安维汀在中枢神经系统转移性肿瘤患者的安全性分析课件

Bevacizumab safety in patients with central nervous system metastases Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr U-P Clin Cancer Res 2010;16:26978 Untreated CNS metastases, no longer a contraindication for bevacizumab in Europe 1. Gordon, et al. J Clin Oncol 2001 2. Besse, et al. Clin Cancer Res 2010 3. Avastin SmPC, Roche Products Limited, 2010 19972009Over 577,000 patients exposed to bevacizumab* *Up to February 2009 CNS = central nervous system Single patient with HCC experiences fatal cerebral haemorrhage from undiagnosed brain metastasis in a Phase I bevacizumab study1 Wealth of safety data analysed, particularly from patients with occult CNS metastases at study entry or patients developing CNS metastases during disease progression2 Exclusion of patients with CNS metastases from bevacizumab trials Contraindication of bevacizumab for patients with untreated CNS metastases removed from the European Summary of Product Characteristics3 Rationale for conducting a review of the safety of bevacizumab in patients with CNS metastases lConsiderable volume of bevacizumab safety data now available, particularly in patients with occult CNS metastases at study entry or patients developing CNS metastases during disease progression1 lIn patients with NSCLC and CNS metastases treated with bevacizumab, the risk of tumour-associated CNS haemorrhage was reported to be similar to rates in control patients with metastases who did not receive bevacizumab2 lAvailability of phase II data supporting the use of bevacizumab in the treatment of high-grade glioma has called into question the exclusion of patients from bevacizumab clinical trials35 1. Besse, et al. Clin Cancer Res 2010; 2. Archer, et al. J Clin Oncol 2008 (abstract) 3. Bokstein, et al. Cancer 2008; 4. Desjardins, et al. Clin Cancer Res 2008; 5. Lai, et al. Int J Radiat Oncol Biol Phys 2008 Retrospective exploratory analysis of safety data from three datasets Besse, et al. Clin Cancer Res 2010 *Cases with occult or new CNS metastases were identified post study entry In ATLAS and PASSPORT, 26 and 115 patients, respectively, had treated CNS metastases and 25 and 106 of these patients, respectively, were evaluable for safety Retrospective exploratory safety analysis A: Randomised controlled trials 13 Phase II/III trials (completed) across several indications (n=8,443) Patients with CNS metastases at baseline excluded 187 patients* with CNS metastases; 91 bevacizumab-treated B: Open-label, single-arm, safety studies C: Prospective studies SAiL and ATHENA studies in NSCLC and breast cancer (n=4,382) Patients with CNS metastases at baseline excluded 321 patients* with CNS metastases; all bevacizumab-treated ATLAS and PASSPORT studies in NSCLC (n=845) Patients with pre-treated CNS metastases (whole-brain radiation therapy/neurosurgery) included 131 patients with CNS metastases; all bevacizumab treated Dataset A: 13 randomised controlled trials Besse, et al. Clin Cancer Res 2010 *Patients with known CNS metastases at baseline were excluded; cases with occult or new CNS metastases were identified post-randomisation MedDRA basket “intracranial haemorrhage” v10.1 8,443 patients enrolled 4,760 patients received bevacizumab Cut-off date: March 31, 2008 187 patients (2.2%) with CNS metastases identified* Review of patient history for cerebral haemorrhages Bevacizumab: 91 patients CRC: n=16 NSCLC: n=36 Breast cancer: n=28 Other: n=11 Non-bevacizumab: 96 patients CRC: n=18 NSCLC: n=43 Breast cancer: n=22 Other: n=13 CRC: n=3,382 NSCLC: n=1,952 Breast cancer: n=1,885 RCC: n=641 Pancreas: n=583 Dataset A: low incidence of cerebral haemorrhage in patients with CNS metastases* Cerebral haemorrhage Bevacizumab (n=91) Non-bevacizumab (n=96) All grades, n (%)3 (3.3)1 (1.0) Grade 4, n30 Grade 5, n01 *Patients with known CNS metastases at baseline were excluded; cases with occult or new CNS metastases were identified post-randomisationBesse, et al. Clin Cancer Res 2010 Dataset A: similar mortality rate for patients with CNS metastases in the bevacizumab and control groups* Bevacizumab (n=91) Non-bevacizumab (n=96) Mortality from time of randomisation to death (%) 30-day mortality 60-day mortality 90-day mortality 0 1 3 1 3 5 Mortality from time of diagnosis of CNS metastasis to death (%) 30-day mortality 60-day mortality 90-day mortality 16 33 55 19 31 51 Besse, et al. Clin Cancer Res 2010 *Patients with known CNS metastases at baseline were excluded; cases with occult or new CNS metastases were identified post-randomisation Dataset B: open-label, single-arm, safety trials ATHENA and SAiL Primary objective of both studies was to assess the safety profile of bevacizumab as first-line treatment in a broader population of patients ATHENA* N=2,216 CNS metastases n=140 SAiL* N=2,166 CNS metastases n=181 Safety population: 4,382 patients CNS metastases: 321 patients Treat until disease progression Besse, et al. Clin Cancer Res 2010 *Cut-off: March 2009 Patients with known CNS metastases at baseline were excluded; cases with occult or new CNS metastases were identified post study entry Breast cancer (locally recurrent/metastatic) First-line bevacizumab + taxane-based chemotherapy NSCLC (advanced/recurrent non-squamous) First-line bevacizumab + platinum-based chemotherapy Dataset B: low overall incidence of cerebral haemorrhage in patients with CNS metastases In both studies, bleeding events were recorded up to 6 months after the last bevacizumab infusion Cerebral haemorrhage, n (%) Patients receiving bevacizumab (n=321) All grades3 (0.9) Grade 12 (0.6) Grade 31 (0.3) Besse, et al. Clin Cancer Res 2010 Dataset C: Prospective PASSPORT study including patients with treated CNS metastases at baseline lPrimary objective was to assess the rate of symptomatic CNS haemorrhage grade 2 during bevacizumab therapy lPatients with CNS metastases were permitted to enter the trial after treatment with whole CNS radiation therapy and/or neurosurgery followed by confirmation of absence of progression or CNS haemorrhage, either clinically or by CT/MRI PASSPORT* Open-label, single arm, phase II study Non-squamous NSCLC and treated CNS metastases (N=115) First- or second-line bevacizumab + chemotherapy or erlotinib according to institutional standards until PD n=106 *Cut-off June 2008 Permitted concomitant treatment included low-dose aspirin, therapeutic heparin/warfarin and corticosteroids Safety-evaluable population Socinski, et al. J Clin Oncol 2009 Besse, et al. Clin Cancer Res 2010 Dataset C: Prospective ATLAS study including patients with treated CNS metastases at baseline lPatients with a history of CNS metastases were eligible for enrolment if they had received treatment with whole brain radiation therapy and/or neurosurgery No PD Evaluable population in dataset C (PASSPORT + ATLAS) Safety population: 845 patients CNS metastases: 131 patients ATLAS* Randomised, double-blind, placebo-controlled, Phase IIIb study Locally advanced/recurrent/ metastatic NSCLC First-line bevacizumab + platinum-based chemotherapy (4 cycles) N=730 Treated CNS metastases n=25 R Bevacizumab + erlotinib until PD Bevacizumab + placebo until PD *Cut-off October 2007 Safety-evaluable population Permitted concomitant treatment included low-dose aspirin and therapeutic heparin; dexamethasone and warfarin not permitted Besse, et al. Clin Cancer Res 2010 Dataset C: low incidence of cerebral haemorrhage in patients with CNS metastases1 lPatients were followed up for adverse events for 30 days (ATLAS)2 or 60 days (PASSPORT)3 after discontinuation of study treatment lMedian number of bevacizumab treatment cycles was 5 in PASSPORT and 4 in ATLAS (range 117 cycles for both) Cerebral haemorrhage, n (%) Safety-evaluable patients receiving bevacizumab (n=131) All grades, n (%)1 (0.8) Grade 2, n (%)1 (0.8) 1. Besse, et al. Clin Cancer Res 2010 2. Akerley, et al. J Clin Oncol 2008 (abstract) 3. Socinski, et al. J Clin Oncol 2009 No difference in rate of cerebral haemorrhage in treated and untreated CNS metastases lIn SAiL and ATHENA, three cases of cerebral haemorrhage were reported in 321 patie