Chemotherapy and trials for brain tumours Kate Cuff Medical Oncologist Princess Alexandra Hospital

Distribution of primary CNS Tumors by Histology All others 13.9% Glioblastoma 20.3% Lymphoma 3.1% Nerve sheath 8.0% Astrocytomas 9.8% Craniopharyngioma 0.7% CBTRUS, Central Brain Tumor Registry of the United States; CNS, central nervous system. Pituitary 6.3% Ependymomas 2.3% Oligodendrogliomas 3.7% Embryonal, including medulloblastoma 1.7% Meningioma 30.1% CBTRUS Report, 2004-2005. 2

Prognostic Classification WHO classification system Released in 1993; updated in 2007 Tumors classified by cell origin and level of aggression (grades 1-4)[1,2] Grade Histology Median Survival, Yrs[2] 1 Pilocytic astrocytoma >10 2 Well-differentiated astrocytoma >5 3 Anaplastic astrocytoma 4 Glioblastoma multiforme WHO, World Health Organization. 1. Wen PY, et al. N Engl J Med. 2008;359:492-507. 2. DeAngelis LM. N Engl J Med. 2001;344:114-123. 3

Malignant Gliomas Annual incidence 7 cases / 100,000 people Glioblastoma Most commonly seen 6th-8th decade of life Incidence 1.6 fold higher in males than females No modifiable risk factors

Challenges to treatment Biologically aggressive Drug delivery Blood brain barrier Toxicity to normal brain Infiltration of malignant cells into brain parenchyma

Timing of chemotherapy Adjuvant After surgery or radiation Defined number of cycles Aim prolong time to recurrence Recurrence Number of cycles limited by side effects improve symptoms, quality of life and slow progression

A bit of history.. Surgery and radiation mainstays of treatment (and still are) Chemotherapy options PCV standard of care for many years Procarbazine Carmustine (BCNU) Vincristine Significant side effects Single agent nitrosurea (lomustine/carmustine) equivalent

Mechanism of action of chemotherapy agents

Side effects of alkylating agents Cell counts Low neutrophils Increased risk of infections Low platelets Increased risk of bleeding Nausea and vomiting Second cancers Leukaemia Solid cancers

NEJM 2005

Stupp Treatment Schema Concomitant Adjuvant TMZ TMZ/RT* R 6 10 14 18 22 26 30 Weeks RT Alone Temozolomide 75 mg/m2 po qd for 6 weeks, then 150–200 mg/m2 po qd d1–5 every 28 days for 6 cycles Focal RT daily — 30 x 200 cGy Total dose 60 Gy *PCP prophylaxis was required for patients receiving TMZ during the concomitant phase. 11

Significant improvement in survival RT RT + TMZ Median, mos 12.1 14.6 2 yr, % 10.9 27.2 3 yr, % 4.4 16.0 4 yr, % 3.0 12.1% 5 yr, % 1.9 9.8 Stupp et al. Lancet Oncology 2009

Adverse events during treatment May be related to Steroids Chemotherapy Radiation Brain tumour

Steroid related adverse events Common Muscle weakness Behavioural changes Visual blurring Tremor Insomnia Reflux High blood sugar Uncommon Hallucinations Psychosis Peptic ulcer Diabetes Dependence

Pneumocystis Jerovecii (Carinii) Pneumonia Mahindra AK, et al. J Neurooncol. 2003;63:263-270. 15

Venous Thromboembolic Disease Common Highest incidence among cancers, comparable to pancreatic and gynecologic malignancies Majority occur in postoperative period > 40% occur outside postoperative period 21% rate at 12 mos; 32% at 24 mos Gerber DE, et al. J Clin Oncol. 2005 16

Treatment options at recurrence Surgery Re-resection BCNU (Carmustine) wafer Repeat radiation Chemotherapy Temozolomide rechallenge Nitrosoureas (CCNU, BCNU) Bevacizumab Clinical trial BCNU, bis-chloroethylnitrosourea (carmustine); CCNU, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; OS, overall survival; PFS 6, 6-month progression-free survival. 17

Bevacizumab (Avastin) VEGF inhibitor Targets angiogenesis

Bevacizumab (Avastin) To date mainly investigated in Phase II trials Usually in combination with irinotecan chemotherapy TGA approved for use in relapsed glioma Not approved on PBS Requires co-payment (~$20,000) No trials have demonstrated a survival benefit

Bevacizumab ± Irinotecan in Recurrent GBM Phase II study in 167 patients Bevacizumab (n = 85) Bevacizumab + Irinotecan (n = 82) Response % 28.2 37.8 6-mo PFS % 42.6 50.3 Survival (months) 9.2 8.7 GBM, glioblastoma multiforme; PFS, progression-free survival. Friedman HS, et al. JCO 2009 20

Bevacizumab adverse events Side effects include Hypertension (9%) Delayed wound healing (2%) Bowel perforation (2%) Intracranial haemorrhage (2%) Venous and arterial clots (4%)

Ongoing clinical trials

Phase III Trials of Bevacizumab in newly diagnosed GBM AvaGlio[1] RTOG 0825[2] Newly Diagnosed GBM ≥ 18 years; KPS 70% to 100% Standard RT + concurrent TMZ (Planned N = 942) Newly diagnosed GBM (planned N = 920) Bevacizumab 10 mg/kg q2w + standard RT (60 Gy D1-5) x 6 wks + TMZ 75 mg/m2 PO/day for 6 wks then 150-200 mg/m2 Days 1-5 of each 6 x 4-wk cycle until progression Wk 4 of chemoRT: Bevacizumab q2w, continuing until completion of adjuvant TMZ 4 wks after chemoRT: Adjuvant TMZ 200 mg/m2 Days 1-5 Q28D for up to 12 courses + placebo Placebo q2w + standard RT (60 Gy D1-5) x 6 wks + TMZ 75 mg/m2 PO/day for 6 wks then 150-200 mg/m2 Days 1-5 of each 6 x 4-wk cycle until progression GBM, glioblastoma; Gy, gray; KPS, Karnofsky performance status; PO, orally; RT, radiotherapy; RTOG, Radiation Therapy Oncology Group;TMZ, temozolomide. 4 wks after chemoRT: Adjuvant TMZ 200 mg/m2 D1-5 Q28D for up to 12 courses + placebo 1. ClinicalTrials.gov. NCT00943826. 2. ClinicalTrials.gov. NCT00884741. 23

Randomised Phase II study of carboplatin and bevacizumab in recurrent Glioblastoma (Cabaret) Recurrent glioblastoma post radiation and temozolomide Bevacizumab ± carboplatin Closed to accrual Results awaited

Angiogenesis-Targeting Agents for Glioblastoma Disease Setting Study Phase Integrins Cilengitide nGBM rGBM Phase III Phase I/II Angiopoietin/Tie 2 CVX-060 VEGF VEGF-trap (aflibercept) VEGFR TKIs (cabozantinib, cediranib, axitinib, pazopanib) Bevacizumab + strategies rGBM, nGBM nGBM, rGBM Phase II Phase I Phase I, II, III Endothelial cell proliferation Metronomic temozolomide Phase II, III nGBM, newly diagnosed glioblastoma multiforme; rGBM, recurrent glioblastoma multiforme; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. ClinicalTrials.gov. 25

Genetic Targets in Glioblastoma EGFR, mutated/ amplified in 45% HER2 mutated in 8% PDGFRα, amplified in 13% MET, amplified in 4% SRC SRC SRC SRC RAS, mutated in 2% PI3K, mutated in 15% PTEN, mutated/ deleted in 36% EGFR, epidermal growth factor receptor; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositol-3-kinase. NF1, mutated/ deleted in 18% AKT, amplified in 2% Proliferation, survival, translation FOXO, mutated in 1% Wick W, et al Neuro-Oncol. 2011 26

Current trials available in Brisbane Elderly Glioblastoma Temozolomide and short course radiation vs short course radiation alone in pts > 65yrs Catnon Addition of temozolomide to radiation in Grade III gliomas without 1p/19q deletion EGFR vaccine Stupp protocol ± vaccine in EGFR mutation positive pts

Where to find trials? Talk to your clinician Australian and New Zealand clinical trials registry http://www.anzctr.org.au/ COGNO (Co-operative trials group for neuro-oncology) http://www.cogno.org.au/

Conclusion Current standard of care Recurrence TMZ + RT followed by 6 months of TMZ Recurrence Treatment options unsatisfactory TMZ / nitrosurea / bevacizumab Involvement in clinical trials encouraged Multiple new therapies under development