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Treatment Paradigms in Recurrent GBM: Today’s Options and Tomorrow’s Promising Directions

Treatment Paradigms in Recurrent GBM: Today’s Options and Tomorrow’s Promising Directions. Thursday, November 20, 2008 Henderson, Nevada. This program is supported by an educational grant from. Clinical Explorations With Targeted Agents in Recurrent GBM. Timothy Cloughesy, MD

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Treatment Paradigms in Recurrent GBM: Today’s Options and Tomorrow’s Promising Directions

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  1. Treatment Paradigms inRecurrent GBM:Today’s Options and Tomorrow’s Promising Directions Thursday, November 20, 2008 Henderson, Nevada This program is supported by an educational grant from

  2. Clinical Explorations With Targeted Agents in Recurrent GBM Timothy Cloughesy, MD Professor and Director Department of Neurology, Neurological Services, Neuro-Oncology Program Jonsson Comprehensive Cancer Center David Geffen School of Medicine at UCLA Los Angeles, California

  3. What Are the Targets? • Genetic abnormalities or pathways activated as a consequence of genetic abnormalities • RTK/MAPK/PI3K • P53 • RB1 • Or critical messengers of those pathways • End biologic processes • Invasion • Angiogenesis • Cell survival • Cell metabolism • Unique cell populations • Stem cells • Endothelial cell • Immune therapies

  4. Wen PY, et al. N Engl J Med. 2008;359:492-507.

  5. CDKN2A(P16/INK4a) CDKN2B CDKN2C Homozygous deletion, mutation in 52% Homozygous deletion in 47% Homozygous deletion in 2% Amplificationin 1% Amplificationin 2% CDK4 CCND2 CDK6 Amplificationin 18% RB1 Homozygous deletion, mutation in 11% RBsignalingalteredin 78% G1/S progression a EGFR ERBB2 PDGFRA MET RTK/RAS/PI(3)Ksignaling alteredin 88% Mutation, amplificationin 45% Mutation in 8% Amplificationin 13% Amplificationin 4% Mutation, homozygous deletion in 18% Mutation, homozygous deletion in 36% PTEN NF1 RAS PI(3)K Mutation in 2% Mutation in 15% Amplification in 2% AKT Proliferationsurvivaltranslation Mutation in 1% FOXO b c Activated oncogenes p53signaling altered in 87% Homozygous deletion, mutation in 49% CDKN2A (ARF) Amplification in 14% MDM2 MDM4 Amplification in 7% TP53 Senescence Apoptosis Mutation, homozygous deletion in 35% Cancer Genome Atlas Research Network. Nature. 2008;[E-pub ahead of print].

  6. Results of Targeted Therapy • RTK (imatinib, gefitinib, erlotinib, AEE788, dasatinib, XL184) • FTI (tipifarnib) • Avb3 integrins (cilengitide) • Multikinase (sorafenib, sunitinib) • SRC (dasatinib) • mTOR (temsirolimus, sirolimus, everolimus) • PI3K (XL765, BEZ235) • PKC (enzastaurine, tamoxifen) • VEGF/R (PTK, AEE788, pazopanib, bevacizumab, AZD2171, aflibercept, CT-322) • Temozolomide

  7. 6-Month PFS and OS: Historical Data *Patients from NABTC phase II studies between February 1998 - December 2002. †Patients from 8 phase II studies with 225 recurrent GBM and 150 recurrent AA. 1. Lamborn KR, et al. Neuro Oncol. 2008;10:162-170. 2. Wong ET, et al. J Clin Oncol. 1999;17:2572-2578.

  8. How Will We Become Successful Using Targeted Agents? • Single agents will not be enough • Need combinations • AIDS • Lymphoma • Leukemia • Need rational combinations • Based on understanding mechanisms of resistance

  9. Studying Targeted Therapies • Is the target present? • Does drug hit the target? • Is target altered? • Impact on downstream signaling? • End biologic effect? • Feedback loop?

  10. First Things First • Is the target present or active? • Do we know how to prescreen? • Does the drug get to the target? • BBB vs BTB • Small molecule vs antibody • Empiric data with rituximab and bevacizumab • How do we measure (peak or trough levels) • PK • Impact of EIAED and other inducers • MTD: if agent hits multiple targets, off-target toxicity may limit escalation of dose

  11. Prescreen for EGFR Inhibition FISH WT EGFR EGFRvIII p-EGFR

  12. Selected Trial of Erlotinib in Patients With Malignant Gliomas Halatsch ME, et al. Cancer Treatment Rev. 2006;32:74-89.

  13. Selected Trial of Gefitinib in Patients With Malignant Gliomas Halatsch ME, et al. Cancer Treatment Rev. 2006;32:74-89.

  14. Targeting VEGF *N = 68. Response to therapy determined by neurologic examination and MRI using the Macdonald criteria. Noncontrast T1 and T2 images and FLAIR images also were evaluated. †N = 31. Response to therapy determined by radiographic imaging. Wagner SA, et al. ASCO 2008. Abstract 2021. Batchelor T, et al. AACR 2008. Abstract LB-247. Fine HA, et al. ASCO 2008. Abstract 2005.

  15. First Things First • Is the target present or active? • Do we know how to prescreen? • Does the drug get to the target? • BBB vs BTB • Small molecule vs antibody • Empiric data with rituximab and bevacizumab • How do we measure (peak or trough levels) • PK • Impact of EIAED and other inducers • MTD: if agent hits multiple targets, off target toxicity may limit escalation of dose

  16. First Things First • Is the target present or active? • Do we know how to prescreen? • Does the drug get to the target? • BBB vs BTB • Small molecule vs antibody • Empiric data with rituximab and bevacizumab • How do we measure (peak or trough levels) • PK • Impact of EIAED and other inducers • MTD: if agent hits multiple targets, off target toxicity may limit escalation of dose

  17. R115777 Plasma Concentration vs Time 1000 Group A (non-EIAEDs) 300 mg Group B (EIAEDs) 600 mg 100 R115777 Plasma Conc. (ng/mL) 10 Dose (mg) 300 300 600 No. pts (group) 5 2A 2B Cmax (ng/mL) 882 722 543 AUC12h (μg x hr/mL) 3.76 3.93 2.24 1 0 2 4 6 8 10 12 14 16 18 20 22 24 Hour Karp JE, et al. Blood. 2001;97:3361-3369.

  18. NABTC 99-01 Tipifarnib • Phase II trial of tipifarnib in recurrent malignant glioma (GBM: n = 67; AG: n = 22) • Group A: Patients not on EIAEDs • Group B: Patients on EIAEDs • PR reported in only in GBM patients (4 in Group A; 1 in Group B) • Exploratory analysis of GBM patients showed a significant difference (P = .01) in PFS favoring Group A (n = 36) to Group B (n = 31) Cloughesy TF, et al. J Clin Oncol. 2006;24:3651-3656.

  19. First Things First • Is the target present or active? • Do we know how to prescreen? • Does the drug get to the target? • BBB vs BTB • Small molecule vs antibody • Empiric data with rituximab and bevacizumab • How do we measure (peak or trough levels) • PK • Impact of EIAED and other inducers • MTD: if agent hits multiple targets, off target toxicity may limit escalation of dose

  20. RTK RTK RTK RTK TK TKL TK TK TK TKL TKL TKL CLK CLK CLK CLK CK MAPK MAPK CK CK CK CDK CDK CDK CDK PKA PKA PKA PKA Kd CAMK CAMK CAMK CAMK Lapatinib < 1 nM 1-10 nM 10-100 nM 100 nM - 1 µM 1-10 µM Imatinib Staurosporine Sorafenib MAPK MAPK Collins I, et al. Nat Chem Biol. 2006;2:689-700.

  21. Considerations • Is the target inhibited? • All of the above plus potency, reversible vs irreversible • VEGFR inhibitors prior to AZD2171 not as potent KDR IC50 < 1 nmol

  22. Examples of Measuring Drug Hitting Target 100 90 C 80 Tumor: 24 25 26 27 28 29 12 13 14 10 15 16 17 11 9 18 19 20 Drug: - - - - - - E E E G E G E G E E E E 70 Sensitivity: - - - - - - I I I I I I I S S S S S 60 pEGFR Detectable AGT (%) 50 EGFR 40 pERK 30 pAKT 20 GAPDH 10 0 20 40 60 80 100 120 140 BG Dose (mg/m2) Schold SC Jr, et al. Neuro-Oncology. 2004;6:28-32.Lassman AB, et al. Clin Cancer Res. 2005;11:7841-7850.

  23. Considerations • Impact on downstream signaling • Biologic effect • Feedback loop

  24. Rapamycin in Recurrent PTEN-Deficient Glioblastoma: Phase I IHC-based screening for PTEN protein expression in newly diagnosed GBM(N = 165) PTEN deficient(67/165 = 40.6%) PTEN positive(98/165 = 59.4%) Exclude fromclinical trial Other eligibility criteria No Yes Exclude fromclinical trial Enroll at tumorrecurrence (n = 15) TTP Tumorrecurrence Tumorfailure Initial diagnosis Surgery 1 (S1) Surgery 2 (S2) Rapamycin Rapamycin Postoprecovery Cloughesy TF, et al. PLoS Medicine. 2008;5:139-151.

  25. A 15 14 13 10 mg cohort 12 11 Tumor (nM) 10 9 Plasma (ng/mL) 8 Patient # 7 5 mg cohort 6 5 4 3 B 2 2 mg cohort 1 Immunoblot 0 0.1 1 10 100 Pt #1 Pt #2 Pt #3 Rapamycin Concentration S1 S2 S1 S2 S1 S2 IB: pS235/236 S6RP pSer 235/236 S6 pSer 240/244 S6 IB: total S6RP 2.0 2.0 IB: tubulin P = .028 P = .002 Rapamycin IHC Pt #2 Pt #3 Pt #1 1.5 1.5 S1 S2 S1 S2 S1 S2 120 100 mTOR Surgery 2 /Surgery 1 Surgery 2 /Surgery 1 C 1.0 1.0 80 Otherkinases 100 80 Other S6K1 pS235/236-S6RPMeal Saturation per Cell 80 60 0.5 0.5 60 60 S235/236 S240/244 40 40 0 0 40 NoRapa RapaPatients NoRapa RapaPatients 20 S6 ribosomal protein 20 20 0 Cloughesy TF, et al. PLoS Medicine. 2008;5:139-151.

  26. Rapamycin in Recurrent PTEN-Deficient Glioblastoma: Ph I Results Ki67 Response Stratified by % S6 Inhibition Cloughesy TF, et al. PLoS Medicine. 2008;5:139-151.

  27. Akt A Pt 2 Pt 5 Pt 11 PIP3 Growth factor receptor PI3K S473 Surgery 1 Surgery 2 Surgery 1 Surgery 2 Surgery 1 Surgery 2 IRS PRAS40 PTEN PIP2 Other P-AKT(Ser473) T246 mTOR S6K1 P-PRAS40(Thr246) Rapamycin B 50 Surgery 1 (S1) C Surgery 2 (S2) pPRAS40 not induced (n = 7) 1.0 40 pPRAS40 induced (n = 7) 0.8 30 NS NS NS NS NS 0.6 NS pPRAS40 IHC (Arbitrary Units) 20 0.4 P = .049 10 0.2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 0 100 200 300 400 500 Patient # TTP (Days) Cloughesy TF, et al. PLoS Medicine. 2008;5:139-151.

  28. Multitargeted Approaches and Defining Mechanisms of Resistance? PIP3 S473 Growth factor receptor PI3K IRS Akt AGENT PTEN PIP2 Other T246 PRAS40 mTOR S6K1 Rapamycin XL 765, BEZ235 Cloughesy TF, et al. PLoS Medicine. 2008;5:139-151.

  29. If We Hit Target, Why Do We Fail? Mechanisms of Resistance • Adaption (upfront) • Feedback loops • Multiple RTK activation • Heterogeneity—selection • PTEN • Stem cell population • Late (acquired) mutation, selection • RTK mutation in kinase domain • MET RTK activation

  30. If We Hit Target, Why Do We Fail? Mechanisms of Resistance • Adaption (upfront) • Feedback loops • Multiple RTK activation • Heterogeneity—selection • PTEN • Stem cell population • Late (acquired) mutation, selection • RTK mutation in kinase domain • MET RTK activation

  31. Adaptive (Upfront) Resistance Feedback Loop Multiple RTK Activation PIP3 S473 Growth factor receptor PI3K Akt IRS Time PTEN MET EGFR ErbB3 ErbB3 ErbB3 PDGFR PIP2 Other T246 PRAS40 Gefitinib mTOR Tumor growth S6K1 Rapamycin Cloughesy TF, et al. PLoS Medicine. 2008;5:139-151.

  32. If We Hit Target, Why Do We Fail? Mechanisms of Resistance • Adaption (upfront) • Feedback loops • Multiple RTK activation • Heterogeneity—selection • PTEN • Stem cell population • Late (acquired) mutation, selection • RTK mutation in kinase domain • MET RTK activation

  33. Adaptive (Upfront) Resistance Resistant cancer cells Tumor size Lethaltumor Relapse Tumor a b Cure c d Time Antiangiogenictherapy Life-span

  34. EGFR inhibition Lack of activation of AKT PTEN and EGFRviii KRAS WT better outcome in metastatic CRC with cetuximab mTOR inhibition PTEN-deficient tumors Identification of feedback loop Context-Dependent Sensitivity ECM Growth factors Growth factors Integrins Plasma membrane PIP3 Signaling andcytoskeletalcomplex P13-k Shc FAK P13-k Grb2 Sos Grb2 Snc Cas Ras Akt/PKB Sos Raf MEK PTEN ERK F-actin, cytoskeleton Othereffects Apoptosis growth Adhesion, migrationinvasion, growth

  35. If We Hit Target, Why Do We Fail? Mechanisms of Resistance • Adaption (upfront) • Feedback loops • Multiple RTK activation • Heterogeneity—selection • PTEN • Stem cell population • Late (acquired) mutation, selection • RTK mutation in kinase domain • MET RTK activation

  36. Late (Acquired) Resistance Time MET EGFR ErbB3 ErbB3 ErbB3 PDGFR NSCLC Glioblastoma Gefitinib Tumor growth EGFR Δ6-273(EGFRvIII)(Δ6-185) L1 CR1 EGF Transmembranedomain L2 CR2 Δ521-603 G719S,G719C P-loop Tyrosinekinasedomain ΔE746-A750 ΔL747-P753insS ATP A-loop ΔL747-T751insS T790M Y Y L858R, L861Q TKI Y Y ATP-binding cleftof the kinase

  37. ECM Growth factors Growth factors Integrins Plasma membrane RTKi PIP3 Other Signaling andcytoskeletalcomplex Shc FAK Grb2 P13-k P13-k Sos Grb2 Snc Cas FTI Ras Akt/PKB Sos Raf Sorafenib MEK PTEN ERK F-actin, cytoskeleton Apoptosis Growth Othereffects Rapamycin Adhesion, migrationinvasion, growth mTOR S6K Cyclin D1

  38. Promise and Problems With Combinations • Need to understand single agent effects before moving to combination • Single-agent MTD not met in combination studies due to toxicity • Erlotinib and CCI-779 • CCI-779 MTD 15 mg, which is less than 1/10 MTD single agent • Sorafenib and erlotinib • Erlotinib MTD 100 mg, which is 50% single-agent MTD • Need to study potent selective inhibitors before considering multikinase inhibitors

  39. Karaman MW, et al. Nat Biotech. 2008;26:127-132.

  40. How Will We Evaluate Targets? • Need to choose and study agents carefully • Biopsy-treat-biopsy • Optimize molecular/tissue evaluations • Each study should provide insight to future studies or combinations (know why you failed) • Do not ignore success • Anti-VEGF, temozolomide, CCNU?

  41. Now Take the Test . . . • To earn CME credit for this activity, please close this window and click the “Test” tab in the CME module underneath

  42. More Hematology/Oncology Available Online! Medical Meeting Coverage: key data plus Expert Analysis panel discussions exploring clinical implications Treatment Updates:comprehensive programs covering the most important new concepts Interactive Cases:test your ability to manage patients clinicaloptions.com/oncology

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