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Systemic Treatment Containing Temozolomide:
The State of the Art and How to Optimize Results
Andrew S. Chi, MD, PhD
Assistant Professor of Neurology
Temozolomide (TMZ) Optimization Overview
• Temozolomide is an effective drug in glioblastoma (GBM)
• Key for optimization may be in selecting the right patients
• Selection using MGMT methylation
• Efficacy of dose-dense (dose intense) temozolomide
• Combination with anti-angiogenic agents
Perry et al, JCO 2010
Temozolomide in Newly Diagnosed Glioblastoma
Oral alkylating agent
Alkylates (methylates) N-7 or O-6 of guanine
Alkylation results in DNA crosslinking, cell death
Synergistic cytotoxicity with radiation
Guanine
•
IFRT with concurrent temozolomide at 75 mg/m2/day
•
Post-radiation: 150-200 mg/m2 for 5/28 days x 6 cycles
Stupp et al. NEJM (2005)
Temozolomide Improves Survival in Glioblastoma (GBM)
EORTC-NCIC Phase III
Survival:
14.6 vs 12 months
10% alive at 5 years
Stupp et al. Lancet Oncol (2009)
Cycles of Post-Chemoradiation Temozolomide?
Comparison of 4 randomized trials of newly diagnosed GBM
Cycles
of TMZ
Median OS
(months)
6
14.6
RTOG 0525 (control) (2013)
6 - 12 (13%)
16.6
RTOG 0525 (dose dense TMZ) (2013)
6 - 12 (13%)
14.9
RTOG 0825 (control) (2014)
6 - 12 (20%)
16.1
RTOG 0825 (bevacizumab) (2014)
6 - 12 (20%)
15.7
Avaglio (control) (2014)
6
16.7
Avaglio (bevacizumab) (2014)
6
16.8
Trial (year published)
EORTC-NCIC (2005)
MGMT Promoter DNA Methylation
• MGMT: O6-methylguanine–DNA methyltransferase
•
Rapidly reverses alkylation at the O6 position of guanine
•
Causes resistance to DNA alkylating agents
• MGMT promoter DNA methylation
•
Prevents transcription of the MGMT protein
•
Cells cannot repair alkylation of O6-methylguanine
•
MGMT methylation may therefore sensitize tumors to
alkylating therapy
• 30-50% of glioblastomas are MGMT methylated
MGMT Methylation and Chemosensitivity
Esteller et al. N Engl J Med (2000)
MGMT Methylation is Prognostic in GBM
EORTC-NCIC
Median OS
MGMT methylated:
21.7 mos
MGMT un-methylated: 12.7 mos
Hegi et al. N Engl J Med 2005
RTOG 0525 Phase III
(dose dense TMZ)
Median OS
MGMT methylated:
21.2 mos
MGMT un-methylated: 14.0 mos
Gilbert et al. JCO 2013
MGMT methylation may be predictive
EORTC-NCIC
MGMT Methylated
MGMT
Unmethylated
Hegi et al. N Engl J Med (2005)
Temozolomide for MGMT un-methylated GBM?
Median OS
(months)
Trial
EORTC-NCIC RT only (all patients)
12.0
EORTC-NCIC MGMT un-methylated
12.7
RTOG 0525 MGMT un-methylated
14.0
RTOG 0825 (bevacizumab) MGMT un-methylated
14.3
• Should MGMT un-methylated GBM patients receive RT alone?
• Clinical trials in newly diagnosed MGMT un-methylated GBM:
• RT alone vs. RT + trial agent?
MGMT inhibition or depletion
•
MGMT inhibitors may be combined with alkylating agents
•
O6- benzylguanine (O6-BG) is a potent MGMT-inactivating agent
•
O6-BG lowers MGMT levels in normal cells, increasing toxicity
from chemotherapy
•
Phase II trial of O6-BG + BCNU in recurrent malignant glioma
(Quinn et al, JCO 2002)
•
•
66% grade 3/4 thrombocytopenia and neutropenia
•
No responses, a few stable disease in 18 patients
Novel MGMT inhibitors with greater tumor specificity in preclinical
evaluation
Tolcher et al. Br J Cancer 2003
MGMT depletion
MGMT removes methylating/alkylating lesions at the O6 position of
guanine by covalently linking methyl/alkyl groups to an internal
cysteine present within the MGMT protein - “suicide substrate”
Hegi et al. JCO 2008
“Dose-Dense” Temozolomide (ddTMZ)
Prolonged exposure to temozolomide can deplete intracellular MGMT
in peripheral blood mononuclear cells
7 on / 7 off
Tolcher et al. Br J Cancer 2003
21 / 28 days
“Dose-Dense” Temozolomide (ddTMZ)
Protracted, low-dose (dose-dense) schedules of
temozolomide may reduce MGMT levels and exhaust activity
Hegi et al. JCO 2008
Phase II trials of ddTMZ in GBM
Hegi et al. JCO 2008
• Numerous small, single institution uncontrolled studies
• Different tumors in various studies (new GBM, recurrent GBM, grades)
• Apparent responses (up to 25%), suggestion of prolonged PFS
• Some studies found correlation with MGMT status, some did not
ddTMZ in the Maintenance Phase of New GBM
RTOG 0525 Phase III trial
ddTMZ: 21 / 28 days at 100 mg/m2
Gilbert et al, JCO 2013
Maintenance ddTMZ Did Not Improve Survival
RTOG 0525 Phase III trial
ddTMZ vs standard TMZ
Gilbert et al, JCO 2013
MGMT status was irrelevant for maintenace ddTMZ
RTOG 0525 Phase III trial
MGMT methylated patients
MGMT un-methylated patients
Gilbert et al, JCO 2013
ddTMZ in Recurrent GBM - RESCUE Trial
50 mg/m2 daily for 1 year
Large, multicenter, phase II, prospective stratification
•
Group A: Anaplastic glioma with progression after treatment
with TMZ on a 5/28 regimen.
•
Group B1 (early): GBM with progression before completion of 6
cycles of adjuvant TMZ.
•
Group B2 (extended): GBM with progression while receiving
adjuvant TMZ beyond the standard 6 cycles but before
completion of adjuvant treatment.
•
Group B3 (rechallenge): GBM with progression after
completion of adjuvant treatment and a treatment-free interval of
greater than 2 months.
Perry et al, JCO 2010
ddTMZ in Recurrent GBM - RESCUE Trial
50 mg/m2 daily - GBM arms
Perry et al, JCO 2010
ddTMZ in Recurrent GBM - RESCUE Trial
50 mg/m2 daily - GBM arms
Responses
(%)
mPFS
(months)
PFS6
(%)
B1 (Early) n = 33
3
3.6
27.3
B2 (Extended) n = 27
0
1.8
7.4
B3 (Rechallenge) n = 28
11
3.7
35.7
GBM Arm
Overall
23.9
Reasons for differences in efficacy are unknown
Perry et al, JCO 2010
ddTMZ in Recurrent GBM - RESCUE Trial
50 mg/m2 daily - GBM arms
mPFS
(months)
PFS6
(%)
Methylated
3.8
40.0
Unmethylated
2.9
36.4
MGMT status
•
MGMT status determined in archival tissue
•
Significance of MGMT status at recurrence is unknown
•
Unclear why MGMT status did not impact prognosis - MGMT depletion?
Perry et al, JCO 2010
TMZ in combination with antiangiogenic agents?
Vascular Normalization Hypothesis
Antiangiogenic agents can “normalize” the abnormal tumor
vasculature, and may result in more efficient delivery of drugs and
oxygen to the targeted cancer cell
Jain R. Science 2005
Bevacizumab + TMZ in Newly Diagnosed GBM
Two Randomized, double-blind, placebo-controlled Phase III trials
Standard therapy +/- bevacizumab
•
RTOG 0825 (Gilbert et al NEJM 2014)
•
•
Avaglio (Chinot et al NEJM 2014)
•
•
978 patients registered
921 patients assigned
Co-primary endpoints for both trials: OS and PFS
Bevacizumab + TMZ in Newly Diagnosed GBM
•
OS not different in either trial
•
RTOG 0825: 15.7 vs 16.1 months
•
Avaglio: 16.7 vs 16.8 months
•
PFS increased with bevacizumab in both trials*
•
RTOG 0825: 10.7 vs 7.3 months*
*HR (0.79) and P value (.007) did not meet pre-defined criteria (p=.004)
•
Avaglio: 10.6 vs 6.2 months (P=.001)
Bevacizumab + TMZ in Newly Diagnosed GBM
RTOG 0825
PFS
OS
Avaglio
Bevacizumab + TMZ in Recurrent gliomas
•
Controlled data not available
•
EORTC 26091 (TAVAREC) randomized trial for
recurrent grade II/III glioma
•
TMZ (standard dosing) vs. TMZ + Bevacizumab
TMZ Alone is Effective in Elderly MG
2 recent randomized trials comparing RT vs. TMZ in elderly patients
with malignant glioma (MG)
•
Nordic (Malmstrom et al, Lancel Oncol 2012)
•
•
60 Gy vs 34 Gy vs standard TMZ x 6 cycles
NOA-08 (Wick et al, Lancet Oncol 2012)
•
60 Gy vs dose dense TMZ x 6 cycles
•
TMZ was similar to RT in efficacy
•
MGMT methylation appeared to predict TMZ efficacy
TMZ alone in Elderly GBM
Nordic
NOA-08
MGMT Methylated
MGMT Methylated
Malmstrom et al, Lancel Oncol 2012
Conclusions, and where do we go from here?
• Optimal use of TMZ - selection of patients who will benefit
• MGMT methylated patients benefit
• TMZ alone is reasonable for elderly MGMT methylated patients
• RT alone is reasonable in all MGMT un-methylated GBM patients
• ddTMZ does not seem to improve efficacy in newly diagnosed GBM,
regardless of MGMT status
• Rationale exists for combination with anti-angiogenic agents,
however no clear survival benefit in newly diagnosed GBM.
• Recurrent GBM setting:
• ddTMZ may have a role, however larger/controlled trials are needed
• TMZ + antiangiogenic agents remain to be evaluated