Combination therapy with temozolomide and bevacizumab in the treatment of hemangiopericytoma/ malignant solitary fibrous

1. Combination therapy with temozolomide and bevacizumab in the treatment of hemangiopericytoma/ malignant solitary fibrous tumor (HPC/SFT): an updated analysis Park MS, Lazar AJ, Trent JC, Conrad CA, Ludwig JA, Wang W, Boonsirikamchai P, Choi H, Patel SR, Benjamin RS, Araujo DM The University of Texas - MD Anderson Cancer Center Houston, TX

2. Background • The hemangiopericytoma/ solitary fibrous tumor (HPC/SFT) spectrum • Varying cellularity • Branched “staghorn” vessels • Diffuse IHC +CD34 reactivity Emerging consensus that HPC/SFT represent a morphological continuum rather than two distinctentities1,2 HPC SFT 1Fletcher CDM. Histopathology 48 (2006) , 3-12 2Gengler et al. Histopathology 48 (2006), 63-74

3. Background • Malignant potential of HPC/SFT is difficult to predict at the time of diagnosis • Limited data regarding the long-term outcome of HPC/SFT in the advanced setting3,4 3Spitz et al. Ann of Surg Oncol;5(4):350-355 4Espat et al. Cancer 2002;95:1746–51

4. Background • Rationale for temozolomide & bevacizumab: • Activity in Glioblastomas5,6 • Irinotecan and bevacizumab (RR 57-60%) • Carboplatin and bevacizumab • Temozolomide and bevacizumab • Our institution’s anecdotal experience in a single patient with meningeal HPC/SFT • Previously heavily treated with multiple surgeries, XRT, chemo- and biologic therapies with no prior response 5Vredenburgh et al. J Clin Oncol 2007;25:4722-2739 6Charles A. Conrad, personal communication

5. Methods • Retrospective review of all HPC/SFT patients treated with temozolomide and bevacizumab at MD Anderson Cancer Center • IRB-approved protocol • Study period: May 2005 – June 2007 • All diagnoses confirmed by a sarcoma pathologist • All had follow-up scans available

6. Methods • Radiologic response: Choi criteria7 • Statistical analysis for progression-free survial: Kaplan-Meier method 7Choi et al. J Clin Oncol 2007;25:1753-1759

7. Results: Patient Characteristics • 14 HPC/SFT patients treated with temozolomide & bevacizumab at MD Anderson Cancer Center, 05/2005-06/2007 • Gender (M/F): 9/5 • Median age: 59 (range 44-75) • Reason for starting treatment: • Symptomatic disease: 7 • Neoadjuvant treatment: 4 • Disease progression: 8 • Local disease recurrence/progression: 3 • Development of metastatic disease: 5

8. Results: Patient Characteristics • Prior surgery: 10 (median = 1.5, range 0-6) • Prior XRT: 7 • Prior chemotherapy: 5

9. Results: Prior Systemic Therapy History *Received regimen after R0 resection as adjuvant therapy

10. Results: Treatment Regimen • All patients treated with: • Median no. of cycles of therapy administered: 7.5 (2.5-20.5) • 1 patient still undergoing therapy at the time of analysis D1 D7 D15 D21 D28 Temozolomide 150 mg/m2 Temozolomide 150 mg/m2 D8 D22 Bevacizumab 5mg/kg Bevacizumab 5mg/kg

11. Results: Response Rate * History of prior systemic therapy; + patient with ongoing therapy Best Response rate: 11/14 (79%) (PR)(≥10% ↓ size, ≥15% ↓ HU) SD: 2/14 (14%); PD 1/14 (7%) (≥10% ↑ size without 15% ↓ HU)

12. 33.8mm 107.8 HU 23.7mm 101.3 HU After 8 cycles Pre-Treatment 15.8mm 75.3 HU After 2 cycles Results: Patient Example 1 PR (↓ SIZE)

13. 13.6mm 37.5 HU After 2 Cycles 18.0mm 52 HU Results: Patient Example 2 14.4mm 115 HU PR (↓ HU) Pre-Treatment 16.4mm 140.1 HU

14. Results: Progression Free Survival Median PFS: 8.6 months

15. Historical HPC/SFT Cohort – Comparisonof Response Rates * History of prior systemic therapy with doxorubicin and cisplatin. Best Response rate (Choi) : 1/5 (20%) (PR)(≥10% ↓ size, ≥15% ↓ HU) SD: 3/5 (60%); PD 1/5 (20%) (≥10% ↑ size without 15% ↓ HU)

16. Historical HPC/SFT Cohort – Comparison of Progression-Free Survivals Median PFS (TMZ/BV): 8.6 months Median PFS (Others): 6.1 months

17. Results: Major Treatment Toxicities • Hematologic Toxicities • Neutropenia (Grade 3): 1 • Thrombocytopenia (Grade 3): 2 • Infectious Toxicities • Fungal pneumonia (Grade 2): 1 • Metabolic Toxicities • Renal Insufficiency (Grade 2): 1 • 1 case of mortality during treatment • Renal failure, DIC, hypotension, cardiac arrest • Death secondary to disease & performance status

18. IHC analysis of tumor specimens for angiogenesis & cell growth biomarkers • 5 patients had tissue specimens readily available for IHC analysis • No strong correlation between levels of IHC expression and clinical outcomes were found in this limited set

19. Conclusions • Hemangiopericytoma/ malignant solitary fibrous tumor (HPC/SFT) are a rare spectrum of tumors with no known effective medical therapy in the advanced setting. • In our retrospective series, combination therapy with temozolomide and bevacizumab has demonstrated clinical benefit in a majority of patients with a low rate of major toxicities. • These findings advocate a role for a larger, prospective phase II study to further investigate the biological mechanism and efficacy of temozolomide and bevacizumab in HPC/SFT.