2011 Oncology Highlights News from ASCO 2011:

Transcription

1 2011 Oncology Highlights News from ASCO 2011: Malignant Glioma David A. Reardon, M.D. Clinical Director Center for Neuro-Oncology Dana-Farber Cancer Institute 450 Brookline Avenue SW-430 Boston, MA T: F: Key Presentations: ASCO 2011 Malignant Glioma Recurrent Patients Immunotherapy (abstract 2506; Okada H) Newly Diagnosed Patients IDH in anaplastic oligodendroglioma (abstract 2002; Frenel JS) RTOG 0525: Standard 5-day TMZ vs dose dense TMZ Clinical Outcome (abstract 2006; Gilbert MR ) Tumor correlative studies (abstract LBA 2000; Aldape K) Bevacizumab plus standard therapy for GBM (abstract 2098; Vredenburgh JJ) 1

2 Phase I/II Vaccine Study Targeting Novel HLA-A2-restricted CTL Epitopes in Combination with Poly-ICLC in Patients with Recurrent Malignant Glioma (Abstract 2506) H. Okada, P. Kalinski, A. H. Mintz, J. A. Engh, L. H. Butterfield, R. H. Hamilton, D.M. Potter, M. Salazar, F. S. Lieberman; University of Pittsburgh Cancer Institute; Oncovir, Inc. Recurrent High Grade Glioma (WHO III or IV) Vaccines (Q2W) Poly-ICLC (twice/week) Booster Vaccine Phase I (Q4W) Poly-ICLC (twice/week) Booster Vaccines Phase 2 (Q3M) Poly-ICLC (once/week) HLA-A2+ < 4 mg decadron/day 2 PD Weeks Up to 3 Years Brain MRI Ultrasound-guided intranodal injections of DC1 (1 or 3 x 10 7 /injection with dose escalation) loaded with 4 glioma-associatedassociated antigen (GAA)-derived HLA-A2-restricted A2 CTL epitopes (IL-13Ra :1A9V, gp :2M, EphA and YKL ) and a pan-dr helper peptide (PADRE) Intramuscular injections of poly-iclc (20 mcg/kg; twice/week) Partial response with biopsy evidence of immunogenicity 57 yr old male with recurrent high grade GBM (2 nd salvage) Pre-Vaccine Post-Vaccine (wk 9) Post-Vaccine (wk 17) Biopsy demonstrates intratumoral infiltration of macrophages and CD8 + T lymphocytes Reactive gliosis, possible residual glioma Numerous CD68 + macrophages CD8 + T cells 2

3 Durable complete responder 62 yr old male with recurrent high grade GBM (1 st salvage) Pre-Treatment Post-Treatment (wk 33) Significant increase in targetspecific T cells by wk 29 (tetramer assay) 8.51x year old male with recurrent GBM of right temporal lobe Prior therapy: surgical resection, radiation therapy, and temozolomide The regimen induced disappearance of gadolinium enhanced mass Durable response >18 months (ongoing) Summary: Phase I/II Vaccine Study in Adult Recurrent Malignant Glioma Regimen well tolerated in 22 patients. Positive immune responses in 13 of 16 patients. No DC1 dose-dependent effects on both safety and immunological activity. Significant up-regulation of type-1 cytokines and chemokines, including IFN- and CXCL10. Two patients demonstrated sustained complete response (including one recurrent GBM with CR of 18+ mo s duration). Nine patients (4 GBM, 5 AG) with PFS >12 mo s. IL-12 levels by DC1 positively correlated with PFS. (J Clin Oncol Jan 20;29:330-6) 3

4 IDH Mutation in GBM Parsons et al. Science 321:1807, GBM tumors: Sequenced entire human genome; copy # analysis - high density oligo arrays; expression analysis: SAGE Point mutations * Amplifications Homozygous deletions Gene No. of tumors Fraction of tumors (%) No. of tumors Fraction of tumors (%) No. of tumors Fraction of tumors (%) Fraction of tumors with any alteration (%) Passenger probability CDKN2A 0/22 0 0/ / <0.01 TP53 37/ /22 0 1/ <0.01 EGFR 15/ / / <0.01 PTEN 27/ /22 0 1/ <0.01 NF1 16/ /22 0 0/ CDK4 0/22 0 3/ / <0.01 RB1 8/ /22 0 1/ IDH1 12/ /22 0 0/ <0.01 PIK3CA 10/ /22 0 0/ PIK3R1 8/ /22 0 0/ * Fraction of tumors with point mutations indicates the fraction of mutated GBMs out of the 105 samples in the Discovery and Prevalence Screens. CDKN2A and CDK4 were not analyzed for point mutations in the Prevalence Screen because no sequence alterations were detected in these genes in the Discovery Screen. Fraction of tumors with amplifications and deletions indicates the number of tumors with these types of alterations in the 22 Discovery Screen samples. Passenger probability indicates the probability obtained using the average of the lower and upper bound background mutation rates (12). IDH1 and IDH2 Mutations in Gliomas Yan H et al. NEJM 360:765,

5 Predictive impact of IDH1 mutation assessed by immunohistochemistry (IHC) and DNA sequencing in anaplastic oligodendrogliomas (abstract 2002) JS. Frenel, C. Leux, D. Loussouarn, A-G Le Loupp, F. Leclair, M. Aumont, S. Martin, MG. Denis, M. Campone; Institut de Cancerologie de l Ouest; Centre Hospitalier Universitaire de Nantes Histologically proven anaplastic oligodendroglioma n = 43 Immunohistochemistry IDH1 mutation: R132H MAb DNA sequencing IDH loci 1. Correlation of techniques 2. Outcome relative to IDH status Results Immunohistochemistry DNA Sequencing Result Number (%) Result Number (%) Mutant 20 (47) R132H mutation 20 (100) WT 23 (53) R132G 2 (9) mutation WT 21 (91) Multi-variate Analysis PFS OS Number (%) HR p-value HR P-value IDH WT 21 (49) 1 1 IDH Mutant 22 (51) Conclusions 1. IDH mutation accurately assessed by IHC (DNA sequencing required if IHC negative) 2. IDH mutation: predicts increased PFS and OS independent of 1p/19q status; age and 3. degree of resection 5

6 RTOG 0525: A randomized phase III trial comparing standard adjuvant temozolomide with a dose-dense schedule in newly diagnosed glioblastoma M.R. Gilbert; Radiation Therapy Oncology Group (abstract 2006) International randomized phase III clinical trial involving ing RTOG, EORTC and NCCTG Primary study objective: determine if dose-intensifying the adjuvant temozolomide improves OS Secondary objectives: Impact of dose-dense on PFS Impact of dose-dense on OS and PFS by MGMT methylation status Toxicity profiles Compare symptom burden, NCF and HRQOL between the two treatment arms Treatment Concomitant RT + TMZ Focal (not IMRT) RT: 30 fx x 200 cgy TMZ 75 mg/m 2 daily during RT Arm 1: mg/m 2 days 1-5 of 28 day cycle; 6-12 cycles Arm 2: mg/m 2 days 1-21 of 28 day cycle; 6-12 cycles Patient Characteristics Category Arm 1 (Std dose) Age < Gender Male Female Race White Non-white Unknown KPS Surgery Biopsy Partial resection Total resection Radiation RTOG/NCCTG EORTC 112 (27%) 299 (73%) 239 (58%) 172 (42%) 319 (78%) 13 (3%) 79 (19%) 138 (34%) 273 (66%) 14 (3%) 167 (41%) 230 (56%) 337 (82%) 74 (18%) Arm 2 (Dose-dense) 111 (26%) 311 (74%) 237 (56%) 185 (44%) 328 (78%) 15 (3%) 79 (19%) 146 (35%) 276 (65%) 13(3%) 188 (45%) 221 (52%) 349 (83%) 73 (17%) Category Arm 1 (Std dose) Neurologic Function No symptoms 140 (34%) Minor symptoms 185 (45%) Moderate symptoms 84 (20%) Severe symptoms 2 (1%) MGMT Status Methylated Unmethylated Unknown (invalid, indeterminate) 122 (30%) 254 (62%) 35 (8%) Arm 2 (Dose-dense) 147 (35%) 196 (45%) 75 (18%) 4 (1%) 123 (29%) 263 (62%) 36 (9%) RPA Class III IV 85 (21%) 251 (61%) 86 (20%) 259 (61%) V 75 (18%) 77 (19%) No significant differences between Arm 1 and Arm 2 6

7 Treatment Related Adverse Events: Concurrent Chemoradiation Concurrent RT + TMZ (n = 1,114) Category Grade 2 Grade 3 Grade 4 Anemia Leukopenia Neutropenia* Lymphopenia Thrombocytopenia Fatigue Nausea/ vomiting *1 Grade 5 toxicity Treatment Related Adverse Events: Adjuvant Phase Adjuvant TMZ (Arm 1 = 351; Arm 2 = 369) Category Grade 2 Grade 3 Grade 4 Arm 1 Arm 2 Arm 1 Arm 2 Arm 1 Arm 2 Anemia* Leukopenia Neutropenia Lymphopenia Thrombocytopenia Fatigue Nausea/ vomiting *1 Grade 5 toxicity in Arm 1 - Grade 3-5 Adverse events were more common in Arm 2 (dd TMZ) (194 vs. 120; p<0.0001) - Mostly lymphopenia (107 vs. 51) and fatigue (33 vs 12) 7

8 Primary Outcomes by Treatment Outcomes by MGMT Status 8

9 Outcomes by Treatment: MGMT Unmethylated Outcomes by Treatment: MGMT Methylated 9

10 Conclusions Dose-dense adjuvant TMZ did not significantly improve OS or PFS in newly diagnosed GBM MGMT methylation status did not predict response to the dose dense schedule MGMT methylation status was prognostic for OS and PFS Dose-dense had more AEs, primarily lymphopenia and fatigue Molecular Correlative Analyses: RTOG 0525 (LBA 2000) K. D. Aldape, M. Wang, E. P. Sulman, D.P Cahill, M. Hegi, H. Colman, G. Jones, A. Chakravarti, M. P. Mehta, D. W. Andrews, L. Long, K. Diefes, L. Heathcock, R. Jenkins, C. J. Schultz, M. R. Gilbert Training Set MDACC n=254 Tumor Analyses (paraffin block) gene mrna (16 bad ; 3 good ) 2. CpG island methylation phenotype (CIMP) 3. MGMT methylation 4-Marker Tumor Profile Integrate Clinical Prognostic Factors (RTOG RPA) Validation Set RTOG 0525 n= IDH-1 mutation status Composite Tumor Marker/ Clinical Predictor Of Outcome 10

11 4-biomarker set in 0525 samples mrna IDH1 CIMP MGMT Clinical RPA Combine clinical RPA with molecular predictor (validation set) Molecular-clinical predictor 11

12 molecular-clinical predictor and patient outcome according to treatment arm Standard Dose Dose Dense Synopsis Strengths: Large sample size (n= ) Training set to develop model; model then applied and validated in clinical trial samples Assays compatible with paraffin-embedded tissue Demonstrated feasibility of obtaining molecular correlates in cooperative group setting Limitations Needle biopsies not included; molecular-clinical predictor may not apply for biopsy-only patients Biomarkers require molecular techniques beyond the scope of some pathology departments Conclusions 4-biomarker set: Improved predictor of outcome compared to either marker alone Tumor biomarkers + clinical prognostic factors (RPA): molecular-clinical predictor enhanced survival discrimination Possible stratification strategy for future clinical trials Possible prognostic marker 12

13 FDA Accelerated Approval: Bevacizumab (BV) for Recurrent GBM Study 1: AVF3708g (BRAIN) (Friedman et al. J Clin Oncol 27:4733, 2009) ge Responding Percenta ORR 25.9% (97.5% CI: 17.0%, 36.1%) Median Duration of Response 4.2 months Single-agent BV (N=85) (95% CI: 3.0, 5.7) Study 2: NCI 06-C-0064E (Kriesl et al. J Clin Oncol 27:740, 2009) ORR 25 Median Duration of Response nding Percentage Respo % (95% CI: 10.9%, 31.3%) 3.9 months Single-agent BV (N=48) (95% CI: 2.4, 17.4) Historical Controls: ORR 5%; PFS 2-3 months Bevacizumab in Combination with Radiation & Temozolomide Followed by Bevacizumab, Temozolomide and Topotecan for Newly Diagnosed Glioblastoma (abstract 2098) J. J. Vredenburgh, A. Desjardins, D. A. Reardon, K. Peters, J. Kirkpatrick, J. E. Herndon II, A. Coan, L. Bailey, S. Threatt, and H. S. Friedman; Duke University Medical Center Newly Dx d GBM n = Maximum safe resection 2. XRT (59.4 Gy) 3. TMZ (75 mg/m2/day) 4. BV (10 mg/kg q 2 weeks) 1. TMZ ( mg/m2) days Topotecan ( mg/m2) days BV 10 mg/kg days 1 & Up to day cycles Primary endpoint: 16 month OS (Stupp NEJM 2005: 50%) Secondary endpoint: safety 13

14 Toxicity Adverse Event Number Patients (%) During XRT Post-XRT Hematologic (grade 4) 4 (5) 21 (26) DVT/PE 1 (1) 3 (4) Wound dehiscence/infection 1 (1) 3 (4) Infection 0 1 (1) CNS hemorrhage 0 1 (1) GI perforation 0 1 (1) Median follow-up: 12 months PFS-6: 83% Stupp NEJM 2005: 54% Outcome Median OS: not reached 96% patients alive at 8 months Stupp NEJM 2005: 86% alive at 6 months Conclusions 1. Preliminary analysis of outcome: encouraging 2. Addition of bevacizumab and topotecan to standard therapy is associated with acceptable safety 3. Randomized clinical trials are essential 14

15 Bevacizumab: Full Approval for Newly Diagnosed GBM Two international phase III clinical trials 1. Radiation Therapy Oncology Group 0825: North America 2. AVAGLIO: USA (limited), Europe, Asia, South/Central America GBM - newly diagnosed - untreated N = 460 XRT: 60 Gy over 6 weeks TMZ: 75 mg/m 2 PO qd Placebo: IV q 2 weeks TMZ: mg/m 2 /day x 5 every 28 days Placebo: IV q 2 weeks Repeat x 6-12 months Randomize N = 460 XRT: 60 Gy over 6 weeks TMZ: 75 mg/m 2 PO qd BV: 10 mg/kg IV every 2 weeks TMZ: mg/m 2 /day x 5 every 28 days BV: 10 mg/kg IV every 2 weeks Repeat x 6-12 months Primary Endpoints: Overall survival; Progression-free survival Timeline: start Q /completed accrual 2011/report 2012/2013 Conclusions: ASCO 2011 CNS Tumors Standard temozolomide chemoradiation 5-day TMZ remains standard of care (RTOG 0525) TMZ dose intensification does not improve outcome for newly diagnosed patients GBM biology is complex and heterogeneous Integration of tumor biomarkers and clinical status: a new paradigm of predicting outcome IDH Promising approaches Addition of bevacizumab for newly diagnosed GBM Immunotherapy strategies 15