Bevacizumab and daily temozolomide for recurrent glioblastoma

BACKGROUND:

The authors performed a phase 2 trial of combined protracted daily temozolomide and biweekly bevacizumab for patients with recurrent glioblastoma who had previously received radiation therapy and temozolomide.

METHODS:

There was no limit on the number of previous disease progressions or previous regimens allowed. Thirty‐two adult patients were enrolled. Patients received temozolomide 50 mg/m² daily and bevacizumab 10 mg/kg intravenously every 14 days. Patients underwent physical examination and brain magnetic resonance imaging every 8 weeks.

RESULTS:

The authors observed a 6‐month progression‐free survival (PFS) rate of 18.8% (95% confidence interval [CI], 7.6%‐33.7%) and a median PFS of 15.8 weeks. The median overall survival (OS) was 37 weeks, the 6‐month OS rate was 62.5% (95% CI, 43.5%‐76.7%), and the 12‐month OS rate was 31.3% (95% CI, 16.4%‐47.3%). Nine patients (28%) had a radiographic response, and 7 patients (22%) had disease progression within the first 8 weeks of treatment. Patterns of progression were available for 21 patients. The authors observed that 52% of patients (n = 11) progressed locally, 38% (n = 8) progressed with a diffuse pattern, and 10% (n = 2) progressed at a distant site. Two patients discontinued therapy secondary to toxicity (prolonged thrombocytopenia and grade 4 pancreatitis). One patient experienced grade 5 pneumonia.

CONCLUSIONS:

The current study demonstrated that a regimen of combined daily temozolomide and biweekly bevacizumab had some activity and was well tolerated. However, the results obtained in this study were inferior to those observed in studies of bevacizumab monotherapy and of combined irinotecan and bevacizumab therapy. The current patient population was more heterogeneous and was pretreated more heavily than patients in previous studies. Cancer 2012;. © 2011 American Cancer Society.     

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study

Background:

We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial.

Methods:

A total of59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg⁻¹ bevacizumab biweekly and 50 mg m⁻² etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2α (HIF-2α) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome.

Results:

Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade ⩾3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism.

Conclusion:

Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).     

贝伐单抗治疗胶质母细胞瘤的进展

贝伐单抗作为全球第一个抗血管生成的单克隆抗体,2009年被FDA批准用于胶质母细胞瘤的挽救治疗,之后贝伐单抗治疗新诊断的胶质母细胞瘤成为众多学者研究的焦点,但最新的研究结果并不支持它在胶质母细胞瘤的一线治疗中应用。     

Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy

BACKGROUND:

The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open‐label, single‐arm trial was evaluated.

METHODS:

Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml‐min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m² for patients on CYP3A enzyme‐inducing anti‐epileptics [EIAEDs] and 125 mg/m² for patients not on EIAEDs) were administered on days 1 and 14 of every 28‐day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression‐free survival at 6 months (PFS‐6), and secondary end points included safety and median overall survival (OS).

RESULTS:

All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0‐7.0 months) and PFS‐6 rate was 16% (95% CI, 5.0%‐32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment‐related deaths.

CONCLUSIONS:

Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously. Cancer 2011;. © 2011 American Cancer Society.     

Emerging clinical principles on the use of bevacizumab for the treatment of malignant gliomas

Despite advances in adjuvant therapy, the prognosis for most patients with high‐grade glioma (HGG) is poor, and almost all HGGs have a likelihood of disease recurrence. HGGs are highly vascularized tumors with elevated expression levels of vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. A compelling biologic rationale, a pressing need for improved therapeutics and positive results from studies of bevacizumab in other tumor types, led to the evaluation of bevacizumab in the treatment of HGG. It was demonstrated previously that bevacizumab, which is a humanized monoclonal antibody that targets VEGF, improved outcomes when combined with chemotherapy (most commonly irinotecan) in patients with recurrent HGG; and, on the basis of an improved objective response rate in 2 prospective phase 2 studies, bevacizumab was granted accelerated approval by the US Food and Drug Administration as a single agent in patients with previously treated glioblastoma (GB). Bevacizumab‐containing therapy has been associated with manageable, class‐specific toxicity; however, severe treatment‐related adverse events are observed in a minority of patients. Preliminary data on bevacizumab‐based therapy in recurrent anaplastic gliomas, in the frontline treatment of GB, and in additional patient populations are also encouraging. With the goal of addressing unanswered questions regarding the optimal use of bevacizumab, the objective of the current review was to provide a summary of the clinical efficacy and safety data on bevacizumab in patients with HGG, the practical issues surrounding the administration of bevacizumab, and ongoing investigations of bevacizumab in additional brain tumor treatment settings. Cancer 2010. © 2010 American Cancer Society.     

Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors

Agents targeting the vascular endothelial growth factor (VEGF) pathway are being used with increasing frequency in patients with recurrent high-grade glioma. The effect of more than one antiangiogenic therapy given in succession has not been established. We reviewed the efficacy of bevacizumab, a VEGF-A monoclonal antibody, in patients who progressed following prior therapy with VEGF receptor tyrosine kinase inhibitors (R-TKi). Seventy-three patients with recurrent high-grade gliomas received VEGF R-TKi (cediranib, sorafenib, pazopanib, or sunitinib) as part of phase I or II clinical trials. Twenty-four of these patients with glioblastoma progressed and received bevacizumab-containing regimens immediately after R-TKi. Those who stopped R-TKi therapy for reasons other than disease progression, or received a treatment that did not include bevacizumab, were excluded from the analysis. The efficacy of bevacizumab-containing regimens in these 24 patients was evaluated. During R-TKi therapy, 6 of 24 patients (25%) had a partial response (PR) to treatment. The 6-month progression-free survival (APF6) was 16.7% and median time-to-progression (TTP) was 14.3 weeks. Grade III/IV toxicities were seen in 13 of 24 patients (54%). Subsequently with bevacizumab salvage therapy, 5 of 24 patients (21%) had a PR, the APF6 was 12.5%, and the median TTP was 8 weeks. Five of 24 patients had grade III/IV toxicities (21%). The median overall survival (OS) from the start of R-TKi therapy was 9.2 months (range: 2.8–34.1+), whereas the median OS after bevacizumab was 5.2 months (range: 1.3–28.9+). Bevacizumab retains modest activity in high-grade glioma patients who progress on R-TKi. However, the APF6 of 12.5% in this cohort of patients indicates that durable tumor control is not achieved for most patients.     

Bevacizumab--current status and future directions.

Angiogenesis is crucial to tumour initiation, survival and metastasis. Vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic factors in cancer development. Bevacizumab (a humanised monoclonal antibody against VEGF) has a reasonable safety profile and proven efficacy in a phase III trial in advanced colorectal cancer. Efficacy of Bevacizumab also looks promising in non small cell lung cancer, renal cancer and a variety of other solid tumours. Questions still surround optimal dosing and the appropriate selection of patients who are most likely to benefit. Future trials will address these questions and provide further translational insights.     

新药贝伐单抗的临床应用进展

血管内皮生长因子（VEGF）在肿瘤血管生成过程中起着关键作用,并已成为抗肿瘤治疗的重要靶点。贝伐单抗为重组人源化抗VEGF的单克隆抗体,其治疗肿瘤具有良好的效果。目前,FDA已批准贝伐单抗用于转移性结直肠癌、转移性乳腺癌、晚期非小细胞肺癌、转移性肾细胞癌的一线治疗。除此之外,贝伐单抗在肝癌、胃癌、食管癌等其他恶性肿瘤的应用也取得令人鼓舞的结果。现就贝伐单抗在多种恶性肿瘤中的临床应用作一综述。     

Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab

Background

Currently, there are no known effective treatments for recurrent glioblastoma once patients have progressed on a bevacizumab-containing regimen. We examined the efficacy of adding nitrosoureas to bevacizumab in patients who progressed while on an initial bevacizumab-containing regimen.

Methods

In this retrospective study, we identified adult patients with histologically confirmed glioblastoma (WHO grade IV) who were treated with lomustine or carmustine in combination with bevacizumab as a second or third regimen after failing an alternative initial bevacizumab-containing regimen. Response rate (RR), 6-month progression free survival (PFS6), and progression-free survival (PFS) were assessed for each treatment.

Results

Forty-two patients were identified (28 males) with a median age of 49 years (range, 24–78 y). Of 42 patients, 28 received lomustine (n = 22) or carmustine (n = 6) with bevacizumab as their second bevacizumab-containing regimen, and 14 received lomustine (n = 11) or carmustine (n = 3) as their third bevacizumab-containing regimen. While the median PFS for the initial bevacizumab-containing regimen was 16.3 weeks, the median PFS for the nitrosourea-containing bevacizumab regimen was 6.3 weeks. Patients had an RR of 44% and a PFS6 rate of 26% during the initial bevacizumab regimen and an RR of 0% and a PFS6 rate of 3% during the nitrosourea-containing bevacizumab regimen. There was increased grade 3–4 toxicity (45% vs 19%, P = .010) during the nitrosourea-containing bevacizumab regimen relative to the initial bevacizumab regimen. Median overall survival was 18.7 weeks from initiation of the nitrosourea-containing bevacizumab regimen.

Conclusion

The addition of lomustine or carmustine to bevacizumab after a patient has already progressed on a bevacizumab-containing regimen does not appear to provide benefit for most patients and is associated with additional toxicity with the doses used in this cohort.     

Bevacizumab and oxaliplatin-based chemotherapy in metastatic colorectal cancer

In metastatic colorectal cancer disease progression correlates with serum VEGF levels. The importance of VEGF in tumor-induced angiogenesis is well described in preclinical models. In this review we discuss the role of anti-VEGF therapy in combination with oxaliplatin-based chemotherapy for the treatment of metastatic colorectal cancer. A recent Phase III clinical trial in patients with metastatic colorectal cancer demonstrated the efficacy of FOLFOX4 in combination with bevacizumab, a recombinant humanized monoclonal antibody with high binding specificity for VEGF, to improve median overall survival when used as second-line therapy. The major adverse events associated with bevacizumab include grade III hypertension, bleeding and the risk of gastrointestinal perforation. Combining bevacizumab with oxaliplatin-based chemotherapy as first-line treatment for patients with metastatic colorectal cancer improves progression-free survival, as seen in the NO16966 and Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) studies, when compared with placebo and historical controls, respectively. Future research will need to focus on the mechanisms whereby bevacizumab enhances the benefit of chemotherapy to identify predictive markers that better define which patient populations will benefit the most from treatment.     

Bevacizumab in high-grade gliomas: past,present, and future

The survival of patients with high-grade gliomas (anaplastic gliomas and glioblastoma) remains poor despite current treatment modalities. However, an enhanced understanding of gliomagenesis is supporting the development of targeted molecular therapies with the potential for improving clinical outcomes. Glioblastoma (GBM) is characterized by extensive microvascular proliferation and the production of large amounts of VEGF. Bevacizumab is a humanized IgG1 monoclonal antibody that selectively binds with high affinity to human VEGF and neutralizes VEGF’s biologic activity. Preclinical data indicate that angiogenesis is essential for the proliferation and survival of GBM cells. A number of studies have evaluated the outcomes of both newly diagnosed and recurrent GBM patients with bevacizumab in a prospective manner. Here, we discuss the role of bevacizumab in the treatment of anaplastic gliomas and GBM in the recurrent and upfront setting.     

Bevacizumab-based therapy in relapsed glioblastoma: rationale and clinical experience to date

Relapsed glioblastoma (GBM) has an extremely poor prognosis and remains an invariably fatal disease, with a median overall survival of 6–7 months. Despite numerous clinical trials over the past 20–30 years, treatment options for relapsed GBM remain limited. In recent years, significant research efforts have focused on the use of antiangiogenic therapies for the treatment of GBM. Bevacizumab is a humanized monoclonal antibody that specifically inhibits the proangiogenic VEGF, with well-established clinical efficacy in a number of solid malignancies, which is now under investigation for the treatment of GBM. In this review, we discuss the available data regarding bevacizumab-based therapy in relapsed GBM, highlighting its potential and ongoing challenges in this difficult-to-treat disease.     

Bevacizumab and irinotecan in recurrent malignant glioma,a single institution experience

Background

Treatment options of recurrent malignant gliomas are very limited and with a poor survival benefit. The results from phase II trials suggest that the combination of bevacizumab and irinotecan is beneficial.

Patients and methods.

The medical documentation of 19 adult patients with recurrent malignant gliomas was retrospectively reviewed. All patients received bevacizumab (10 mg/kg) and irinotecan (340 mg/m² or 125 mg/m²) every two weeks. Patient clinical characteristics, drug toxicities, response rate, progression free survival (PFS) and overall survival (OS) were evaluated.

Results

Between August 2008 and November 2011, 19 patients with recurrent malignant gliomas (median age 44.7, male 73.7%, WHO performance status 0–2) were treated with bevacizumab/irinotecan regimen. Thirteen patients had glioblastoma, 5 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. With exception of one patient, all patients had initially a standard therapy with primary resection followed by postoperative chemoradiotherapy. Radiological response was confirmed after 3 months in 9 patients (1 complete response, 8 partial responses), seven patients had stable disease and three patients have progressed. The median PFS was 6.8 months (95% confidence interval [CI]: 5.3–8.3) with six-month PFS rate 52.6%. The median OS was 7.7 months (95% CI: 6.6–8.7), while six-month and twelve-month survival rates were 68.4% and 31.6%, respectively. There were 16 cases of hematopoietic toxicity grade (G) 1–2. Non-hematopoietic toxicity was present in 14 cases, all G1-2, except for one patient with proteinuria G3. No grade 4 toxicities, no thromboembolic event and no intracranial hemorrhage were observed.

Conclusions

In recurrent malignant gliomas combination of bevacizumab and irinotecan might be an active regimen with acceptable toxicity.     

Bevacizumab plus erlotinib in Chinese patients with untreated,EGFR-mutated,advanced NSCLC (ARTEMIS-CTONG1509): A multicenter phase 3 study

1. Download : Download high-res image (205KB)
2. Download : Download full-size image

     

Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells

In various cell types, the neuro- and endocrine peptide somatostatin induces inhibitory and anti-secretory effects. Since somatostatin receptors, especially of the subtype sst2A, are constantly over-expressed in gliomas, we investigated the influence of somatostatin and the receptor subtype-selective peptide/non-peptide agonists octreotide and L-054,522 on the secretion of the most important angiogenesis factor produced by gliomas, vascular endothelial growth factor (VEGF). Cultivated cells from solid human gliomas of different stages and glioma cell lines secreted variable amounts of VEGF, which could be lowered to 25% to 80% by co-incubation with somatostatin or sst2-selective agonists (octreotide and L-054,522). These effects were dose-dependent at nanomolar concentrations. Stimulation with different growth factors (EGF, bFGF) or hypoxia considerably increased VEGF production over basal levels. Growth factor-induced VEGF synthesis could be suppressed to <50% by co-incubation with somatostatin or an sst2-selective agonist; this was less pronounced in hypoxia-induced VEGF synthesis. The effects were detected at the protein and mRNA levels. These experiments indicate a potent anti-secretory action of somatostatin or sst2 agonists on human glioma cells that may be useful for inhibiting angiogenesis in these tumors.     

Angiogenesis and vascular targeting in Ewing sarcoma

Ewing sarcoma is the second most common type of bone cancer in children and young adults. In recent years, the mechanisms by which these tumors develop and maintain their vascular supply have been elucidated. Additional work has demonstrated that inhibition of angiogenic pathways or disruption of established vasculature can attenuate the growth of Ewing sarcoma mouse xenografts. Early clinical data suggest that these results also may extend to patients with Ewing sarcoma who are treated with antiangiogenic or antivascular therapies. For the current review, the authors summarized the available data supporting this approach. Cancer 2010. © 2009 American Cancer Society.     

Anti-VEGF therapy: a new approach to colorectal cancer therapy

The purpose of this review is to discuss the inhibition of vascular endothelial growth factor as a treatment for advanced colorectal cancer. The review will begin by summarizing the theory behind vascular endothelial growth factor inhibition and how this affects tumor angiogenesis. The major clinical trials that have examined antivascular endothelial growth factor agents to treat patients with advanced colorectal cancer will then be described. Finally, there is a commentary regarding the status of targeted agents currently in development for the treatment of advanced colorectal cancer and a discussion of the potential future considerations for the use of antivascular endothelial growth factor agents in clinical practice.     

雌激素与贝伐单抗等因子对SKBR-3乳腺癌细胞VEGF表达影响观察

目的：观察不同浓度雌激素对SKBR-3乳腺癌细胞血管内皮生长因子（vascularendothelialgrowthfactor,VEGF）表达的影响,并探讨不同浓度雌激素作用条件下,贝伐单抗（VEGF单抗）、曲妥珠单抗（HER-2单抗）、紫杉醇和胰岛素样生长因子1受体（insulin-likegrowthfactorreceptor,IGF-1R）抗体对SKBR-3乳腺癌细胞VEGF表达的影响。方法：利用RT-PCR方法检测SKBR-3乳腺癌细胞在不同浓度雌激素以及VEGF单抗（0．5μg／mL）、HER-2单抗（0．04μg／mL）、紫杉醇（1．5μg／mL）和IGF-1R抗体（2．5μg／mL）作用下,SKBR-3乳腺癌细胞VEGF的表达状况,利用ELISA方法检测培养液上清中VEGF蛋白浓度。结果：1）无雌激素组SKBR-3乳腺癌细胞VEGF表达为1．0618±0．0085（vEGF／GAPDH,下同）,低浓度雌激素（0．05μg／mL,）组为1．0047±0．0061,差异有统计学意义,P=0．002,高浓度雌激素（O．2μg／mL）组为1．0868±0．0135,差异有统计学意义,P〈0．001。2）用与不用紫杉醇SKBR-3乳腺癌细胞VEGF表达分别为1．0496±0．0288和1．0618±0．0085,F=0．058;用与不用IGF=1R单抗为1．0884±0．0036和1．06184-0．0085,F=0．073;用与不用HER-2单抗分别为0．9887±0．0037和1．0618±0．0085,F=0．075;同时,在应用紫杉醇、IGF1R单抗、HER-2单抗基础上加用雌激素VEGF表达不受影响。3）用与不用VEGF单抗SKBR-3乳腺癌细胞VEGF表达分别为1．0057±0．0043、1．0618±0．0085,差异有统计学意义,F=0．132,P=0．04;但雌激素与VEGF单抗对VEGF表达影响没有协同作用。结论：不同雌激素浓度对SKBR-3乳腺癌细胞VEGF表达影响明显;紫杉醇、IGF-1R单抗和HER-2单抗不影响SKBR3乳腺癌细胞VEGF表达,与雌激素也无协同作用;VEGF单抗升高VEGF表达,也与雌激素没有协同作用。