1. Optimizing Chemotherapy for Malignant Glioma State of the Art & Future Directions Roger Stupp, MD Multidisciplinary Oncology Center University Hospital (CHUV) Lausanne / Switzerland

2. Meta-analysis: Survival Lancet 359:1011-1018, 2002 12-mo surv: 40%  46% 24-mo surv: 15%  20% median: + 2 mo

4. TMZ & RT: Treatment Scheme TMZ 75mg/m 2 qd x 6-7 wks TMZ 200 mg/m 2 qd x 5 day repeat every 28 days x 6 cycles wks Focal Radiotherapy (30 x 2 Gy, 60 Gy) Tumor volume with 2-3 cm margin

5. TMZ & RT: Promising Survival Stupp R et al. J Clin Oncol. 2002;20:1375-82 Stupp R & Hegi ME. ASCO Education Book, 2003

6. Phase III Trial of Concomitant and Adjuvant Temozolomide and Radiotherapy for Newly Diagnosed Glioblastoma Multiforme EORTC 26981-22981 and NCIC CE.3 Roger Stupp , WP Mason, MJ Van Den Bent, M Weller, B Fisher, MJB Taphoorn, K Belanger, AA Brandes, JG Cairncross, C Marosi, U. Bogdahn, J. Curschmann, RC Janzer, S Ludwin, T Gorlia, A Allgeier, D Lacombe, E Eisenhauer, RO Mirimanoff On behalf of the European Organization for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups and National Cancer Institute of Canada Clinical Trials Group

7. Treatment Schema Temozolomide 75 mg/m 2 po qd for 6 weeks, then 150–200 mg/m 2 po qd d1–5 every 28 days for 6 cycles Focal RT daily — 30 x 200 cGy Total dose 60 Gy Concomitant TMZ/RT* Adjuvant TMZ Weeks 6 10 14 18 22 26 30 RT Alone R 0 *PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.

9. Patient Characteristics 17 16 Biopsy only 83 84 Debulking surgery 67 75 Baseline Steroids (%) 87/13 88/12 PS 0–1 vs 2 (%) 64/36 61/39 M/F (%) 56 (19–70) 57 (23–71) Median age, yr TMZ/RT n=287 RT Alone n=286

11. During RT ± TMZ: Grade 3/4 Toxicities Hemato. tox. Non-hem. tox. 1 1 Visual 3 2 Infection <1 1 Nausea/Vomiting 1 1 Rash/Dermatologic 9 6 Fatigue/Constitutional Sx 3 0 Thrombocytopenia 1 0 Febrile neutropenia 4 0 Neutropenia 3 0 Leukopenia <1 0 Anemia TMZ/RT n=287 % RT Alone n=286 %

12. Adjuvant TMZ Treatment Delivery n=287* *22% (n=64) randomized to TMZ/RT did not receive any adjuvant TMZ. Reason for Early Discontinuation: Cycle completed

13. Progression Free Survival months 0 6 12 18 24 30 36 42 0 10 20 30 40 50 60 70 80 90 100 RT TMZ/RT Median PFS, mo: 5.0 6.9 1-yr PFS: 9% 27% 2-yr PFS: 2% 11% HR [95% C.I.]: 0.54 [0.45-0.64] p <0.0001 TMZ/RT RT TMZ/RT RT % Stupp et al. N Engl J Med 2005, 352:987-996 O N Number of patients at risk : 281 286 104 26 11 4 0 0 260 287 154 77 51 24 8 1

14. Overall Survival months 0 6 12 18 24 30 36 42 0 10 20 30 40 50 60 70 80 90 100 RT TMZ/RT Median OS, mo: 12.1 14.6 2-yr survival: 10% 26% HR [95% C.I.]: 0.63 [0.52-0.75] p <0.0001 RT TMZ/RT TMZ/RT RT % Stupp et al. N Engl J Med 2005, 352:987-996 O N Number of patients at risk : 261 286 240 144 59 23 2 0 219 287 246 174 109 57 27 4

15. Subset Analysis Overall Survival 0.0 0.5 1.0 1.5 2.0 Hazard Ratio with 95% C.I. Stupp et al. N Engl J Med 2005, 352:987-996 (appendix) Males (175/185) Females (110/102) Baseline steroids (215/193) No Baseline steroids (70/94) Mini-mental status ≥ 29 (148/149) ≤ 28 (126/128) WHO PS = 0 (112/116) PS = 1 (140/135) PS = 2 (34/36) Biopsy Only (46/47) Resected (240/240) Age < 50 (81/90) ≥ 50 (205/197) ITT Population (286/287)

19. MGMT Promoter Methylation is Prognostic 0 5 10 15 20 25 30 35 40 0 10 20 30 40 50 60 70 80 90 100 months Overall Survival Unmethylated N = 114 (55%) Methylated, N = 92 (45%) N=206 Unmeth Meth Median OS, mo: 12.2 18.2 HR [95% CI]: 0.45 [0.32-0.61] Logrank test: p <0.0001 Risk of death reduced by 55% Hegi et al. N Engl J Med, 352: 997-1003, 2005

20. MGMT is Predictive for Benefit from TMZ Treatment Unmethylated MGMT RT TMZ/RT Median OS, mo: 11.8 12.7 2-yr survival: 1.9% 13.8% Logrank : p = 0.062 Logrank : p = 0.0074 Hegi et al. N Engl J Med 2005, 352:997-1003 months 0 4 8 12 16 20 24 28 32 36 40 0 10 20 30 40 50 60 70 80 90 100 Overall Survival TMZ / RT RT Methylated MGMT 0 5 10 15 20 25 30 35 40 0 10 20 30 40 50 60 70 80 90 100 TMZ / RT RT months RT TMZ/RT Median OS mo: 15.3 21.7 2-yr surviva,l 22.7% 46.0%

21. Treatment after Progression 22 17 Palliative Care only 5 4 Repeat RT 23 23 Surgery 25 65 Temozolomide 58 72 Any Additional Chemotherapy TMZ /RT n=287 % RT Alone n=286 % At the discretion of treating physician

22. PFS: MGMT Methylation Status: a predictive factor for TMZ benefit months 0 4 8 12 16 20 24 28 32 36 40 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : 54 54 28 9 0 0 0 0 0 0 0 53 60 44 18 8 8 8 7 5 3 1 45 46 33 15 7 3 2 1 0 0 0 40 46 35 28 18 14 10 6 3 1 0 Unmeth, RT alone Unmeth, TMZ/ RT Meth, RT alone Meth, TMZ/ RT Overall Wald test: p <0.0001 (df=3) Progression Free Survival Meth, TMZ / RT Meth, RT Unmeth, TMZ / RT Unmeth RT Hegi et al. N Engl J Med 2005, 352:997-1003

23. RTOG0525/EORTC Intergroup Phase III Study TMZ daily x 6 wks R Radiotherapy (30 x 2 Gy) Concomitant Phase Adjuvant (maintenance) Phase (6 mo) Dose dense TMZ (100 mg/m2 daily x 21d) Stratify by: MGMT methylation Tissue For additional information contact: RTOG: www.rtog.org or EORTC: www.eortc.be ; or the study chairs: Mark Gilbert: [email_address] or Roger Stupp: [email_address]

24. 1p/19q LOH predicts response to PCV-chemotherapy J. Gregory Cairncross et al JNCI 90:1473-79, 1998

25. EORTC 26951: RT ± adj. PCV R Radiotherapy (33x1.8 Gy) Adj. PCV (6 cycles) N=185 N=183 Progression-free survival P=0.002 Overall survival P=0.226 van den Bent et al., Proc ASCO 2005 {abstr #1503} van den Bent et al., J Clin Oncol 24:2715-2722, 2006

26. EORTC 26951: Genetic markers 1p/19q LOH 1p LOH 19q LO H No LOH 1p/19q LOH No 1p LOH PCV + PCV - PCV + PCV - Overall survival by genetic marker Genetic marker and treatment van den Bent et al. J Clin Oncol 24: 2715-2722, 2006

27. RTOG 94-02: Chemo for oligos R Radiotherapy (33x1.8 Gy) Adj. PCV (6 cycles) N=185 N=183 Cairncross et al. J Clin Oncol 24:2707-2714, 2006

28. RTOG 94-02: Chemo for oligos R Radiotherapy (33x1.8 Gy) Adj. PCV (6 cycles) N=185 N=183 Cairncross et al. J Clin Oncol 24:2707-2714, 2006

29. TMZ in Oligos Adapted from Stupp et al. Curr Opin Neurol 2005

30. TMZ in low-grade glioma Adapted from Stupp et al. Curr Opin Neurol 2005