Nuevas drogas en Gliomas más allá de la Temozolamida. Córdoba 2010

Transcripción

1 Nuevas drogas en Gliomas más allá de la Temozolamida Córdoba 2010

2 20 30% of gliomas are reclassified when the tumor material is independently reviewed. These difficulties in the diagnosis of brain tumors are not to be understood as simple mistakes. In a systematic series on a cohort of 500 brain tumor patients routinely reviewed as a part of daily patient care, some degree of disagreement was present in 42.8%, which was considered serious in 8.8% Gene Expression-based Classification of Malignant Gliomas Correlates Better with Survival than Histological Classification CANCER RESEARCH 63, , 2003 Histopathological criteria have changed over time. In 1990s, endothelial proliferation even in the absence of necrosis in astrocytic tumors classify these tumors as GBM WHO 2007 necrosis in mixed AOA classify as GBM or GBM-O Interobserver variation of the histopathological diagnosis in clinical trials on glioma: a clinician s perspective Acta Neuropathol (2010) 120:

3 ARCH NEUROL/VOL 65 (NO. 7), JULY 2008 Stem/precursor cell Group A Differentiation LOH 1p-19q19q Glioma cell Original mutation/s LOH 10q CDKN2A deletion EGFR amplification Group B 2a A B 1 Adhesion Cell cycle arrest B 2 Group B 1 TP53 mutations Minor or no EGFR/PI3K pathway mutations Group B 2b Minor or no EGFR/PI3K pathway mutations Proliferation Migration Cell cycle progression

4 Methylation also was tightly associated with mutation in the IDHI gene in 78 percent of cases "Discovery of molecular factors that define subgroups of glioma will help us identify new therapeutic options for patients," Such findings are critical to treatment based on the genetic or epigenetic profile of each patient's disease Francis Collins director at the National Institutes of Health

5 Nimotuzumab Table 1. Summary of targeted therapies for malignant glioma

6 5 yr. EORTC-NCIC trial Glioblastoma ,4 9,8

7 online March 9, 2009

8 GBM recurrente A PESAR DEL TRATAMIENTO TODOS RECURRIRÁN (6-8 meses). POCAS OPCIONES EFICACES DE TRATAMIENTO A LA RECURRENCIA. LA SOBREVIDA LUEGO DE LA RECURRENCIA ES DE APROXIMADAMENTE 6 A 7 MESES.

9 Gefitinib Erlotinib Nimotuzumab Cetuximab

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12 Second line nimotuzumab plus chemotherapy in recuurent high grade glioma MUGGERI, CERRAT0, MARTINETT0, DIEZ Nimotuzumab (N) is a humanized mab against the EGFR extracellular ligand binding domain with hígh affinity and specificity. Retrospective, March February 2010, 23 patients WHO III, n = 9 WHO IV, n =14 Median age 54 years (30-67). All EGFR amplification N 200 mg weekly x 6 as induction and twice a month untíl progression + temozolomide in 7 Two 200 mg/m2/day for 5/28 Five 75 mg/m2 for 15/30 lomustine 110 mg/m2 doses each 40 days in 16 Median follow up 25 months (10-215) Response documented by MRI (MacDonald criteria) week 8 and assessed every 12 weeks.

13 Second line nimotuzumab plus chemotherapy in recuurent high grade glioma MUGGERI, CERRAT0, MARTINETT0, DIEZ Week 8 2 evidence of improvement less than 25% limit to assess PR progressed at week 18 and 19 1 PR progression at week SD 6 and 12 months PFS 30 and 8% 6,12 and 18 months overall survival after N 82, 42 and 30% Five of the 23 evaluable patients are currently alive Only EGFR (more than 10 copies) show statistically significant impact benefit on survival (p = 0.04)

14 88% GB TIENEN ANORMALIDADES EN LAS VÍAS ras/map Kinasa, PI3K/AKT, Rb, P53 BEVACIZUMAB CIDERANIB PAZOPANIB TEMSIROLIMUS ENZASTAURINA CILENGITIDE NORMALIZACIÓN DE LA MICROCIRCULACIÓN SENSIBILIZACIÓN DEL ENDOTELIO CONTRA AGENTES CITOTÓXICOS REDUCCIÓN DE VEGF INDUCIDO POR RADIOTERAPIA

15 Fase No II significant previo Rta: difference. 26% The median SLP6m: follow-up 7% time SLP: 1,3 for msurviving patients SVm: was 4,4 8.7 m months Enzastaurina 500 mg/d 1 dosis 1125 mg 174 ptes GB 1 o 2 recurrencia post RT-TMZ LOMUSTINE Lomustina mg/m2 cada 6 sem 92 ptes median of one cycle (1-8). mean cycle dose median PFS 1.6 months median OS 7.1 months 6-month PFS rate was 19%

16 65 GB recurrente 1linea de QT previas Temsirolimus 250 mg/sem EV Rta Macdonald 0% SLP6m 7,8% SLP 2,3 meses SVm 4,4 meses Toxicidad G3 62%

17 INTEGRINAS CILENGITIDE Cilengitide en GB recurrentes

18 Fase II CEDIRANIB en Glioblastoma recurrente # Rta parcial n:16 56% SLP6m n:30 27,6% SLPm A phase II trial of AZD2171 (cediranib), an oral pan-vegf receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. T. Batchelor, A. G. Sorensen, M. Ancukiewicz, D. G. Duda, D. N. Louis, S. R. Plotkin, P. Ivy, P. Y. Wen, J. S. Loeffler, R. Jain 111 días (16 sem) HTA 50%, fatiga, diarrea, proteinuria 81% toxicidad Grado 3 40% toxicidad Grado 4 NO hemorragias 50% dosis por toxicidad SVm 226 días (32 sem) # Batchelor T et al. Proc ASCO 2007;Abstract 2001 Fase III Cediranib in Combination With Lomustine Chemotherapy in Recurrent Glioblastoma (REGAL) Treatment Group A: Experimental Experimental Treatment Group B Experimental plus active comparator Treatment Group C: Active Comparator Active comparator plus placebo Cediranib 30 mg/day oral, until progression Cediranib 20 mg/day oral, until progression + Lomustine 110 mg/m2 / Q6W oral, until progression Lomustine 110 mg/m2 / Q6W oral, until progression

19 LBA7 A PHASE III RANDOMIZED STUDY COMPARING THE EFFICACY OF CEDIRANIB AS MONOTHERAPY, AND IN COMBINATION WITH LOMUSTINE, WITH LOMUSTINE ALONE IN RECURRENT GLIOBLASTOMA PATIENTST. Batchelor ESMO 2010

20 LBA7 A PHASE III RANDOMIZED STUDY COMPARING THE EFFICACY OF CEDIRANIB AS MONOTHERAPY, AND IN COMBINATION WITH LOMUSTINE, WITH LOMUSTINE ALONE IN RECURRENT GLIOBLASTOMA PATIENTST. Batchelor ESMO 2010

21 LBA7 A PHASE III RANDOMIZED STUDY COMPARING THE EFFICACY OF CEDIRANIB AS MONOTHERAPY, AND IN COMBINATION WITH LOMUSTINE, WITH LOMUSTINE ALONE IN RECURRENT GLIOBLASTOMA PATIENTST. Batchelor ESMO 2010

22 LBA7 A PHASE III RANDOMIZED STUDY COMPARING THE EFFICACY OF CEDIRANIB AS MONOTHERAPY, AND IN COMBINATION WITH LOMUSTINE, WITH LOMUSTINE ALONE IN RECURRENT GLIOBLASTOMA PATIENTST. Batchelor ESMO 2010

23 Bevacizumab 10 mg/kg + CPT mg/m2 o 340 mg/m2 cada 2 semanas 32 ptes (23 GB, 9 Gliomas III) 17 más de una progresión GIII GIV GIII + IV RESPUESTA 6/9 (66%) 14/23 (61%) 20/32 (63%) SLPm 30 sem 20 sem 23 sem (IC 15-30) SLP6m 56% 30% 38% SV6m 72% SVm NA 40 sem Eventos adversos serios: 3 TVP 1 ACV Ningún sangrado

24 UPDATED JULIO 2009 END POINT 1 : Tasa de rta SLP 6 meses END POINT 2 : Sobrevida Seguridad 1 Ciclo = 6 semanas

25 CARACTERÍSTICAS DE LOS PACIENTES NO PSEUDOPROGRESIÓN 20% INCLUIDOS LUEGO DE LA SEGUNDA RECAÍDA

26 RESULTADOS 8,9 9,3

27 EVENTOS ADVERSOS Eventos vasculares 10% Complicaciones de la herida quirúrgica 5% Solo perforaciones intestinales con irinotecan 2,4% vs 1,3 % muertes relacionadas al tratamiento 4,8% suspensión del tto con beva y 17,7 % en rama combinada

28 BEV n : 85 BEV+CPT11 n : 82 CCNU 1 n : 92 TMZ/BCNU 2 n : 56 TMZ 3 n : 112 Todos los NCCGT 4 n : 345 Todos los NABTC 5 n : 437 RTA (%) 28,2 37,8 4,3 9,6 5,4-7 SLP 6 meses 42,6 50, , Sobrevida (%) BRAIN STUDY 12 meses , meses meses meses La incidencia de eventos vasculares fue del 7% y más frecuente en el brazo combinado. Los casos de perforación intestinal 2,5% solo sucedieron con CPT11. Complicaciones de la herida quirúrgica 2,4 vs 1,3% más frecuente sin CPT11. Sobrevida al año de la recurrencia 38% y 16% vivos a los 30 meses valores nunca antes alcanzados. 1Fine et al. ASCO 2008; 2 Wick et al. JCO 2010; 3 Van den Bent et al JCO 2009; 4 Yung et al. Br JC 2000; 5 Ballman et al. Neuro-oncol 2008 BEV: Bevacizumab, CPT11: Irinotecan, CCNU: Lomustine, TMZ: Temozolomide, Rta: respuesta, SLP 6 meses: sobrevida libre de progresión a 6 meses, NCCGT: North Central Cancer treatment Group, NABTG: North American Tumor Coalition

29 Bevacizumab for recurrent GBM R n=85 n=82 Bevacizumab, at PD: + CPT11 Bevacizumab + CPT11 Prados et al. ECCO-ESMO 2009; Abstract 8721 Cloughesy et al. ASCO 2010; Abstract 2008 *Progression-free survival Overall survival Bevacizumab Bev + CPT 2-yr survival rate: 16% Comments: No phase III data, no controls Bevacizumab and CPT11 in both arms Median survival modest, encouraging 2-year survival Friedman, H et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27(28): No formal conclusions allowed Further investigations needed Anti-tumor effect or anti-edema effect? Optimal dose and schedule? cf. Wick, Weller, van den Bent & Stupp. Letter to the Editor. J Clin Oncol 2010;28:e188-9

30 BEVACIZUMAB EN GLIOMAS DE ALTO GRADO RECAÍDOS A UNA O DOS LÍNEAS DE QUIMIOTERAPIA Alejandro D Muggeri, J. P. Alderuccio, Blanca D Diez. Retrospectivamente 16 pacientes febrero abril 2010, mediana de edad 51 años (27 69) oligodendroglioma anaplásico 2 glioma mixto anaplásico 3 glioblastoma 11 Recaídos a 1 o 2 líneas de tratamiento bevacizumab monodroga o + quimioterapia. Todos recibieron en 1ra linea radioterapia temozolomida 6 segunda línea distinta a bevacizumab, Mediana de seguimiento 10 meses (3-20) Respuesta evaluada por RNM y criterios RANO Mediana SLP 5 m, SLP a los 6 m 56%, mediana SV15 m 0 dehiscencia de sutura, 1 falleció sangrado tumoral con plaquetopenia severa 1 TVP durante el tratamiento

31 A proinvasive adaptation has been inferred from MRI imaging in a subset of. GBM patient that had developed multifocal recurrence of tumors during the course of anti-vegf therapy. These data implicate that GBMs impaired in angiogenesis, for example, when targeted with anti-vegf agents, can evade from their inability to induce angiogenesis by becoming more invasive. Du R et al: Cancer Cell 13: , Angiogenesis Invasive Switch

32 Bevacizumab for recurrent malignant gliomas Efficacy, toxicity, and patterns of recurrence A.D. Norden et al, Neurology 2008;70: Recurrence pattern analysis identified a significant increase in the volume of infiltrative tumor relative to enhancing tumor in bevacizumab responders

33 TMZ 50 mg/m2/d on a continuous (28/28) basis for a maximum of 12monthsor until progression occurred. Group A. Anaplastic glioma (ie, AA, AO, AOA) with progression after treatment with TMZ on a 5/28 regimen. GroupB1(early). GB Mwith progression while receiving adjuvanttmz before completion of six cycles of adjuvant TMZ. Group B2 (extended). GBM with progression while receiving extended adjuvant TMZ beyond the standard six cycles but before completion of adjuvant treatment. Group B3 (rechallenge). GBM with progression after completion of adjuvant treatment and a treatment-free interval of greater than 2 months. Phase II Trial of Continuous Dose-Intense Temozolomide in Recurrent Malignant Glioma: RESCUE Study Perry JCO 2010

34 Ninety-one patients with GBM Phase II Trial of Continuous Dose-Intense Temozolomide in Recurrent Malignant Glioma: RESCUE Study Perry JCO 2010

35 Comparable to those seen with targeted therapies such as bevacizumab and cediranib,for which 6-month PFS is 25% to 46% Phase II Trial of Continuous Dose-Intense Temozolomide in Recurrent Malignant Glioma: RESCUE Study Perry JCO 2010

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37 Lai et al ASCO 2009 N=75 overall survival secondary TTP and 12-month survival. TMZ+BV until progression or 24 months --- on BV only. Resections frozen tissue (>200mg). MGMT 52/70 patients with ~40% showing methylation. ischemic stroke, pulmonary embolus, wound breakdown, GI bleeding/perforation, and renal dysfunction. Isolated cases of retinal detachment and optic neuropathy

38 Lai et al ASCO 2009 Lai 57 n=70 (31-75) 50% Lai 25 98% 92% 13 89% 58% 17

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42 Phase I/IIa Study of Cilengitide and Temozolomide WithConcomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients WithNewly Diagnosed Glioblastoma Stupp, J Clin Oncol 28: month PFS rate, was 69% an improvement of approximately 15% over TMZ/ RTTMZ alone After a minimum follow-up of 2 years, six patients had not progressed. OS compares favourably median of 16.1 months 2-year survival rate of 35% The benefit limited to GBM with MGMT promoter methylation

43 Ongoing studies Cilengitide: Centric (Merck & EORTC) Bevacizumab AvaGlio (Roche) Diagnosis Step 1: central MGMT methylation status max 28 days MGMT methyl 11/9/2010 MGMT not methyl. or undetermined R Novel strategies / phase II trials Step 2: Randomization versus TMZ Control + Cilengitide Radiotherapy Concomitant Phase Adjuvant (maintenance) Phase R Bevacizumab qow (10 mg/kg) TMZ / RT TMZ / RT Concomitant Phase 43 6 months Adjuvant (maintenance) Phase

44 This study is ongoing, but not recruiting participants

45 Before I came here I was confused about this subject. Now having listened to your lecture, I am still confused, but at a higher level. Enrico Fermi, 1938 Nobel Laureate in Physics