acknowledgement of support progress in the war against ......resection of ≥ 98% mean tumor volume...
TRANSCRIPT
1
Progress in the War Against Progress in the War Against Brain TumorsBrain Tumors
Henry S. Friedman, MDHenry S. Friedman, MDThe Preston Robert The Preston Robert TischTisch Brain Tumor Center Brain Tumor Center
at Dukeat Duke
Acknowledgement of Support
Henry S. Friedman, MD receives clinical trial and speaking engagement (honorarium and travel) support from Genentech and other pharmaceutical companies.
Brain Tumor Therapeutic Options
• Surgery
• Radiation
• Chemotherapy
• Anti-Angiogenic Agents
• Gene Therapy
• Vaccines
• Monoclonal Antibody Targeted Therapy
• Oncolytic Viruses
• Molecular Pathway Inhibitors
• Immune Augmentation
Brain Tumor Therapeutic Options
IncidenceDistribution of All Primary Brain and CNS Tumors by Histology
Glioblastoma20.3%
Astrocytomas9.8%
Ependymomas2.3%
Oligodendrogliomas3.7%
Embryonal, including Medulloblastoma
1.7%Meningioma
30.1%
Pituitary6.3%
Craniopharyngioma0.7%
Nerve Sheath8.0%
Lymphoma3.1%
All Other13.9%
CBTRUS Report: 2004-2005.
Malignant Glioma
Hess et al. Cancer 101:2293, 2004CBTRUS; Statistical Report, 2005-2006
GBM (grade 4) – 60% 13,000 cases/yr
LGG (grade 2) - 25%5,000 cases/yr
AA (grade 3) 10%2,000 cases/yr
AO (grade 3) 5%800 cases/yr
2
Glioblastoma:Overall Characteristics
• Grade IV malignant glioma
• Most malignant, invasive, difficult-to-treat primary brain tumor
• Frequency: most common in older adults (peak age, 55–65 years)
• Recurrence: rapid growth; size may double every 10 days
• Median survival: ~ 1 year
GBM Clinical Prognostic Factors: Age, Performance S tatus (PS), Resection(RTOG recursive partitioning analysis (RPA) class)
RPA Clinical Median OSClass Feature (months)3 age < 50; PS = 0 174 age < 50; PS = 1-2 15
age > 50; GTR/STR5 age > 50; biopsy 10
Mirimanoff, R.-O. et al. J Clin Oncol; 24:2563-2569 2006
Anaplastic Astrocytoma:Overall Characteristics
• Grade III malignant glioma
• Less aggressive than GBM, malignant with somewhat better prognosis
• Frequency: highest in young adults (30–40 years)
• Recurrence: often as a higher-grade glioma
• Challenge: difficult to remove completely with surgery
• Median survival: 3–4 years
Glioblastoma (GBM)
Courtesy of M. Prados, MD
• Invasive
• Hypoxic
• Phenotypically heterogeneous
• Resistant to therapy
Therapy of Glioblastoma: Surgery
• Major resection increases duration and quality of survival compared to biopsy or minimal resection
• Not a curative intervention
Extent of Tumor Resection is Associated with Improved Outcomes
Study Conclusion
Stummer W, et al.Lancet Oncol. 2006;7:392-401
Complete resection (using fluorescence-guided surgery) results in longer progression-free surviva l rates
Laws ER, et al. J Neurosurg. 2003;99:467-473
Resection (vs. biopsy) is a strong prognostic facto r for survival in the Glioma Outcomes Project
Lacroix M, et al. J Neurosurg. 2001;95:190-198
Significant survival advantage associated with resection of ≥ 98% mean tumor volume
Keles GE, et al. Surg Neurol. 1999;52:371-379
Extent of tumor removal and residual tumor volume are significant factors in predicting time to tumor progression and mean survival
Current Treatment: Surgery
3
Surgical Management
Therapeutic Impact of Radical Surgery in Glioblastoma
>98% >98%
All patients (n=416)
No prior treatment(n=233)
P<0.0001 P=0.02
Lacroix M, et al. J Neurosurg. 2001;95:190-198.
< 98%< 98%
0
2
4
6
8
10
12
14
<98% <98%
Med
ian
surv
ival
, m
os
Therapy of Glioblastoma: Radiotherapy
• Addition of radiotherapy to surgery increases duration and quality of survival
Treatment of Glioblastoma: Radiotherapy
Study
Shapiro 1976
*Anderson 1978
*Walker 1978
*Walker 1980
*Kristiansen 1981
*Sandberg-Wolheim 1991
Surgery Alone
15
14
23
Chemo
30
31
42
RT
23
36
37
47
RT + Chemo
44.5
62
*statistically significant
Median Survival (weeks)
Therapy of Glioblastoma: Chemotherapy
• Addition of nitrosoureas to surgery and radiotherapy produces a small increase in duration of survival
• Addition of Temozolomide to surgery and radiotherapy produces a small increase in 2 year progression free survival and overall survival
Current Treatment: Chemotherapy
Fine et al. 1 Stewart 2 Spiegel et al. 3
Date of meta-analysis 1993 2002 2007
Trials analyzed, n 16 12 16
Patients analyzed, n >3,000 3,004 >3,000
Agent(s) used Various Various Various
Absolute increase in survival, %
1 year 10.1 6.0 15.0*
2 year 8.6 4.0 17.0*
1. Fine HA, et al. Cancer. 1993;71:2585-2597.2. Stewart LA. Lancet. 2002;359:1011-1018.3. Spiegel BM, et al. CNS Drugs. 2007;21:775-787.
Three Major Meta-analyses
* TMZ treatment group only.
ChemotherapyMeta-analysis of Chemotherapy
in High-Grade Glioma
05
101520253035404550
1-year survival 2-year survival
% o
f pat
ient
s
No chemotherapyChemotherapy
Stewart LA. Lancet. 2002;359:1011–1018.
4
TMZ spontaneously converts to MTIC at physiologic pH
Denny BJ et al. Biochemistry. 1994;33:9045-9051.
Temozolomide (TMZ): Second-generation Alkylating Agent
MTIC, 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide.
C
N
NN
O
NN
NH2
OCH3
pH > 7.0Spontaneous
hydrolysis NN
O
NN
CNH2
NH
CH3
O
NN
CNH2
NH2
Temozolomide MTIC AIC Methyldiazoniumion
+ N N–CH3
TemozolomideUSA Clinical Trials
Phase 1 Adult (Mayo clinic)
Phase 1 Children (CCG)
Phase 2 1st relapse GBM (national)
Phase 2 1st relapse AA (national)
Phase 2 Newly diagnosed malignant glioma (Duke)
Yung WKA et al. Br J Cancer. 2000;83:588-593.
Temozolomide in Glioblastoma at First Relapse: Study Schematic
• Histologically confirmed glioblastoma
• Failed radiotherapy ± chemotherapy with nitrosourea
• KPS ≥ ≥ ≥ ≥ 70
• No stereotactic or interstitial radiotherapy
TemozolomideTemozolomide(n = 112)(n = 112)
200 mg/m200 mg/m 2 2 qd x 5 dqd x 5 doror
150 mg/m150 mg/m 22 qd x 5 dqd x 5 d
ProcarbazineProcarbazine(n = 113) (n = 113)
150 mg/m150 mg/m 2 2 qd x 5 dqd x 5 doror
125 mg/m125 mg/m 2 2 qd x 5 dqd x 5 d
6-moPFS
KPS, Karnofsky performance status;PFS, progression-free survival.
Ran
dom
izat
ion
Temozolomide (TMZ) in Glioblastoma at First Relapse:
Progression-free Survival (PFS) Rates
* p = 0.008.† Hazard ratio = 1.47.‡ p = 0.00063.
TMZ PCB
PFS at6 mo, % 21 8*
Median PFS, wks (mo) † 12.4 (2.89) 8.32 (1.88)‡
Yung WKA et al. Br J Cancer. 2000;83:588-593.
PF
S ra
te
0.0
0.2
0.4
0.6
0.8
1.0
TMZ
PCB
Time from start of treatment (months)
0 3 6 9 12 15 18
PCB, procarbazine.
Yung WKA et al. J Clin Oncol. 1999;17:2762-2771.
Temozolomide in Anaplastic Astrocytoma at First Relapse: Study Schematic
• Histologically confirmed anaplastic astrocytoma
• Failed radiotherapy ±chemotherapy with nitrosourea
• KPS ≥ ≥ ≥ ≥ 70
• No previous stereotactic or interstitial radiotherapy
No prior No prior chemotherapy chemotherapy
200 mg/m200 mg/m 2 2 qd x 5 dqd x 5 d
Prior Prior chemotherapy chemotherapy
150 mg/m150 mg/m 2 2 qd x 5 dqd x 5 d
6-moPFS
KPS, Karnofsky performance status;PFS, progression-free survival.
Temozolomide in Malignant Glioma* at First Relapse: Survival Rates
Yung WKA et al. J Clin Oncol. 1999;17:2762-2771.
* Intent-to-treat population, includes anaplastic astrocytoma and anaplastic oligoastrocytoma.
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24
Sur
viva
l rat
es
Time (months) from start of treatment
Overall survival
Progression-free survival
6-mo PFS = 46%
Median = 13.6 months
5
TemozolomideDuke Phase 2
Eligibility
• Newly diagnosed GBM, GS, AA
• Surgery or biopsy
• Measurable enhancing lesion > 1.5 cm2 within 3 days or > 14 days from surgery
TemozolomideDuke Phase 2
Treatment plan
• 200 mg/m 2 po x 5 days every 4 weeks
• 4 cycles given prior to RT
• PE/MRI every 4 weeks
• Radiographic response criteria
TemozolomideDuke Phase 2
GBM response
• 33 patients with GBM
– 3 complete responses
– 14 partial responses
– 5 stable disease
– 11 progressive disease
Friedman, HS, et al. J Clin Oncol. 1998;16:3851-3857
Treatment scheme. TMZ, temozolomide; RT, radiothera py.
Kaplan-Meier estimates of median survival of all pa tients (intent-to-treat).
R. Stupp NEJM 2005
RT RT + Temo2 year survival (%) 10.4 26.5
2 year PFS (%) 1.5 10.7
Median survival (M) 12.1 14.6
6
Stupp R et al. NEJM 352:987,2005Temozolomide 75 mg/m2 po qd for 6 weeks,
then 150–200 mg/m2 po qd d1–5 every 28 days for 6 cycles
Focal RT daily — 30 x 200 cGy
Total dose 60 Gy
Adjuvant TMZ
6 10 14 18 22 26 30
RT AloneWeeksR
AN
DO
MIZ
E
RT/TMZ
0
Survival RT RT + TMZ
2-year 10.9% 27.3%
3-year 4.4% 16.0%
4-year 3.0% 12.1%
5-year 1.9% 9.8%
5 Year Follow-Up
Stupp Lancet Oncol 2009
PFS
OS
O6-alkylguanine-DNAAlkyltransferase (AGAT) Resistance
to Chemotherapy
Nitrosourea Alkyl group DNA X L
O6-guanine AGAT
Procarbazine Methyl group Mismatch
06-alkylguanine DNA Alkyltransferase (AGT)
N
N
N
N NH2
OCH3
O -methylguanine6
NH
N
N
N NH2
O
Guanine
Alkyltransferase
Irreversible inactivation
NH2
NH
CH2 CH
CO
COOH
CH3 S
NH2
NH
CH2 CH
CO
COOH
SH
• Ubiquitous DNA repair protein
• Removes theCH3 groupsfrom the O6-methylguanine
• Irreversiblyinactivated
• De novosynthesis required for recovery
AGT and Response to Temozolomide
% AGT + cells< 20% ≥≥≥≥ 20%
Responder 15 1
Non-Responder 10 10
AGT/MGMT Gene
Coding SequencePromoter
No Expression X AGT
Yes Expression AGT
+ Methylation
- Methylation
7
5 Year Survival EORTC/NCIC Trial
Group Radiation aloneRadiation +
TemozolomideTotal 1.9% 9.8%
MGMT unmethylated 0 8.3%
MGMT methylated 5.2% 13.8%
• Bevacizumab – what doesn’t it treat?
Anti-Angiogenesis
6/19/1990
Rationale for Bevacizumab in GBMVEGF is highly expressed
in Human GBM
Anti-VEGF inhibits growth of
GBM xenograft
VEGF expression correlateswith tumor grade and outcome
Sur
viva
l (w
eeks
)
r = -0.42
VEGF mRNA signal Nature • Vol 362 • 29 April 1993
Bevacizumab Development Timeline - 1James Vredenburgh
+ Patti Beaver
February 2004
LOI to Genentech – deniedIND to FDA – denied
September 2004Virginia Stark-Vance
shows Henry Friedman MRIs of 8 Bevacizumab + CPT-11 treated patients
(7 responders)
Bevacizumab Development Timeline - 2
Henry Friedman calls Art Levinson
Genentech says Go!
FDA approves IND from James Vredenburgh
James Vredenburgh / Annick Desjardins Trials
BRAIN Trial(Henry Friedman, PI)
FDA Approval in Recurrent GBM
Treatment plan
WeeksRepeat for up to 1 year
IrinotecanEIAED: 340 mg/m²Non-EIAED: 125 mg/m²
1 2 3 4 5 6
Bevacizumab: 10 mg/kg
MRI
Combination bevacizumab/irinotecan
Weeks Repeat for up to 1 year
1 2 3 4 5 6
8
Recurrent AA
(Grade 3)
Near CR after 4 cycles of BV/Irinotecan
A B
C D
Pre-treatment After 4 cycles Is this a “glorified steroid” effect?(If so, would not expect durable anti-tumor control )
Grade 3 Grade 4
OUTCOME Duke(n = 35)
TMZ 1st PD1
(n=162)Duke
(n = 33)TMZ 1st PD2
(n = 112)
CR/PR (%) 61 35 53 5
SD (%) 33 27 41 40
PD (%) 6 38 6 55
PFS (wks) 30 22 23 12
6 mth PFS (%)
OS (weeks)
65
65
46
54
43
42
21
30
1 Yung Journal of Clinical Oncology 17:2762, 1999. En dure2 Yung British Journal of Caner 83:588, 2000.
Vredenburgh J et al. Clin Ca Res 13:1253, 2007Vredenburgh J et al. J Clin Oncol 25:4722 , 2007Desjardins A et al. Clin Cancer Res 14:7068, 2008
Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma
Henry S. Friedman, Michael D. Prados, Patrick Y. We n, Tom Mikkelsen, David Schiff, Lauren E. Abrey, W.K. Alfr ed Yung, Nina Paleologos, Martin K. Nicholas, Randy Jensen, James
Vredenburgh, Jane Huang, Maoxia Zheng, and Timothy Cloughesy
Journal of Clinical Oncology, 27(28):4733-4740, 200 9.
BRAIN(phase II, multicenter, noncomparative trial)
167 patients with glioblastoma in first or second relapse
Prior radiotherapy and temozolomide
Stratification by Karnofsky score (70-80, 90-100)First, second relapse
BEV (n=85)
10 mg/kg q2 weeks
Optional Post-Progression
PhaseBEV + CPT-11
(n=44)
BEV + CPT-11(n-82)
EIAED: 40 mg/m 2 IV/90 minNon-EIAED: 125 mg/m 2 IV/90 min
First progressive disease
• Primary endpoints (by independent radiology review)• OR rate• 6-month PFS
• Additional measurements• Updated safety and survival
BEV=bevacizumab, CPT-11=irinotecan, EIAED=enzyme-indu cing antiepileptic drug, OR=objective response, PFS=progression-free survival.
Summary of Efficacy
Bev Bev (n = 85)(n = 85)
Bev/CPT Bev/CPT (n = 82)(n = 82)
Independent Radiology Review
6 month PFS: %6 month PFS: % 35.6 35.6 51.051.0
ORR: %ORR: % 21.2 21.2 34.1 34.1
Investigator
6 month PFS: %6 month PFS: % 44.7 44.7 60.9 60.9
ORR: %ORR: % 38.8 38.8 46.3 46.3
6-month PFS by External Review
+: censored subjects
9
Overall SurvivalBevacizumab Bevacizumab
(n=85)(n=85)Bevacizumab/CPTBevacizumab/CPT--11 11
(n=82)(n=82)
No. of deaths (%)No. of deaths (%)Median (Median (momo), 95% CI), 95% CI
31 (37)31 (37)8.2 (8.1, 8.2 (8.1, --))
34 (42)34 (42)8.7 (7.8, 8.7 (7.8, --))
Duration of Overall Survival (months)Duration of Overall Survival (months)
Proportion S
urvivingP
roportion Surviving
Summary
• Bevacizumab is active against recurrent glioblastoma
• There were rare CNS hemorrhages and no unique toxicities in GBM patients
• FDA approved bevacizumab for recurrent glioblastoma May 5 th, 2009
Response Rate and PFS6 in Pooled Analyses of Trials for Relapsed Glioblastoma
Publication Sample Size
Response Rate
6-month PFS
Overall Survival
12-month Survival
8 MD Anderson trials 1986-1995
(Wong 1999)
225 6% 15% 5.7 mo 21%
16 NCCTG trials 1980-2004
(Ballman 2007)
345 n/a 9% 5.1 mo 14%
12 NABTC trials 1998-2002
(Lamborn 2008)
437 7% 16% 6.9 mo 25%
Lomustine control arm from Phase III study of enzastaurin
(Fine et al 2008)
92 4.3% 19% 7.1 mo 24%
AVF3708g 85 28.2% 42.6% 9.3 mo 37.6%
G1
Response Rate and PFS6 Significantly Higher Than Historical Controls
Six-month progression-free survival:Bevacizumab arm vs historical controls
0
10
20
30
40
50
60
Wong et al.
1999(n=225)
Lamborn et al.
2008(n=437)
Fine et al.
2008Lomustine
(n=92)
Patients
with P
FS6, %
0
10
20
30
40
50
60
Patients
with O
RR (
CR +
PR),
%
Wong et al.
1999(n=225)
Lamborn et al.
2008(n=437)
Fine et al.
2008Lomustine
(n=92)
AVF3708gBevacizumab
by IRF(n=85)
AVF3708gBevacizumab
by INV(n=85)
AVF3708gBevacizumab
by IRF(n=85)
AVF3708gBevacizumab
by INV(n=85)
Response rate:Bevacizumab arm vs historical controls
G2
The Addition of Bevacizumab to Standard Radiation Therapy and Temozolomide Followed by Bevacizumab, Temozolomide and Irinotecan for Newly Diagnosed GlioblastomaJames J. Vredenburgh, Annick Desjardins, David A. Reardon, Katherine B. Peters, James E. Herndon, II, Jennifer Marcello, John P. Kirkpatrick, John H. Sampson, Lei ghann Bailey, Stevie Threatt, Allan H. Friedman, Darell D . Bigner, and Henry S. Friedman
Clinical Cancer Research 17(12): 4119-4124, 2011.
Treatment PlanPart A
Weeks1 2 3 4 5 6
Bevacizumab10 mg/kg
Temozolomide75 mg/m2/day
Radiation therapy
Slide 51
G1 <slide>GBM-006<slide><title>Response Rate and PFS6 in Pooled Analyses of Trials for Relapsed Glioblastoma<title><rank>1<rank><keywords><keywords><QCname><QCname><QCdate><QCdate><QCcomment><QCcomment>GenenUser, 3/16/2009
Slide 52
G2 <slide>CC-006<slide><title>Response Rate and PFS6 Significantly Higher than Historical Controls<title><rank>1<rank><keywords> Historical Control<keywords><QCname><QCname><QCdate><QCdate><QCcomment><QCcomment>GenenUser, 3/25/2009
10
Treatment PlanPart B
IrinotecanEIAED: 340 mg/m²Non-EIAED: 125 mg/m²
Bevacizumab: 10 mg/kg
Bevacizumab / Irinotecan
Temozolomide200 mg/m 2/day
Weeks
1
MRI
8763 542
Study Dates
• Study Opened: 8/15/07
• Accrual: 125 patients through 3/26/09
• Median Follow-Up: 48.6 mos
Progression free survival
Total # PDMedian PFS
(95% CI)
6-month PFS
(95% CI)
1-year PFS
(95% CI)
2-year PFS
(95% CI)
3-year PFS
(95% CI)
125 119 14.0 months
(12.5 mo, 15.9
mo)
87.2%
(80.0%, 92.0%)
63.2%
(54.1%, 71.0%)
17.6%
(11.5%, 24.7%)
7.2%
(3.5%, 12.6%)
Overall Survival
Total # DiedMedian survival
(95% CI)
6-month OS
(95% CI)
1-year OS
(95% CI)
2-year OS
(95% CI)
3-year OS
(95% CI)
125 111 20.9 months
(18.0 mo, 24.1 mo)
92.8%
(86.6%, 96.2%)
81.6%
(73.6%, 87.4%)
42.4%
(33.7%, 50.9%)
20.0%
(13.5%, 27.4%)
Conclusions
• The addition of bevacizumab to daily temozolomide and radiation therapy is safe
• The addition of irinotecan and bevacizumab to standard 5-day temozolomide is tolerable
• Bevacizumab/temozolomide and radiation followed by bevacizumab/temozolomide and irinotecan appear to improve the progression-free survival compared to historical controls
• Phase III trials are necessary
(n=460)
(n=460)
Treatment starts28-49 days
post surgeryConcurrent phase Maintenance phase
for 6 cyclesMonotherapy phase
until PD
Debulking surgery or
biopsy
Placebo15 mg/kg q3wmonotherapy until disease progression
TMZ 150-200 mg/m²/qd
days 1-5 q28dBEV 10 mg/kg q2w
Bevacizumab15 mg/kg q3wmonotherapy until disease progression
4-weektreatment
break
AVAglio* Phase III BEV + TMZ and Radiotherapy in Newly Diagnosed GBM: Study Design
RT 2 Gy 5 days/week for6 weeks
TMZ 75 mg/m²/qdBEV 10 mg/kg q2w
RT 2 Gy 5 days/week for6 weeks
TMZ 75 mg/m²/qdPlacebo 10 mg/kg q2w
TMZ 150-200 mg/m²/qd
days 1-5 q28dPlacebo
10 mg/kg q2w
*Genentech/Roche Sponsored StudyChinot, et al. Adv Ther 2011;28:334-340.
BEV=bevacizumab; GBM=glioblastoma; PD=progressive d isease; RPA=recursive partitioning analysis; RT=rad iotherapy; TMZ=temozolomide
Randomization with stratification
4-7 weeks post surgery
Based on RPA class and country
11
RTOG 0825* Phase III Concurrent Chemoradiation and Adjuvant TMZ + BEV vs Conventional Concurrent Chemoradiation and
Adjuvant TMZ in Newly Diagnosed GBM: Study Design
3 weeks of chemoradiation
therapy
TMZ days 1-5 q28d
Placebo q2w
12-cycle maximum
TMZ days 1-5 q28d
BEV q2w
12-cycle maximum
4-weektreatment
break
3 weeksRT 30 Gy in 2 fractionDaily TMZ qd ×××× 21d
Placebo q2w(continues without stop)
3 weeksRT 30 Gy in 2 fractionDaily TMZ qd ×××× 21dBEV q2w (continues
without stop)
Randomization ( ≤10 days after start of
RT)Stratification by
MGMT methylation status and
molecular profile
*Independently Sponsored Study that is supported by Genentech/Roche with study drug and, in some instan ces, funds
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0825
as of 12/11.
BEV=bevacizumab; GBM=glioblastoma; RT=radiotherapy; RTOG=Radiation Therapy Oncology Group; TMZ=temozol omide
AVAglio Results
Standard of Care Arm
ExperimentalArm
PFS (mo) 6.2 10.6
OS (mo) 16.1 16.8
KPS > 70 (mo) 6 9
QoL stable or better (mo) 4 8
Grade 5 tox (%) 2.7 4.5
ICH (%) 2.2 2.6
Pseudoprogression (%) 9.3 2
RTOG 0825 Results
Standard of Care Arm
ExperimentalArm
PFS (mo) 7.3 10.7
OS (mo) 16.1 15.7
Bevacizumab treated patients had poor information processing, global cognitive function and executive function
Bevacizumab Beyond Progression Treatment Plan
Part A
Bevacizumab10 mg/kg
Temozolomide75 mg/m2/day
Radiation therapy
Weeks2 3 4 5 610
Treatment PlanPart B
Bevacizumab
Temozolomide
200 mg/m2/day
Weeks
0
MRI
7652 431
For 12 months
8
Treatment PlanPart C
Until progression
Bevacizumab
Weeks
0
MRI
7652 431 8
12
Treatment PlanPart D
Bevacizumab
Treating physician
best management
Weeks
0
MRI
7652 431
For 12 months
8
• TK gene/herpes virus
• Does anyone have a vector that will work and be safe?
Gene Therapy
• Direct presentation
• Dendritic cell presentation
• Do you use generic or tumor specific antigen?
Vaccines
Extracellular Domain
EGFBindingDomain
1 5 6 273
NH2 COOH
Intracellular DomainDeleted
Segment
TransmembraneSegment
1 5 6 273LEU-GLU-GLU-LYS-LYS-VAL-CYS-...-PRO-ARG-ASN-TYR-VAL-VAL-THR-ASP-HIS
Wild Type Amino Acid Sequence
CTG-GAG-GAA-AAG-AAA-GTT-TGC-...-CCC-CGT-AAT-TAT-GTG-GTG-ACA-GAT-CACWild Type cDNA Sequence
CTG-GAG-GAA-AAG-AAA-GGT-AAT-TAT-GTG-GTG-ACA-GAT-CACVariant III cDNA Sequence
LEU-GLU-GLU-LYS-LYS-GLY-ASN-TYR-VAL-VAL-THR-ASP-HISVariant III Amino Acid Sequence
Epidermal Growth Factor Receptor Mutation (EGFRvIII )
LEU-GLU-GLU-LYS-LYS -GLY-ASN-TYR-VAL-VAL-THR-ASP-HIS- CYS-KLH PEPvIII-KLH(CDX-110)
ACTIVATE / ACT II Trial
Immunologic MonitoringLeukapheresis
PEPvIII-KLH + GM-CSFwith temozolomide(Every 1 month i.d.)
6000 cGy
with Temozolomide
PEPvIII-KLH + GM-CSF(Every 2 weeks i.d.)
Temozolomide:
- 200 mg/m 2 5/28 days
- 100 mg/m 2 21/28 days
<R710-A>: CD107a AX6 80<R710-A>: CD107a AX6 80<R710-A>: CD107a AX6 80<R710-A>: CD107a AX6 80
1.141.141.141.14
IL-2
TNF-αααα
IFN-γγγγ
0.310.310.310.31
4.194.194.194.19
ACT II A
ACT II B
Table IV. Data for RPA IV, Corrected for time to Ra ndomization
Median OS, wks
Actuarial2-year OS
Vaccine Patients 113 60%
Patients treated with XRT/Temozolomide
63 0%
Patients treated with Older Regimens 54 11%
EGFRvIII vaccine Median OS
ACT III (n = 65) 24.6 months
ACT II (n = 22) 24.4 months
ACTIVATE (n = 18) 24.6 months
Matched control 15.2 months
13
Pre-Vaccine Primary Tumor Post Vaccine Recurrent Tumor
wtEGFR wtEGFR
EGFRvIII EGFRvIII
EGFRvIII-expressing Cells Eliminated by Vaccine
Detection of Cytomegalovirus Antigens in Malignant Astrocytomas by Immunohistochemistry
E
HCMV pp65
F
HCMV pp65
I
HCMV pp65
HCMV IE1
C D
HCMV IE1
H
HCMV IE1
B
Smooth Muscle Actin
A
Negative control
G
Smooth Muscle Actin
Malignant Glioma SamplesLung from CMV-infected AIDS
Patient
Summary
• EGFRvIII is a unique tumor- specific antigen
• Vaccines with PEPvIII-KLH (CDX-110) are immunogenic
• EGFRvIII+ tumor cells are less frequent by IHC afte r vaccine in most patients.
• Temozolomide enhances immunogenicity
• Repetitive, multi-center studies in selected patien t populations show prolong TTP and overall survival
• Vaccination against CMV antigens may also prove to be a successful vaccine approach
Celldex Phase 3Rindopepimut
Surgery RT + Temo
Temo + Vaccine
Temo + placebo
• Route of administration?
• Armed or unarmed?
Monoclonal Antibody Targeted Therapy
Importance of Peritumoral Targeting
14
Radioimmunotherapy (RIT): 131I-81C6 via Surgically Created Resection Cavity (SCR C)
131I-81C6Activity Distribution
81C6murine monoclonal antibody (Mab) to tenascin-C
Tenascin C- Abundant target in malignant glioma
- Not expressed on normal brain
Neuradiab Completed Trials
Consistent clinical benefit, progressive improvements
Trial Dosing Indication n =Survival (weeks)
Control (weeks)
Phase I Fixed Recurrent GBM 28 52 23
Phase I Fixed Recurrent GBM 14 52 23
Phase II Fixed Recurrent GBM 39 68 23
Phase I Fixed Newly Diag GBM 32 80 53
Phase II Fixed Newly Diag GBM 27 79 53
Phase II Fixed Newly Diag GBM 33 84 53
Phase II Pt Spec Newly Diag GBM 20 91-102* 64
193 patients
*Subsequent analysis after 231 weeks using time of surgery as t=0
of 10 trials published7
(S+XRT)
(+Tem)
MR1-1
Ia II Ib III
Pseudomonas exotoxin (PE)
Amino Acid
Function
1-252
Receptor binding
253-364
Cytosoltranslocation
365-399
Unknown
400-635
Inhibits proteinsynthesis
MR1-1 Ia II Ib IIIEGFRvIII
MR1-1 Patient 7
a) Baseline T1-weighted MRI b) 72-hour T1-weighted MRI c) Gd-DTPA Concentration
(0.05 – 0.5 μMol/mL)
d) I-124 HSA Concentration
(0.1 – 1.0 μCi/mL)
GlioblastomaImaging of Immunotoxin
Delivery to Tumor
15
D2C7 (scdsFv)-PE38KDEL
VH
VL
NH2
COOH
S
S
II III
280
KDEL
Peptide Linker
Green Pseudomonas Bacterial Toxin (Bomb)
EGFRwt/ EGFRvIII
Red Guidance Molecule Oncolytic Viruses
• Poliovirus
ResultsPatient Characteristics
Nbre of patients n = 14
Age, years
Median 59
Range 21-70
Sex
Male (%) 9 (64)
Female (%) 5 (36)
Karnofsky performance status
90 (%) 9 (64)
80 (%) 4 (29)
70 (%) 1 (7)
Type of surgery at diagnosis
Gross total resection (%) 12 (86)
Partial resection (%) 2 (14)
Biopsy (%) 0
Prior treatment
Radiation therapy (%) 14 (100)
Temozolomide (%) 14 (100)
median nbre of cycles (range) 9 (1-14)
Bevacizumab (%) 7 (50)
median nbre of cycles (range) 13 (2-25)
Gliadel wafers (%) 1 (8)
Results
Table 2. Dose escalation and current survival status
Dose level N=14 Survival post PVSRIPO infusion (months) DLT
1.0 x 10E8 TCID50 1 27+ 0
3.3 x 10E8 TCID50 6 26+, 7, 3.5+, 3.3+, 2.5+, 1.9+ 0
1.0 x 10E9 TCID50 1 6 0
3.3 x 10E9 TCID50 2 6, 11+ 0
1.0 x 10E10 TCID50 4 20, 12, 15, 14+ 1
Total # FailedMedian survival in
months (95% CI)
6-month survival (95%
CI)
12-month survival
(95% CI)
18-month survival (95%
CI)
14 5 15.2 (5.6, ∞) 80% (40.9%, 94.6%) 70% (32.9%, 89.2%) 43.8% (11.9%, 72.6%)
16
Dose level Patient Bevacizumabstatus
Survival since PVSRIPO infusion (months)
Status
1 1 Failure 27+ Alive with no deficit, no progression
2 2 Naïve 26+ Alive with no deficit, no progression
3 3 Failure 6 Died 6 months post infusion
4 4 Failure 6 Died 6 months post infusion
5 5 Naïve 20 Died 20 months post infusion
5 6 Naïve 12 Died 12 months post infusion
5 7 Naive 15 Died 15 months post infusion
5 8 Prior exposure, no failure
14+ Intracranial hemorrhage at catheter removal, walking and back to work, improving
4 9 Failure 11+ Alive, gait difficulties
2 10 Naive 7 Died 7 months post infusion
2 11 Failure 3+ Alive, speech difficulties
2 12 Naive 3+ Alive, stable deficits
2 13 Failure 2+ Alive, right hemiparesis
2 14 Naive 2+ Alive, stable deficits
2 Single ptprotocol
Naive 6+ Alive, speech difficulties
Survival as of 8/27/14
Patient 2 – 26 + months
Baseline 6/13/12 10/25/12 3/29/13 07/21/14
• Iressa
• Tarceva
• Gleevec
• Rapamycin
• Others
Molecular Pathway Inhibitors
COMPREHENSIVE GENOMIC ANALYSIS OF GLIOBLASTOMA
Chin, L., Meyerson, M. and the TCGA (The Cancer Genome Atlas)Investigators: Comprehensive genomic characterization d efines novelcancer genes and core pathways in human gliomas. Nature 455: 1061-1068, 2008.
Parsons, D.W., Jones, S., Zhang, X., Lin, J.C.-H., Leary, R. J., Angenendt,P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G., Olivi, A. , McLendon, R.,Rasheed, B.A., Keir, S., Nikolskaya, T., Nikolsky, Y., Busa m, D.A.,Tekleab, H., Diaz, Jr., L.A., Hartigan, J., Smith, D.R., Str ausberg, R.L.,Marie, S.K.N., Shinjo, S.M.O., Yan, H., Riggins, G.J., Bign er, D.D.,Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein , B.,Velculescu, V.E., and Kinzler, K.W.: An integrated genomic analysis ofhuman glioblastoma multiforme. Science 32:1807-1812, 200 8.\\\\
MOST FREQUENTLY ALTERED GBM CAN-GENES
Point mutations Amplifications
Gene Number of tumors
Fraction of tumors
Number of tumors
Fraction of tumors
CDKN2A 0/22 0% 0/22 0%
TP53 37/105 35% 0/22 0%
EGFR 15/105 14% 5/22 23%
PTEN 27/105 26% 0/22 0%
NF1 16/105 15% 0/22 0%
CDK4 0/22 0% 3/22 14%
RB1 8/105 8% 0/22 0%
IDH1 12/105 11% 0/22 0%
PIK3CA 10/105 10% 0/22 0%
PIK3R1 8/105 8% 0/22 0%
MOST FREQUENTLY ALTERED GBM CAN-GENES
Homozygous deletions
Gene Number of tumors
Fraction of tumors
Fraction of tumors with any alteration
CDKN2A 11/22 50% 50%
TP53 1/22 5% 40%
EGFR 0/22 0% 37%
PTEN 1/22 5% 30%
NF1 0/22 0% 15%
CDK4 0/22 0% 14%
RB1 1/22 5% 12%
IDH1 0/22 0% 11%
PIK3CA 0/22 0% 10%
PIK3R1 0/22 0% 8%
17
Cancers Sequenced at Genome-Wide Level
Tumor Type
CCC = clear cell carcinoma; AML = acute myelogenous leukemia.Courtesy of Bert Vogelstein.
Cod
ing
Mut
atio
ns/T
umor
200
20406080
100
0
180160140120
20 - 80
12 Core Cancer Pathways
Courtesy of Bert Vogelstein.
TGFß/SMADSignaling
WNTSignaling
Hedgehog/GLISignaling
DNA DamageSignaling
HIF1ɑSignaling
JAK/STATSignaling
NOTCHSignaling
Conrol of G1/SSignaling
Chromatin Remodeling
Apoptosis
PIK3/PTENSignaling
RAS/RAFSignaling
All Cancers
RTK/RAS/PI-3K Signaling Altered in 88% of GBM Tumors
The Cancer Genome Atlas Research Network. Nature. 2008;455:1061-1068. Permission requested.
NF1 PTENHomozygous
deletion mutation in 36%
Homozygous deletion
mutation in 18%
Mutation,amplification
in 45%
RTK/RAS/PI-3Ksignalingaltered in
88%
EGFR ERBB2 PDGFRA MET
Amplification in 13%
Mutationin 8%
Amplification in 4%
Mutation in 2% Mutation in 15%
Amplification in 2%
Mutation in 1%
Proliferationsurvival
translation
RAS PI3K
AKT
FOXO
P53 Signaling Altered in 87% of GBM Tumors
MDM2
Activated Oncogenes
Homozygous deletion mutation in 49%
TP53
CDKN2A(ARF)
MDM4
Homozygous deletion
mutation in 35%
Apoptosis Senescence
Amplification in 14%
Amplification in 7%
P53signalingaltered in
87%
The Cancer Genome Atlas Research Network. Nature. 2008;455:1061-1068.
RB Signaling Altered in 78% of GBM Tumors
CDKN2A(P16/IIJK4A) CDKN2B CDKN2C
CDK4 CDK6CCND2
RB1
Homozygous deletion in 2%
Homozygous deletion in 47%
Homozygous deletion mutation in 52%
Amplificationin 8%
Amplificationin 2%
Amplificationin 1%
Homozygous deletion mutation in
11%
G1/S progression
RBsignalingaltered in
78%
The Cancer Genome Atlas Research Network. Nature. 2008;455:1061-1068.
Single Agent Targeted Therapy: Unselected Recurrent Malignant Glioma
Modest rate of radiographic response and/or stable disease does not translate into durable anti-tumor activity
Target Agents Anti-Glioma Benefit
EGFR
PDGFR
mTOR
Farnesyl Transferase
Protein Kinase C β
Gefitinib; Erlotinib; Cetuximab
Imatinib
CCI-779; Sirolimus
Tipifarnib
Enzastaurin
Minimal
Minimal
Minimal
Minimal
Minimal
18
Volume 360:765-773 February 19, 2009 Number 8
IDH1 and IDH2 Mutations inGliomas
Hai Yan, M.D., Ph.D. , D. Williams Parsons, M.D., Ph.D., Genglin Jin, Ph.D.,Roger McLendon, M.D. , B. Ahmed Rasheed, Ph.D. , Weishi Yuan, Ph.D., IvanKos, Ph.D., Ines Batinic-Haberle, Ph.D., Siân Jones, Ph.D. , Gregory J.Riggins, M.D., Ph.D., Henry Friedman, M.D. , Allan Friedman, M.D. , DavidReardon, M.D. , James Herndon, Ph.D. , Kenneth W. Kinzler, Ph.D., Victor E.Velculescu, M.D., Ph.D., Bert Vogelstein, M.D., and Darell D. Bigner, M.D.,Ph.D.
Page 104
IDH2
Aconitase
IDH3
α-KG DH
Citrate Citrate
IDH1
Mitochondria
Cytosol
Peroxisome
NADP+
Isocitrate
α-KG
IDH1
NADP+
NAP+
NADH
NADP+
NADPH
Succinate
Cholesterol synthesis
NADPH
Reduced glutathione
NADPH
Glutamate
Aconitase
IsocitrateIsocitrate
α-KG α-KG
Gamma radiation, UVB phototoxicity, singlet oxygen
Gamma and ionizing radiation, high glucose, TNF-α, heat shock Glutamate DH
H+-TH
Glucose-stimulated insulin secretion
Normal Functions of IDH1 and IDH2 in the cell
Some information based on work by JW Park and
colleagues, as well as by C Newgard and colleagues
Page 105
IDH1
Targeted therapy?
Isocitrate – Blue
NADP+ - Red
Arg132 – Yellow
Ser94 – Orange
Asp279 - Cyan
isocitrate α-ketoglutarate
0%
20%
40%
60%
80%
100%IDH2 mutated
IDH1 mutated
0/21
1/7
27/3043/51
3/3
38/52
34/367/7
11/13
6/1230/15 0/55 0/4940/30
Yan et al.
IDH1 and IDH2 are frequently mutated in gliomas
IDH1 R132 mutations in other cancers
• 16/85 acute myeloid leukemias
• 2/30 prostate cancers
• 1/60 B-acute lymphoid leukemia
• 1/12 colorectal cancer
• IDH1 and IDH2 mutations are not present in thousands of other
cancer samples analyzed
Mardis et al., 2009
Kang et al., 2009
Sjoblom et al., 2006
Yan et al., 2009
Bleeker et al., 2009
Park et al., 2009
IDH1 and IDH2 mutations at residues R132 and R172
Yan et al. NEJM 2009
19
Glioma patients with IDH mutations are clinically distinct
from patients without IDH mutations
The median survival
Patients with mutated IDH: 39 months
patients with wildtype IDH1:13.5 months
Survival of Adult Patients with Malignant Gliomas W ith or Without IDH Gene Mutations
the median survival was 65 months for patients with mutated IDH1 or IDH2, as compared to 19 months for patients with wildtype IDH1 and IDH2.
IDH1 mutations produce 2-hydroxyglutarate
Dang et al. Nature 2009
LC-MS Metabolite Profiles R132H vs WT
Isocitrate α-KetoglutarateIDH1
NADP+ NADPH
IDH1 wild type IDH1 mutant
2-hydroxyglutarate
IDH1R132H
NADPH NADP+
Immune Augmentation
• Nivolumab + Ipilimumab
• Grade IV rGBM after RT + TMZ• Karnofsky PS > 70
Checkmate 143: Phase IIb Study of Nivolumab vs Nivolumab + Ipilimumab vs Bevacizumab in rGBM
Sponsor: Bristol-Myers Squibb
Status Open: study start date 01/01/2014.• Primary endpoint: OS (nivolumab vs bevacizumab and nivolumab plus ipilimumab vs bevacizumab)• Secondary endpoints: PFS, ORR, OS (nivolumab plus ipilimumab vs nivolumab)
Cohort 1: Safety Lead-In (N=20)
Nivolumab 1 mg/kg IV + Ipilimumab 3 mg/kg IV q3wNivolumab 3 mg/kg IV q2w
Completion of 4 doses or discontinuation prior to c ompleting 4 doses (all randomized patients)
Safety endpoint: determine safety and tolerability
Nivolumab 3 mg/kg IV q2w until PD or study drug discontinuation (post-
treatment follow-up)
Cohort 2 (N=240)
Randomization 1:1:1
Bevacizumab 10 mg/kg IV q2wNivolumab 3 mg/kg IV q2wNivolumab 1 mg/kg IV + Ipilimumab 3
mg/kg IV q3w (4 doses): Then Nivolumab3 mg/kg IV q2w
1:1
Sampson JH, et al. Presented at ASCP 2014 (abstr TPS2101
PD PDPD
Summary
• Brain Tumors, and Cancer in General are Entering a New Era of Genetic and Molecular Analysis, Followed by Individualized Treatment
• Multiple Molecular “Targets” Will Be Identified and Treated
• Growth Signaling Pathways Will Be Identified and Treated
• Immunotherapy including immune augmentation may be highly effective therapy
20
DUKE STANDARD OF CAREMalignant Glioma
Newly Diagnosed
Best Available Therapy:
Surgery
RT + Temo + Avastin
Avastin + Temo
Clinical Trials:
Upfront ChemoCED – MABChemoVaccineStem Cell
DUKE STANDARD OF CAREMalignant Glioma
Recurrent Disease
Regional Therapy Trials Non- Regional Therapy Trials
Chemo SmallMoleculeInhibitors
Commercially availableagents off-label
VaccinePoliovirus Biologics
• Nihilism - lack of hope
• Reliance on community standard of care
• Lack of active regimens
• Insurance denials - to centers- for clinical trials
Major Impediments to SuccessfulTherapy of Brain Tumors
Political CommentaryPolitical Commentary
21