OSU ASCO 2014 Review Neuro-oncology

Vinay K. Puduvalli, MD Professor of Neurology and Neurosurgery

Director, Division of Neuro-oncology Ohio State University Comprehensive Cancer Center James Cancer Hospital and Solove Research Institute

Columbus OH

Background • Gliomas: Astrocytic or Oligodendroglial lineage, some are mixed

Oligoastrocytic – WHO grade II gliomas (LGG): observation vs RT, Role of chemo?

• Astrocytoma • Oligodendroglioma • Oligoastrocytoma

– WHO grade III gliomas: RT, Role of chemo? • Anaplastic astrocytoma • Anaplastic oligodendroglioma • Anaplastic Oligoastrocytoma

– WHO grade IV gliomas: Stupp regimen; patient selection for Rx • Glioblastoma • Gliosarcoma

• Lymphoma: DeAngelis regimen • Brain mets: 1-3 (surgery/SRS +/- WBRT); multiple (WBRT) • Quality of life

Summary

• Potentially practice changing data in low grade gliomas • Personalizing therapy for patients with newly

diagnosed glioblastoma – emerging role of markers and their application to therapy

• New therapeutic agents – phase 0/1 trials • Posthoc and retrospective analysis of several trials or

populations with leads for future trials • Novel imaging methods to delineate patient selection

or for assessing treatment response • Immune mediated therapies • Quality of life studies-– VTE, fatigue, cognitive

outcomes

R9802 SCHEMA

Presented By Jan Buckner at 2014 ASCO Annual Meeting

Phase III study of radiation therapy (RT) with or without procarbazine, CCNU, and vincristine (PCV) in low-grade glioma: RTOG 9802 with Alliance, ECOG, and SWOG Jan C. Buckner, Stephanie L. Pugh, Edward G. Shaw, Mark R. Gilbert, Geoffrey Barger, Stephen Coons, Peter Ricci, Dennis Bullard, Paul D. Brown, Keith Stelzer, David Brachman, John H. Suh, Christopher J. Schultz, Jean-Paul Bahary, Barbara Jean Fisher, Harold Kim, Albert D Murtha, Walter J. Curran, Minesh P. Mehta;

RTOG-9802 Outcomes 251 eligible patients were accrued from 1998 to 2002 Median follow up is 11.9 years; 55% of patients have died

RTOG-9802 Outcomes Is RT- PCV more toxic than RT in low grade glioma patients?

RTOG-9802 Conclusions

• First prospective trial to show a treatment related improvement in survival in low grade gliomas

• Favorable prognostic factors identified by multivariate analysis – Treatment with PCV – Oligodendroglial morphology – Female gender

• Early toxicity with PCV; expected and not unmanageable • Impact of molecular analysis remains to be determined • PCV versus Temozolomide remains a question

Correlation of Molecular Subtypes with Survival in AVAglio

H. Phillips, Sandman T, Li C, Cloughesy T, Chinot O, Wick W, Nishikawa R, Mason W, Henriksson R, Saran F, Lai A, Moore N, Hegde P, Abrey L, Bourgon R, Garcia J, Bais C

OS

12.1

14.6

26.5

10.4

Adults Age<70

Can subsets of newly diagnosed patients be identified by molecular markers who benefit from Bevacizumab upfront?

Background: Glioblastoma: IDH1 mutation and gCIMP

Background: Glioblastoma Gene Expression Subtypes and Impact of IDH1 mutation/ gCIMP

Results: BEV Effect on OS was Evident Only in the Proneural Subtype

Glioblastoma with wtIDH1

Results: Effect of BEV on OS Univariate and Multivariate Analyses

Conclusions

• Authors concluded that addition of Bev to RT/TMZ may result in improved survival in GBM patients with wtIDH1 Proneural tumors (17.1 m vs 12.2m – HR 0.42 95% CI: 0.24-0.72 p=0.002)

• Post-hoc subgroup analysis – hence all results must be interpreted with caution and need to be prospectively validated – could be prognostic and not predictive for treatment - not for clinical use yet

• Need to identify subset is important for prospectively selecting right patient for potentially toxic treatments

EORTC 26082: RT + concurrent plus adjuvant Temsirolimus versus chemo-irradiation with temozolomide in newly

diagnosed GBM with unmethylated MGMT promoter – a randomized multicenter, open-label, Phase II study.

Wick W. and EORTC

GFR/ PI3K/ mTOR inhibition

RT + concurrent plus adjuvant Temsirolimus versus chemo-irradiation with temozolomide

PFS OS

A 6-gene signature for outcome prediction of Gr II-III glioma Lautenschlager T, Huebner A, Oehlke O, Juratli T, Li B, Meng W, Ibrahim A, Chakravarti A

OSU, Univ of Frieburg, CG Carlus Univ Dresden

Randomized Ph II placebo controlled study of dendritic cell vaccine with ICT-107 in newly diagnosed GBM patients

Wen P, Reardon D, Phuphanich S, et al

• Dendritic cells (DC) are antigen presenting cells that could potentially help direct immune mechanisms against tumor cells

• GBM patients have reduced antigen presentation by dendritic cells and decreased number and function of cytotoxic and helper T cells

• DC vaccines increases antigen presentation function of dendritic cells • T cells derived from such dendritic cells can target GBM • ICT-107 an autologous 6-antigen DC vaccine

Study Design

Primary Endpoint: OS Sec Endpoints: - PFS - Immune response - Safety

Trial Design

Results: OS and PFS

Results: MGMT status and HLA-A2 subgroup

Conclusions- ICT107 vaccination

• Promising results in a subset of MGMT-promoter methylated and HLA-A2 patients

• Additional studies stratifying patients on these categories are indicated

• Several other biomarkers are being looked at to refine patient selection

ASCO 2014 -Additional points of interest • German multicenter study - MGMT promoter methylation as a prognostic marker

for benefit from dose-dense temozolomide rechallenge in progressive glioblastoma –randomized DIRECTOR trial

• Lee et al -A randomized placebo controlled pilot study of armodafinil for fatigue in patients with gliomas undergoing RT.

• Austrian multicenter retrospective study: Association of tumor infiltrating lymphocytes (TILs) with brain edema and overall survival in brain metastases (more in lung, melanoma and renal ca than breast ca)

• Edwin et al - VTE in patients with glioblastoma: high risk of primary and secondary VTE and increased risk of bleeding but not necessarily with anticoagulation – importance of preventive measures.

• Sloan et al: Targeting tumor initiating cells in GBM- SHH pathway inhibition using vismodegib (Smo inhibitor)– not active as single agent but combination therapies warranted.

• Berghoff et al - PD1 and PDL1 expression in GBM - PD1 staining predominantly in TILs. PDL-1 follows a fibrillary or a membranous pattern rather than predominantly membranous staining as seen in other tumors – significance for treatment uncertain.

• Desjardine et al- Phase I trial of intratumoral CED of oncolytic polio/rhinovirus recombinant (PVSRIPO) in recurrent GBM - oncolysis and live-attenuated vaccination – recognizes nectin like molecule 5 (oncofeto protein)

Thank you.