LOWER GRADE GLIOMA
FUTURE DEVELOPMENTS
Patrick Roth
Department of Neurology & Brain Tumor Center
University Hospital Zurich
Disclosures
Honoraria for lectures / advisory board participation:
Bristol-Myers Squibb, Covagen, Medac, Molecular Partners, MSD, Novartis, Novocure, Virometix
Research support
MSD, Novocure
• Old drugs – new questions
• Wait or treat?
• Temozolomide or PCV?
• New therapeutic targets and drugs
• Mutant IDH
• Further targets
Buckner et al., N Engl J Med 2016
Lower-grade gliomas
Which patients shall we treat immediately?
Lower-grade gliomas
Wait or treat immediately?
• The optimal timing of further treatment following surgery remains unclear
• Treatment of lower-grade astrocytomas is not curative
• Adjuvant treatment can impair the patient's quality of life• RT → delayed cognitive dysfunction
• Chemotherapy → fatigue
• Early post-surgical treatment would only be warranted if it improves OS, without
detrimental effect on quality of survival
• Oligo-symptomatic favorable prognosis astrocytoma patients may be candidates
for a ‘watch and wait’ strategy
Stratification: center, age (≤ vs > 40 yrs), size (< 2 vs ≥ 2 cm), tumor grade (II vs III)
Radiotherapy 50.4 Gy (28 x 1.8 Gy)
Then: 12 cycles Temozolomide200 mg/m2 day 1-5/28 days
Random
IDH mutantAbsence of 1p/19q co-deletionNo indication for immediate RT/CTX
No very favorable risk profileWait and See
Further treatment at PD(2nd Surgery, RT/TMZ)
• Primary endpoint: Next Intervention Free Survival
• Secondary endpoints: OS, QoL, Neurocognitive function
• Radiogenomics
• Tissue collection
Lower-grade gliomas
IWOT study: wait or treat?
IDH mutated 1p/19q intact lower grade glioma following resection: Wait Or Treat?
7
Early treatment arm
Active surveillance arm
1st treatmentRT/TMZ
1st treatmentRT/TMZ
2nd treatmentBIC
2nd treatmentBIC
OS
OS
Randomization
Rationale endpoint:
• PFS not possible in view of inherent differences between arms
• Radiological progression likely to be modest
• Decision for 2nd treatment will indicate level of progression
• 2nd treatment is major event in life of patients
• Not 2nd surgery without further RT or chemotherapy
IWOT trialPrimary endpoint: next intervention free survival (NIFS)
Procarbazine Lomustine (CCNU) Vincristine
p.o. p.o. i.v.
Alkylating agent
Breaking of DNA
strands
Alkylating nitrosourea
compound
Breaking of DNA
strands
Vinca alkaloid
Mitotic inhibitor –
inhibiting the assembly
of microtubule
structures
Good penetration trough
blood-brain-barrier
Good penetration trough
blood-brain-barrier
Moderate to low penetration
trough blood-brain-barrier
Dose limiting side
effects:
Hematotoxicity
emetogenic
Dose limiting side
effects:
Hematotoxicity
Dose limiting side effects:
Peripheral neuropathy
1p/19q co-deleted 1p/19q co-deleted
RT plus PCV: standard of care in 1p/19q co-deleted WHO grade III gliomas
Cairncross al., J Clin Oncol 2013
1p/19q co-deleted anaplastic gliomas
PCV or temozolomide?
van den Bent al., J Clin Oncol 2013
Primary Endpoint: Progression-free survival, Arm A vs B Secondary: Time to neurocognitive deterioration
Newly diagnosed anaplastic glioma
and high-risk LGG with
1p/19q codeletion
RT→ PCV
(6 cycles)
TMZ/RT → TMZ (6-12 cycles)
N=180
N=180
RT:
LGG: 5040 cGy
AG: 6120 cGy
CODEL (Alliance N0577; EORTC 26081)
Newly diagnosed co-deleted grade 2 and 3 gliomas
adapted from Friedrich et al., Curr Opinion Oncol 2018
Vaccination
IDHmut inhibitors
Mutant IDH as a therapeutic target
AG-881: oral, reversible, brain-penetrant inhibitors of mutant IDH1/2 enzymes
• IC50 ranges from < 1nM (IDH1-R132H) to 32 nM
• Anti-tumor activity in a orthtopic rodent glioma model
AG-881 was explored in patients with advanced solid tumors including gliomas
Primary endpoint: safety and tolerability, determination of MTD and RP2D
Secondary endpoint: preliminary clinical activity
Targeting mutant IDH
AG-881
Mellinghoff et al., ASCO 2019
Targeting mutant IDH
AG-881: study design
Mellinghoff et al., ASCO 2019
Targeting mutant IDH
AG-881: responses in glioma patients
Mellinghoff et al., ASCO 2019
Targeting mutant IDH
AG-881: responses in glioma patients
Mellinghoff et al., ASCO 2019
Targeting mutant IDH
IDH-1R132H peptide vaccination
• IDH1R132H encodes for a neo-antigen that is exclusively expressed by
glioma cells
• A peptide vaccine derived from this neo-antigen may induce an anti-
tumor immune response
• The IDH1R132H peptide vaccine may be combined with the standard of
care in patients with newly diagnosed IDH1R132H-mutant glioma
NOA-16 study
IDH-1R132H peptide vaccination
• Patient with IDH1R132H-mutant gliomas
• IDH1R132H peptide vaccine administered subcutaneously with
Montanide after completion of RT, TMZ/RT or 3 cycles of TMZ
• Primary endpoint: safety and tolerability
• Secondary endpoint: T cell and antibody responses
Platten et al., ASCO 2018
IDH1R132H peptide vaccination
Outcome
Platten et al., ASCO 2018
IDH1R132H peptide vaccination
Immune responses in the peripheral blood
BRAFV600E
A novel therapeutic target in gliomas (?)
Presence of BRAFV600E mutation
• 66% pleomorphic xanthoastrocytoma (PXA)
• 18% ganglioglioma
• 9% pilocytic astrocytoma
• Other gliomas: rare
24 patients, median age 32 years
◆ 6 glioblastomas (3 SD)
◆ 5 anaplastic astrocytomas (1 PR, 2 SD)
◆ 7 pleomorphic xanthoastrocytomas (1 CR, 2 PR, 3 SD)
◆ 3 anaplastic gangliogliomas (1 PR)
◆ 2 pilocytic astrocytomas (1 PR)
◆ 1 higher grade gliomaKaley et al., J Clin Oncol 2018
BRAF inhibitionVemurafenib for glioma therapy
TRK: tropomyosin receptor kinase or
neurotrophic receptor tyrosine kinase
Gene Protein Ligand
NTRK1 → TrkA nerve growth factor
NTRK2 → TrkB brain-derived neurotrophic factor (BDNF)
NTRK3 → TrkC neurotrophin-3 (NT-3)
NTRK fusions
Fusions of NTRK1/2/3 and various partner genes → chimeric oncoprotein
NTRK fusions result in aberrant TRK signalling via dimerization
→ Activation of down-stream signaling: MAPK, PI3K/AKT pathways
Okamura et al., JCO Precis Oncol 2018
Cocco et al. Nat Rev Clin Oncol 2018
NTRK fusionsDistribution and frequency
Larotrectinib in adult patients with brain tumors
Primary brain tumors
Clinicalpathological features
Drilon et al., ASCO 2019
Patients with primary brain tumors
Drilon et al., ASCO 2019
Larotrectinib & NTRK fusion positive gliomasResponse and treatment duration
Drilon et al., ASCO 2019
=> Larotrectinib may be active in TRK fusion-positive gliomas
=> Larotrectinib is overall well tolerated
• Ongoing clinical trials:
• IWOT: early vs. delayed radiochemotherapy in IDH-mutant, 1p/19q-
intact lower-grade gliomas
• CODEL: RT/PCV vs. RT/Temozolomide in 1p/19q co-deleted gliomas
• Targeting mutant IDH by pharmacological inhibitors and peptide
vaccines is currently explored in clinical trials
• Novel molecular targets include BRAF mutations and NTRK
fusions
Lower-grade gliomasOngoing and future developments
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