monday night with research to practice: an 8-part live cme webcast series

Copyright © 2010, Research To Practice, All rights reserved.

Part V: Central Nervous System CancersMonday, October 18, 20107:30 PM - 8:30 PM ET

Monday Night with Research To Practice: An 8-Part Live CME Webcast Series

Tracy Batchelor, MD, MPHExecutive DirectorStephen E and Catherine Pappas Center for Neuro-OncologyAssociate Professor of Neurology, Harvard Medical SchoolAssociate Neurologist, Massachusetts General HospitalBoston, Massachusetts

James J Vredenburgh, MDProfessor of MedicinePreston Robert Tisch Brain Tumor CenterDuke University Medical CenterDurham, North Carolina

Neil Love, MDModeratorResearch To PracticeMiami, Florida

Disclosures for Moderator Neil Love, MD

Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abraxis BioScience, Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, Lilly USA LLC, Millennium Pharmaceuticals Inc, Myriad Genetics, Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi-Aventis and Spectrum Pharmaceuticals Inc.

Disclosures for Tracy Batchelor, MD, MPH

Consulting AgreementsRoche Laboratories Inc, Schering-Plough Corporation

Research SupportAstraZeneca Pharmaceuticals LP, Millennium Pharmaceuticals Inc.

Disclosures for James J Vredenburgh, MD

N/A = Not Applicable

Advisory Committee and Consulting Agreements

Genentech BioOncology

Paid Research N/A

Speakers Bureau N/A

Case History: Dr Batchelor

• A 37 year old man presents with a generalized seizure

• Left fronto-parietal mass deemed unresectable

• Biopsy: Anaplastic astrocytoma

WHO Grading of Astrocytic Tumors of the CNS

Grade I• Subependymal giant cell astrocytoma• Pilocytic astrocytoma

Grade II

• Pilomyxoid astrocytoma• Diffuse astrocytoma• Pleomorphic xanthoastrocytoma

Grade III • Anaplastic astrocytoma

Grade IV

• Glioblastoma• Giant cell glioblastoma• Gliosarcoma

Louis DN et al. Acta Neuropathol 2007;114(2):97-109.

1) What treatment would you recommend for this patient?

98%

2%

0%

0%

0% 20% 40% 60% 80% 100%

Radiation therapy

Temozolomide

Radiation therapy plus temozolomide

Other

Case History: Dr Batchelor (continued)

• Received radiation therapy/temozolomide on RTOG 98-13

• Follow-up MRI 9 months after diagnosis revealed increased size of the mass

• Biopsy: GBM

2) What treatment would you recommend for this patient?

2%

5%

2%

5%

65%

21%

0%

0%

0% 10% 20% 30% 40% 50% 60% 70%

Bevacizumab

Chemo/bevacizumab

Temozolomide

Nitrosourea

Combination PCV

Cyclophosphamide

Platinum-based regimen

Other


• Phase II study with cilengitide monotherapy, with radiographic partial response

• After > 1 year on cilengitide, nodular enhancement outside the radiation field

• Cediranib x 4 months with initial tumor reduction followed by progression of FLAIR signal abnormality


Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma

Stupp R et al.J Clin Oncol 2010;28(16):2712-8.

Hypothesized Mechanisms of Action of Cilengitide

With permission from Stupp R et al. Presentation. ASCO 2010;Abstract TPS152.

Survival Outcomes of Cilengitide Combined with Temozolomide and Radiation Therapy

Stupp R et al. J Clin Oncol 2010;28(16):2712-8.

Overall(n = 52)

MethylatedMGMT Promoter

(n = 23)

UnmethylatedMGMT Promoter

(n = 22)

Median progression-free survival (PFS)

8.0 mo 13.4 mo 3.4 mo

PFS rate at 24 mo 15% 28% 5%

Median overall survival (OS) 16.1 mo 23.2 mo 13.1 mo

OS rate at 24 mo 35% 46% 20%


Phase II Study of Cediranib, an Oral Pan-vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma

Batchelor TT et al.J Clin Oncol 2010;28(17):2817-23.

Efficacy of Cediranib for Recurrent GBM

Volumetric criteria

Partial response by MRI 3-D measurement (n = 30) 56.7%

Minor response (n = 30) 20.0%

Macdonald criteria

Partial response (n = 30) 26.6%

Alive and progression-free at 6 months (n = 31) 25.8%

Progression-free survival 117 days

Overall survival 227 days

Batchelor TT et al. J Clin Oncol 2010;28(17):2817-23.


• Received bevacizumab/irinotecan (9 months) and bevacizumab/carboplatin (2 months) with stability of FLAIR until significant clinical decline

• Death 3 years after initial diagnosis

• Autopsy: extensive tumor infiltration throughout the left hemisphere, basal ganglia, splenium of the corpus callosum and right parietal and occipital lobes


Updated Safety and Survival of Patients with Relapsed Glioblastoma Treated with Bevacizumab in the BRAIN StudyCloughesy T et al.Proc ASCO 2010;Abstract 2008.

BRAIN Study: Updated Survival Data Comparing Bevacizumab versus Bevacizumab plus Irinotecan in Recurrent GBM

Bevacizumab(n = 85)

Bevacizumab + Irinotecan (n = 82)

12-months survival 38% 38%




Cloughesy T et al. Proc ASCO 2010;Abstract 2008.

BRAIN Study: Updated Safety Data Comparing Bevacizumab versus Bevacizumab plus Irinotecan in Recurrent GBM

Grade > 3 BevacizumabBevacizumab +

Irinotecan

Hypertension 10.7% 3.8%

Cerebral Hemorrhage 0% 1.3%

Venous Thromboembolism 3.6% 10.1%

Arterial Thromboembolism 3.6% 2.5%

GI Perforation 0% 2.5%

Cloughesy T et al. Proc ASCO 2010;Abstract 2008.


Long-Term Survival from the Initial Trial of Bevacizumab and Irinotecan

Desjardins A et al.Proc ASCO 2010;Abstract 2045.

Efficacy and Safety of Bevacizumab plus Irinotecan in Recurrent GBM (N = 35)

Partial Response

Median Overall Survival

6-Month Survival

4-Year Survival

57% 9.7 months 46% 8.6%

Desjardins A et al. Proc ASCO 2010;Abstract 2045.

Adverse events

Thromboembolic events 11%

Grade 2 fatigue 11%

>Grade 3 GI toxicity 11%

Grade 2 proteinuria 6%

CNS hemorrhage 3%

In the past year, how many new patients with GBM have you managed?

Patterns of Care Survey of US-Based Medical Oncologists (n = 100)

Patients

Median = 4 patients

12%

47%

26%

15%

>5

3-5

1-2

0

In the past year, how many patients with recurrent GBM have you treated with bevacizumab?


Median = 1 patient

18%

22%

35%

25%

>2

2

1

0

Patients

Have you observed a clinically meaningful antitumor response to bevacizumab?


62%Yes

What type of antitumor response to bevacizumab have observed in a patient with GBM?


22%

12%

13%

25%

37%

Other improvements

Partial response

Near complete response

Stable disease

Tumor shrinkage

— Erik Rupard, MDFort Gordon, GA

I have a patient in his early 60s with an unresectable, infratentorial Grade II astrocytoma with cerebellar involvement.

Generally, we treat patients who have low grade disease with radiation therapy alone.

Is there a role for adding in temozolomide for a patient like this man?

— Frank Rodriguez, MDFort Myers, FL

I am treating a 27-year-old woman with a resected anaplastic astrocytoma. She is receiving radiation therapy/temozolomide and tolerating therapy well.

Would the thought leaders consider adding bevacizumab to temozolomide in an off-protocol setting, given her age, after she finishes chemo/radiation?

Case History: Dr Vredenburgh

• A 46 year old man with GBM

• Radiation therapy/temozolomide followed by temozolomide x 8 before progression

• Tumor EGFRv3-positive, PTEN-normal

3) What treatment would you generally recommend?

6%

2%

12%

69%

11%

0%

0%

0%

0% 10% 20% 30% 40% 50% 60% 70% 80%

Bevacizumab

Chemo/bevacizumab

Temozolomide

Nitrosourea

Combination PCV

Cyclophosphamide

Platinum-based regimen

Other

Case History: Dr Vredenburgh (continued)

• Received bevacizumab/erlotinib x 8 months, with response and clinical improvement

• Developed 1+, 2+, 3+ proteinuria

Case History: Dr Vredenburgh (continued)

• Patient continues receiving bevacizumab 5 mg/kg plus erlotinib for 19 months

MRI at Diagnosis

MRI at Progression

MRI Post-bevacizumab/erlotinib


Clinical Features, Mechanisms, and Management of Pseudoprogression in Malignant Gliomas

Brandsma D et al.

Lancet Oncol 2008;9(5):453-61.

Brandsma D et al. Lancet Oncol 2008;9(5):453-61.

Clinical Features of Pseudoprogression

• Discordance between the radiologic findings and the clinical status — most patients are asymptomatic

• Lesions decrease in size or stabilize without additional treatments

• Can occur in up to 20% of patients who have been treated with temozolomide plus radiation therapy

• Can explain ~ 50% of all cases of MRI-progression

• Adjuvant temozolomide should be continued


Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group

Wen PY et al.

J Clin Oncol 2010;28(11):1963-72.

Response Criterion

Complete Response Complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically

Partial Response ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no new lesions; stable or reduced corticosteroid dose; and stable or improved clinically

Stable Disease Does not qualify for complete response, partial response, or progression; and stable clinically

Progression ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration

Wen PY et al. J Clin Oncol 2010;28(11):1963-72.

Current McDonald Criterion

Wen PY et al. J Clin Oncol 2010;28(11):1963-72.

Select RANO Criterion

• Progression within 12 weeks after completion of chemoradiotherapy can only be defined using diagnostic imaging if there is a new enhancement outside of the radiation field or if there is viable tumor on histology.

In the past year, how many patients with GBM in your practice experienced “pseudoprogression”?


7%

24%

25%

15%

>2

2

1

0

Not familiar with pseudoprogression

Patients

29%


Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

Stupp R et al.N Engl J Med 2005;352(10):987-96.


Effects of Radiotherapy with Concomitant and Adjuvant Temozolomide versus Radiotherapy Alone on Survival in Glioblastoma in a Randomised Phase III Study: 5-year Analysis of the EORTC-NCIC Trial

Stupp R et al.Lancet Oncol 2009;10(5):459-66.

Survival Benefit of Adjuvant Temozolomidein GBM

Radiation Alone

Radiation-Temozolomide1

Hazard Ratio p-value

Overall Survival (Median)

12.1 months 14.6 months 0.63 < 0.001

2-Year Survival 10.4% 26.5%Not

ReportedNot reported

PFS (Median) 5.0 months 6.9 months 0.54 < 0.001

Temozolomide was administered at 75mg/m2 PO QD for up to seven weeks with RTPost-RT, temozolomide was administered at 150 mg/m2, days 1-5 cycle 1, and then temozolomide 150-200mg/m2 q 28 days in cycles 2-6

Stupp R et al. N Engl J Med 2005;352(10):987-96.

Phase III Trial of Radiation Therapy with or without Temozolomide for Newly Diagnosed GBM: Five-Year Survival Analysis

Stupp R et al. Lancet Oncol 2009;10(5):459-66.

Hazard ratio

Median survival

Two years

Five years

Overall XRT XRT + T

1.00.6

12.1 mo14.6 mo

10.9%27.2%

1.9%9.8%

MGMT unmethylated XRT XRT + T

1.00.6

11.8 mo12.6 mo

1.8%14.8%

0%8.3%

MGMT methylated* XRT XRT + T

0.50.3

15.3 mo23.4 mo

23.9%48.9%

5.2%13.8%

* Hazard ratio relative to MGMT unmethylated XRT


Bevacizumab (BEV) in Combination With Temozolomide (TMZ) and Radiation Therapy (XRT) Followed by BEV, TMZ, and Irinotecan for Newly Diagnosed Glioblastoma Multiforme (GBM)

Vredenburgh JJ et al.Proc ASCO 2010;Abstract 2023.

Survival Outcomes of Bevacizumab, Temozolomide and Radiation Therapy

Vredenburgh JJ et al. Proc ASCO 2010;Abstract 2023.

Efficacy data (n = 75) Outcome

Median progression-free survival (PFS) 14.2 months

Two-year PFS 13.3%

Median overall survival (OS) 21.2 months

Two-year OS 45%


Phase II trial of Bevacizumab in Combination with Temozolomide and Regional Radiation Therapy for Up-front Treatment of Patients with Newly Diagnosed Glioblastoma Multiforme

Lai A et al.Proc ASCO 2009;Abstract 2000.

Bevacizumab in Combination with Radiation and Temozolomide in Up-front Management of GBM

Bevacizumab-Radiation-

Temozolomide (n = 70)

Radiation-Temozolomide

(Matched Control-Group) p-value

Progression-Free Survival

13.0 months 8.1 months 0.0395

Overall Survival 25.0 months 21.1 months 0.4

Lai A et al. Proc ASCO 2009;Abstract 2000.

RTOG-0825: Phase III Trial Evaluating the Role of Bevacizumab in the Up-Front Management of GBM

Target Accrual: 720

Radiation therapyTemozolomide

Placebo

Radiation therapyTemozolomideBevacizumab

Newly diagnosed GBMPartial or complete surgical resection within 3-5 weeks

R

www.clinicaltrials.gov, October 2010.

In the past year, how many patients with GBM have you treated with bevacizumab + temozolomide + radiation after primary surgery?


Patients

Median = 1 patient

4%

15%

20%

60%

>3

2-3

1

0

— Richard Polkinghorn, MDBrunswick, ME

Recently, I treated two men in their 40s who had GBMs with nearly complete resections and radiation therapy/temozolomide.

I sent them to Duke and both were put on bevacizumab and continued temozolomide. That’s in variance with many of our consultants in Boston, who do not tend to use bevacizumab as initial adjuvant therapy.

Any thoughts?

— Neal Fishbach, MDFairfield, CT

I was intrigued by reports at ASCO this year, which raised the issue of whether radiation therapy was indicated in elderly patients with GBM. What do the investigators think about that data?

Treating patients with temozolomide alone would probably result in a big improvement in quality-of-life for some patients.

Case History: Dr Batchelor

• A 68-year-old man presents with a generalized seizure

• MRI: Right parietal mass

• Subtotal-resection of a pathologically-confirmed GBM

MRI at Diagnosis

4) Which additional diagnostic tests would you obtain on this patient?

MGMT methylation status of the tumor

Chromosome 1p and 19q testing

Spinal MRI to screen for extent of tumor

dissemination

None 28%

10%

23%

39%

0% 10% 20% 30% 40% 50%


• Patient receives radiation and temozolomide• Evidence of tumor progression at 26-months after

initial diagnosis

MRI at Progression

5) How would you manage the patient now?

Hospice care

Dose-dense temozolomide

Bevacizumab monotherapy

Bevacizumab + irinotecan

Second course of radiation 1%

57%

35%

4%

3%

0% 10% 20% 30% 40% 50% 60%


• Patient started on bevacizumab therapy with objective improvement

• Remains on bevacizumab therapy for 24 months with sustained disease control and mild fatigue

MRI Post-bevacizumab

6) Would you continue bevacizumab?

1%

99%

0% 20% 40% 60% 80% 100%

Yes

No


NOA-08 Randomized Phase III Trial of 1-week-on/1-week-off Temozolomide Versus Involved-Field Radiotherapy in Elderly (Older Than Age 65) Patients With Newly Diagnosed Anaplastic Astrocytoma or Glioblastoma (Methusalem)Wick W et al. Proc ASCO 2010;Abstract LBA 2001.

NOA-08 Phase III Trial Design

Temozolomide 100 mg/m2 daily x 7 q14d

Radiotherapy daily 30 x 1.8-2 Gy

• Anaplastic astrocytoma or• Glioblastoma• Age > 65

R

PD PD

Radiotherapy daily 30 x 1.8-2 Gy

Temozolomide 100 mg/m2 daily x 7 q14d

Wick W et al. Proc ASCO 2010;Abstract LBA 2001.

Survival Outcomes for Temozolomide versus Radiotherapy

ITT Population (N = 373)

Radiotherapy(n = 179)

Temozolomide (n = 194)

Median overall survival 293 days 245 day

12-month overall survival 38.3% 30.8%

Hazard ratio (95% CI) 1.24 (0.94-1.63)

The rate of adverse and serious adverse events was higher in the temozolomide arm

Wick W et al. Proc ASCO 2010;Abstract LBA 2001.


Glioblastoma (GBM) in Elderly Patients: A Randomized Phase III Trial Comparing Survival in Patients Treated with 6-week Radiotherapy (RT) Versus Hypofractionated RT Over 2 Weeks versus Temozolomide Single-Agent Chemotherapy (TMZ)Malmstrom A et al.

Proc ASCO 2010;Abstract LBA 2002.

Nordic Clinical Brain Tumor Study Group Phase III Trial Design

Radiotherapy 60 Gy (2 Gy x 30)

Radiotherapy 34 Gy(3.4 Gy x 10)

• Glioblastoma

• Age ≥ 60

Temozolomide x 6(200 mg/m2 d 1-5 q 28 d)

R

Malmstrom A et al. Proc ASCO 2010;Abstract LBA 2002.

Survival Outcomes with Radiation Therapy versus Temozolomide (TMZ)

TMZ(n = 119)

RT 60 Gy(n = 100)

RT 34 Gy(n = 123)

Median overall survival (ITT)1 8.3 months 6.0 months 7.5 months

60-70 years old 7.9 months 7.6 months 8.8 months

>70 years old2 8.0 months 5.2 months 7.1 months

1 ITT60 Gy vs TMZ, p = 0.0260 Gy vs 34 Gy, p = 0.3234 Gy vs TMZ, p = 0.18

2 >70 years old60 Gy vs TMZ, p < 0.00160 Gy vs 34 Gy, p = 0.0234 Gy vs TMZ, p = 0.17

Malmstrom A et al. Proc ASCO 2010;Abstract LBA 2002.

Is there data to support retreatment with bevacizumab in patients with progressive primary CNS tumors?

I’m interested in your comment regarding telling patients on bevacizumab to get out and exercise. I may have missed something, but is that to counter-act the fatigue that occurs with the drug?Sarasota, FL

monday night with research to practice: an 8-part live cme webcast series

Documents

millennium pharmaceuticals

spectrum pharmaceuticals

cilengitide monotherapy

tracy batchelor

dr batchelor continuedphase

temozolomideothercase

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