Precision medicine for gliomas

Transcription

1 Precision medicine for YAZMIN ODIA, MD MS LEAD PHYSICIAN OF MEDICAL NEURO-ONCOLOGY DISCLOSURES Novocure: Advisory Board for Optune in No other financial conflicts of interest Glioma OVERVIEW INFILTRATIVE, MALIGNANT, PRIMARY BRAIN TUMOR WHO 2016 GLIOMA CLASSIFICATION Not resectable Not curable CNS-born ATRX loss, p53 mutation Astrocytoma Rarely metastasize IDH-WT Astrocytoma Pre- IDH-WT, Secondary Primary 1

2 11/29/2017 Glioma imaging Glioma imaging MRI FINDINGS WHO Grade II-III Gliomas MRI FINDINGS WHO Grade IV s Glioma PROGNOSIS Glioma prognosis PROGNOSIS by Age and Grade Prognosis better for Oligodendro Explained by 1p/19q co-deletion Reifenberger J, AJP 1994 II III IV RTOG Boots-Sprenger SHE, Modern Pathology,

3 Mutations in Isocitrate Dehydrogenases linked to Gliomagenesis Prognosis predicted by mutations in IDH1 (and IDH2) WHO 2016 GLIOMA CLASSIFICATION ATRX loss, p53 mutation Astrocytoma IDH-WT Astrocytoma Pre- IDH-WT, Secondary Primary Boots-Sprenger SHE, Modern Pathology, 2013 WHO 2016 GLIOMA CLASSIFICATION WHO 2016 GLIOMA CLASSIFICATION Molecular Profile ATRX loss, p53 mutation Astrocytoma ATRX loss, p53 mutation Astrocytoma IDH-WT Astrocytoma Pre- IDH-WT, Secondary IDH-WT Astrocytoma Pre- IDH-WT, Secondary BRAF mutation/fusion PA and PXA Histone 3 (K27M) mutant diffuse midline Primary WHO Grade BRAF mutation/fusion PA and PXA Histone 3 (K27M) mutant diffuse midline Primary Worse Prognosis 3

4 TREATMENT: IDH-WT WHO Grade III-IV Astrocytomas + radiation + concurrent/adjuvant temozolomide TREATMENT: s + radiation + concurrent/adjuvant temozolomide IDH-WT Astrocytoma Pre- IDH-WT, Secondary Primary Stupp R, NEJM 2005 TREATMENT: s MGMT promoter methylation status predicts response TREATMENT: s MGMT promoter methylation status predicts response O6-methylguanine methyltransferase (MGMT) DNA repair gene MGMT promoter hypermethylation leads to gene silencing Predicts response to alkylating chemotherapy, like temozolomide and nitrosoureas Predicts response to oxidizing radiation Hegi ME, NEJM

5 TREATMENT: s (TTF) at recurrence (2010) and upfront (2016) TREATMENT: s + radiation + concurrent/adjuvant temozolomide + TTF Median OS increased by 3-5 months 2-Year Survival rates increased by ~15% Low Compliance Stupp R, JAMA 2016 TREATMENT: s + radiation + concurrent/adjuvant temozolomide + TTF Survival Benefit extends to 4 and 5-year TREATMENT: s + radiation + concurrent/adjuvant temozolomide + TTF MEDIAN OVERALL SURVIVAL 2-YEAR SURVIVAL 6 mos <5% 12 mos 10-12% + Temozolomide mos 21-29% Stupp R, JAMA TMZ + TTF mos 43% Stupp R, NEJM 2005 and JAMA

6 TREATMENT: Extrapolated to WHO II-III, IDH-WT Astrocytomas + radiation + concurrent/adjuvant temozolomide + TTF(?) IDH-WT Astrocytoma Pre- IDH-WT, Secondary Primary TREATMENT: Extrapolated to WHO II-III, IDH-WT Astrocytomas TTF trials pending for WHO III Patient compliance and physician acceptance remain low Unclear benefit in WHO II Unclear benefit in elderly and/or poor functional status Hypofractionated (shortened) radiation course Temozolomide alone for MGMT hypermethylated tumors TREATMENT: Implications of Molecular Profile TREATMENT: IDH-mutant Gliomas ATRX loss, p53 mutation Astrocytoma ATRX loss, p53 mutation Astrocytoma IDH-WT Astrocytoma Pre- Primary 6

7 TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro ATRX loss, p53 mutation Astrocytoma Pre- Primary TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro + + Procarbazine, CCNU, Vincristine (PCV) TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro 1p/19q Intact Astrocytomas 1p/19q Intact Astrocytomas 1p/19q Co-deleted Oligodendro van den Bent MJ, JCO 2013 EORTC p/19q Co-deleted Oligodendro Cairncross G, JCO 2013 RTOG

8 TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro Procarbazine, CCNU, Vincristine (PCV) WHO grade III + PCV + radiation WHO grade II Observe: LOW RISK (<40 years, unilateral, & gross total resection) PCV + radiation: HIGH RISK (>40 years, bilateral, or subtotal resection) TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro PCV superior to temozolomide, but more toxic TOXICITY vs. CONTROL PCV TEMOZOLOMIDE Toxicity 10-40% <10% Noncompliance/Refusal 5-10% <5% Response Rate % 35-80% Median Time to Progression 7.2 years 3.2 years Median Overall Survival 10.5 years 7.6 years Lassman AB, CNS Onc 2015 TREATMENT: IDH-mutant, 1p/19q co-deleted Oligodendro Balancing Treatment Toxicity vs. Disease Control PCV vs. TMZ? upfront or deferred to recurrence? -induced cognitive deficits TREATMENT: IDH-mutant Astrocytomas ATRX loss, p53 mutation Astrocytoma Pre- 8

9 TREATMENT: IDH-mutant Astrocytomas + radiation + concurrent/adjuvant temozolomide? + PCV + radiation? TREATMENT: IDH-mutant Astrocytomas + radiation + concurrent/adjuvant temozolomide? + PCV + radiation? Additive benefit of molecular profiles PCV + RT RT only 1p/19q co-deletion > IDH1 mutations > MGMT hypermethylation Toxicity vs. Control Timing Cairncross JCO 2014 RTOG9402 alone for WHO grade II? TREATMENT: Multimodal Approach TREATMENT: Multimodal Approach 9

10 TREATMENT: Multimodal Approach TREATMENT: Bevacizumab (VGEF) inhibits angiogenesis Genomics & Molecular Profiling Initial promising results: Progression-free but not overall survival benefit Dramatic MRI response due to steroid-like effect Increasing concern for more invasive phenotype after exposure Palliative benefit only TREATMENT: EGFR amplification and/or EGFRvIII mutation TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance 10

11 TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance pulse dosing? TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance pulse dosing? Rindopepimut vaccine targeted EGFRvIII TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance pulse dosing? Rindopepimut vaccine targeted EGFRvIII negative! TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance pulse dosing? Rindopepimut vaccine targeted EGFRvIII negative! ABT414 antibody drug conjugate (ADC) Anti-EGFR antibody + cytotoxic Monomethyl Auristatin F or MMAF 11

12 TREATMENT: EGFR amplification and/or EGFRvIII mutation EGFR inhibitors poor CNS penetrance pulse dosing? Anti-EGFR antibody + cytotoxic Monomethyl Auristatin F or MMAF Promising early response, now in Phase III trial TREATMENT: for rare glioma subtypes BRAF-V600E and possibly BRAF fusion alterations in PXA or PA Rindopepimut vaccine targeted EGFRvIII negative! ABT414 antibody drug conjugate (ADC) Regimen based on BRAF-V600E mutant melanoma BRAF inhibitor with/without concurrent MEK inhibitors Initial promising results, ongoing trials H3-K27M Diffuse Midline Glioma Limited options, prognosis remains poor Ongoing trials targeting mutation and downstream effects TREATMENT: TREATMENT 12

13 TREATMENT: Vaccines CTLA-4 and OX40 Inhibitors Checkpoint Inhibitors TREATMENT: Vaccines Negative or In Development Rindopepimut; Polio, Heat Shock (HSPPC-96), Toca TREATMENT: Vaccines Negative or In Development TREATMENT: Vaccines Negative or In Development 511/FC CTLA-4 Inhibitors Checkpoint Inhibitors CTLA-4 Inhibitors in development Ipilimumab combination therapy, reduced dose Checkpoint Inhibitors CTLA-4 Inhibitors Checkpoint Inhibitors Nivolumab and Pembrolizumab in trials for 13

14 TREATMENT: Vaccines Negative or In Development TREATMENT: Multimodal CTLA-4 Inhibitors Checkpoint Inhibitors Multimodal Response linked to high mutational load TREATMENT: Evolving Gliomas - SUMMARY GLIOMAS - SUMMARY TREATMENT: Personalized Guided by Genomic and Molecular Profiles Advanced by Clinical Trials Highly Variable and Unpredictable Course Genomics & Molecular Targets Quality of Life & Patient Preferences 14

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