonstrated
TransMID (Tf-CRM107)[5,6]
Cytotoxin Progressive or Recurrent (unresectable)
Terminated following interim analysis (unlikely to meet trial criteria for efficacy)
Trabedersen (AP12009)[7] TGF-βoligonucleotide
Progressive or Recurrent Grade III and IV gliomas
Serious adverse events
Cilengitide[8,9] Integrin inhibitor Newly diagnosed, MGMT-methylated
No OS, PFS benefit demonstrated
Nimotuzumab[10] EGFR mAb Newly diagnosed No PFS, OS benefit demonstrated
4. Kunwar S et al. Neuro Oncol. 2010;12(8):871-881. 5. Clinicaltrials.gov. NCT00083447. 6. Drugs.com. Celtic terminates Transmid trial. Available at: http://www.drugs.com/news/celtic-pharma-terminates-transmid-trial-ksb311r-ciii-001-5246.html. Accessed December 17, 2015. 7. Clinicaltrials.gov. NCT00761280. 8. Tactical Therapeutics. Glioblastoma—overcoming resistance in malignant brain cancer. Available at: http://www.tacticaltherapeutics.com/ glioblastoma/. Accessed December 17, 2015. 9. Stupp R et al. Lancet Oncol. 2014;15(10):1100-1108. 10. Westphal M, Bach F. J Clin Oncol. 2012 (suppl):30. Abstract 2033.
EGFR, epidermal growth factor receptor; mAb, monoclonal antibody; MGMT, O6-methylguanine DNA methyltransferase; MOA, mechanism of action; mOS, median OS; OS, overall survival; PFS, progression-free survival; TGF-β, transforming growth factor-beta; Tf, transferrin; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.
1. Wick W et al. J Clin Oncol. 2010;28(7):1168-1174.2. Batchelor TT et al. J Clin Oncol. 2013;31(26):3212-3218.3. Dresemann G et al. J Neurooncol. 2010;96(3):393-402.
48
PD-1/PD-L1 in Glioblastoma
PD-1 was found to be expressed in 29% of tumor-infiltrating lymphocytes in glioblastoma tumor samples[1]*
• Expressed in 88% of newly diagnosed and 72% of recurrent glioblastomas†
PD-L1 was highly expressed in glioblastoma tumors[1]*:
• Low expression associated with proneural/G-CIMP glioblastoma subtypes[1]
• High expression associated with mesenchymal subtype[1]
• Immune suppressive heterogeneity has been observed between molecular subtypes[2]
PD-L1 expression correlated with glioblastoma molecular subtypes:
1. Berghoff AS et al. Neuro Oncol. 2014;pii:nou307. 2. Gilbert MR. Oral presentation at EANO 2014.
* Expression assayed by IHC in retrospective cohort.[1]
† Expression pattern of variable extent.[1]
G-CIMP, glioma CpG island methylator phenotype; IHC, immunohistochemistry; PD-1, programmed death-1; PD-L1, PD ligand-1; TIL, tumor-infiltrating lymphocyte.
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PD-1/PD-L1 in Glioblastoma (cont’d)
*Retrospective analysis (N=563).[1]
• Correlation between PD-L1 expression and response to PD-1 pathway inhibitors has been considerably variable across tumor types[1,2] − Predictive value of PD-L1 expression remains under investigation in
ongoing trials, including trials in glioblastoma1
− Positivity cutoffs used in PD-L1 IHC assays can also affect correlation[3]
PD-L1 expression in tumor samples did not correlate with patient survival*[1]
1. Berghoff AS et al. Neuro Oncol. 2014;pii:nou307. 2. Gettinger SN. Oral presentation at WCLC 2013. MO19.09.3. Goodman A. The ASCO Post. 2014;5(7).
IHC, immunohistochemistry; PD-1, programmed death-1; PD-L1, PD ligand-1.
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Emerging Biomarkers: PD-L1
Expression in[1,2]
Primary glioblastoma(membranous)
16.7%–38.3%
Primary glioblastoma(diffuse/fibrillary)
72.2%–88%
Prognostic Value
• Tumor cell expression of PD-L1 (and PD-1) associated with poor outcomes in glioblastoma patients[2]
Clinical Significance• Lower expression of PD-L1 on monocytes
was predictive for improved survival in glioblastoma patients treated with an autologous peptide vaccine[3]
• Tumor-expressed PD-L1 is being evaluated for value as a biomarker across multiple tumor types[4]
PD-1, programmed death-1; PD-L1, PD ligand-1. 1. Berghoff AS et al. Neuro Oncol. 2015;17(8):1064-1075.
2. Nduom EK et al. Neuro Oncol. 2016; 18(2): 195-205 3. Bloch O et al. Oral presentation at ASCO 2015. 2011. 4. Preusser M et al. Nat Rev Neurol. 2015;11(9):504-514. doi: 10.1038/nrneurol.2015.139.
Immunotherapeutic Approaches for Glioblastoma
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• Out of all ongoing trials, 19 are Phase III trials*,†[1]
– All novel agents in Phase III trials are immunotherapies[1]
– Immunotherapies are the most likely adjuvant treatments to effectively target glioblastoma with minimal toxicity[2]
Immunotherapies in Phase III Trials for Glioblastoma
Trial[1] MOA Study Arms Study EligibilityNCT01765088(China)
Chemotherapy + cytokine RT Adjuvant TMZ ± IFN-α Newly diagnosed grade III
or IV glioma
NCT00045968 Vaccine DCVax-L vs placebo with standard treatment‡
Newly diagnosed, resectable glioblastoma
NCT01480479 Vaccine Rindopepimut +TMZ vs KLH+TMZ with standard treatment‡
Newly diagnosed, resectable EGFRvIII+ glioblastoma
NCT02017717 Checkpoint Inhibition
Nivolumab vs nivolumab+ipilimumab vs bevacizumab after RT+TMZ
Recurrent glioblastoma
1. Clinicaltrials.gov. “Glioblastoma” + “Interventional” + “Adult” + “Phase III” + “Recruiting” or “Active, not recruiting” search results. Accessed December 22, 2015.
2. Bloch O, Parsa AT. Neuro Oncol. 2014;16(5):758-759.
* Criteria for Phase III: Open trials for agents that are intended to directly treat tumors and that have not yet failed.
† 8 are academic/ISRs and 7 are industry-sponsored.[3]
‡ Standard therapy, involving (attempted) surgical resection and chemoradiation.[3]
DCVax-L, dendritic cell vaccine L; EGFRvIII, epidermal growth factor receptor variant III; IFN-α, interferon alfa; ISR, industry-sponsored research; KLH, keyhole limpet hemocyanin; MOA, mechanism of action; RT, radiotherapy; TMZ, temozolomide.
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Cell-based vaccines[1,2]:DCs pulsed with tumor cells or TAAs, or tumor cell–derived vaccines transferred back to body to induce immune response
Immunotherapeutic Approaches in Glioblastoma: Vaccines
Tumor cells DCs
Peptide-based vaccine[1,2]:Mimic TAAs or tumor-targeting peptides to induce immune response (± adjuvant)
TAAs
1. Reardon DA et al. Expert Rev Vaccines. 2013;12(6):597-615.2. Hegde M et al. Discov Med. 2014;17(93):145-154.3. Mohme M et al. Cancer Treat Rev. 2014;40(2):248-258.DC, dendritic cell; TAAs, tumor-associated antigens.
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Phase III, randomized, double-blind study evaluating addition of DCVax-L to the current standard of care in newly diagnosed glioblastoma[1]
DCVax-L: Phase III Trial in Newly Diagnosed Glioblastoma
N=300
SOC + DCVax-L
SOC + Placebo
Key Inclusion Criteria• Newly diagnosed, resectable
glioblastoma• Age 18–70 years• KPS ≥70• No PD at the end of RT course• Adequate BM and liver function
R2:1
Start Date: December 2006Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)Status: Ongoing, but not recruitingStudy Director: Northwest Biotherapeutics
• Primary Outcome Measure: PFS• Secondary Outcome Measure:
OS and TTP
Crossover option upon PD
Cell-based vaccine
1. Clinicaltrials.gov. NCT00045968.
BM, bone marrow; DCVax-L, dendritic cell vaccine-L; KPS, Karnofsky performance status; OS, overall survival; PD, progressive disease; PFS, progression-free survival; R, randomized; RT, radiotherapy; SOC, standard of care; TTP, time to progression.
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ICT-107: Phase II Clinical Data
Key Efficacy and Safety Data[3,4,6] • PFS (ICT-107 vs placebo): 11.4 vs 10.1 mo• QoL (FACT-BR): Similar between groups• OS: Benefit not significant• Strongest activity observed in HLA-A2 subgroup
• No treatment-related Grade > 4 AE observed
• Trend for less steroid use in ICT-107 arm (30% vs. 44%)
• KPS maintained longer in those receiving ICT-107
• ICT-107 (ImmunoCellular Therapeutics, Ltd): Autologous DC vaccine targeting six different antigens associated with glioblastoma[1,2]
ICT-107
PlaceboR
Newly diagnosed glioblastoma
RT+TMZ TMZ or ICT-107 or placebo
Induction MaintenanceN=124
Phase II, randomized, double-blind study evaluating addition of ICT-107 to the current standard of care in newly diagnosed glioblastoma[2]
• Phase III trial design currently being finalized[4]
• Orphan drug designation in US and Europe[5]
MGMT-stratified
Cell-based vaccine
1. Reardon DA et al. Expert Rev Vaccines. 2013;12(6):597-615.2. Clinicaltrials.gov. NCT01280552. 3. Wen P et al. Oral presentation at ASCO 2014. 2005. 4. Market Watch. ICT-107. Available at: http://www.marketwatch.com/story/immunocellular-
therapeutics-presents-updated-ict-107-phase-ii-data-in-patients-with-newly-diagnosed-glioblastoma-at-the-2014-asco-annual-meeting-2014-06-01. Accessed December 17, 2015.
5. ImmunoCellular Therapeutics, Ltd. Overiew of ICT-107. Available at: http://www.imuc.com/pipeline/ict-107. Accessed December 17, 2015.
6. Wen P et al. Poster presented at ASCO 2015. 2036.
AE, adverse event; DC, dendritic cell; HLA-A2, human leukocyte antigen A2; MGMT, O6-methylguanine DNA methyltransferase; FACT-BR, Functional Assessment of Cancer Therapy –Brain ; KPS, karnofsky Performance Status; OS, overall survival; PFS, progression-free survival; QoL, quality of life; R, randomized; RT, radiotherapy; TMZ, temozolomide.
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• Rindopepimut (Celldex Therapeutics): EGFRvIII-targeted peptide vaccine[1]
– Three Phase II clinical trials demonstrated consistent improvement in mPFS and mOS over historical controls:
Rindopepimut: Phase II Clinical Data
Trial N Study Design Patients mPFS (mo) mOS (mo)ACTIVATE[2] 18 RT+TMZ rindopepimut
• Newly diagnosed• EGFRvIII+• GTR• No PD through CRT
14.2 26
ACT II[3,5] 22RT+TMZ rindopepimut standard or dose-intensified TMZ
Overall: 15.2
Overall: 23.6
ACT III[4,5] 65 RT+TMZ rindopepimut TMZ 12.3 24.6
Peptide-based vaccine
– Safety: Across clinical trials, rindopepimut toxicity has been generally mild and limited to skin reactions at injection site, fatigue, rash, nausea, and pruritus[2-4]
• Rindopepimut is currently being investigated in Phase III and II trials[1,5]
1. Babu R, Adamson DC. Core Evidence. 2012;7:93-103.2. Sampson JH et al. J Clin Oncol. 2010;28(31):4722-4729.3. Sampson JH et al. Neuro Oncol. 2011;13(3):324-333.4. Lai RK et al. Presentation at SNO 2011.5. Clinicaltrials.gov. NCT00643097.
CRT, chemoradiotherapy; EGFRvIII, epidermal growth factor receptor variant III; GTR, gross total resection; mo, months; mOS, median overall survival; mPFS, median progression-free survival; PD, progressive disease; RT, radiotherapy; TMZ, temozolomide.
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HSPPC-96: Overview and Key Data
HSPPC, heat shock protein peptide-complex; SOC, standard of care; mOS, median overall survival; mPFS, median progression free survival; MGMT, Hypermethylation of the O6-methylguanine-DNA-methyltransferase
1. Bloch O. Poster presentation at ASCO 2015. Abstract #2011.2. Clinicaltrials.gov. NCT00905060.
HSPPC-96: Autologous tumor-derived heat shock protein peptide vaccineA phase II clinical trial was designed to evaluate the addition of HSPPC-96 to SOC for newly diagnosed glioblastoma
Agenus Inc
Trial Design and Key Data[1,2]
Trial Ph Arm Patients N Key Data
Single arm[1] II
•HSPPC-96 administered at 25 µg per dose once weekly, then monthly with SOC
• Newly diagnosed GBM• ≥ 90 % tumor resection 46
• mOS = 23.8mo • mPFS = 17.8mo• PD-L1 High mOS = 18mo • PD-L1 Low mOS =
44.7mo• Adverse events = No
severe (grade 3/4) adverse events; vaccine well tolerated
Protein peptide vaccine
• Expression of PD-L1 on peripheral monocytes has been shown to be elevated in glioblastoma patients and was evaluated as a predictor of survival [1]
• A multivariate proportional hazards model revealed MGMT methylation status and PD-L1 expression as the greatest independent predictors of survival [1]
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Summary of Investigational Therapies and Unmet Needs
Glioblastoma Pipeline
• Most targeted agents yielding promising results in Phase I and II trials have failed Phase III trials[1,2]
• 19 Phase III trials are currently ongoing[3]
Immunotherapy for
Glioblastoma
• Immune escape mechanisms have emerged as a therapeutic target[4]
• All four novel agents in Phase III are immunotherapies[3]
• Combining treatment modalities may result in increased effectiveness[5,6]
Survival • No treatment has improved mOS over TMZ in the past 10 years[1,2]
mOS, median overall survival; TMZ, temozolomide.
1. Anton K et al. Hematol Oncol Clin N Am. 2012;26(4):825-853.2. Ohka F et al. Neurol Res Int. 2012; 2012:878425. doi:
10.1155/2012/878425.
3. Clinicaltrials.gov. “Glioblastoma” + “Interventional” + “Adult” + “Phase III” + “Recruiting” or “Active, not recruiting” search results. December 17, 2015.
4. Jackson CM et al. Clin Cancer Res. 2014;20(14):3651-3659.5. Zitvogel L et al. J Clin Invest. 2008;118(6):1991-2001.6. Drake CG. Ann Oncol. 2012;23(suppl 8):viii41-viii46.
