LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade...
Transcript of LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade...
![Page 1: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/1.jpg)
LOWER GRADE GLIOMA
FUTURE DEVELOPMENTS
Patrick Roth
Department of Neurology & Brain Tumor Center
University Hospital Zurich
![Page 2: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/2.jpg)
Disclosures
Honoraria for lectures / advisory board participation:
Bristol-Myers Squibb, Covagen, Medac, Molecular Partners, MSD, Novartis, Novocure, Virometix
Research support
MSD, Novocure
![Page 3: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/3.jpg)
• Old drugs – new questions
• Wait or treat?
• Temozolomide or PCV?
• New therapeutic targets and drugs
• Mutant IDH
• Further targets
![Page 4: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/4.jpg)
Buckner et al., N Engl J Med 2016
Lower-grade gliomas
Which patients shall we treat immediately?
![Page 5: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/5.jpg)
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
![Page 6: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/6.jpg)
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?
![Page 7: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/7.jpg)
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)
![Page 8: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/8.jpg)
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
![Page 9: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/9.jpg)
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
![Page 10: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/10.jpg)
adapted from Friedrich et al., Curr Opinion Oncol 2018
Vaccination
IDHmut inhibitors
Mutant IDH as a therapeutic target
![Page 11: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/11.jpg)
![Page 12: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/12.jpg)
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
![Page 13: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/13.jpg)
Targeting mutant IDH
AG-881: study design
Mellinghoff et al., ASCO 2019
![Page 14: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/14.jpg)
Targeting mutant IDH
AG-881: responses in glioma patients
Mellinghoff et al., ASCO 2019
![Page 15: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/15.jpg)
Targeting mutant IDH
AG-881: responses in glioma patients
Mellinghoff et al., ASCO 2019
![Page 16: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/16.jpg)
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
![Page 17: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/17.jpg)
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
![Page 18: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/18.jpg)
Platten et al., ASCO 2018
IDH1R132H peptide vaccination
Outcome
![Page 19: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/19.jpg)
Platten et al., ASCO 2018
IDH1R132H peptide vaccination
Immune responses in the peripheral blood
![Page 20: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/20.jpg)
BRAFV600E
A novel therapeutic target in gliomas (?)
Presence of BRAFV600E mutation
• 66% pleomorphic xanthoastrocytoma (PXA)
• 18% ganglioglioma
• 9% pilocytic astrocytoma
• Other gliomas: rare
![Page 21: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/21.jpg)
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
![Page 22: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/22.jpg)
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
![Page 23: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/23.jpg)
Cocco et al. Nat Rev Clin Oncol 2018
NTRK fusionsDistribution and frequency
![Page 24: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/24.jpg)
Larotrectinib in adult patients with brain tumors
![Page 25: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/25.jpg)
Primary brain tumors
Clinicalpathological features
Drilon et al., ASCO 2019
![Page 26: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/26.jpg)
Patients with primary brain tumors
Drilon et al., ASCO 2019
![Page 27: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/27.jpg)
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
![Page 28: LOWER GRADE GLIOMA FUTURE DEVELOPMENTS · 2020. 1. 29. · • Treatment of lower-grade astrocytomas is not curative ... 12 cycles Temozolomide 200 mg/m2 day 1-5/28 days Random IDH](https://reader035.fdocuments.net/reader035/viewer/2022062610/6109e71e05ee483ef21719b9/html5/thumbnails/28.jpg)
• 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