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