Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial

Sandmann, Thomas; Bourgon, Richard; Garcia, Josep; Li, Congfen; Cloughesy, Timothy F.; Chinot, Olivier; Wick, Wolfgang; Nishikawa, Ryo; Mason, Warren P.; Henriksson, Roger; Saran, Frank; Lai, Albert; Moore, N.; Kharbanda, Samir; Peale, Franklin; Hegde, Priti S.; Abrey, Lauren E.; Phillips, Heidi S.; Bais, Carlos

doi:10.1200/jco.2015.61.5005

Cited by 251 publications

(201 citation statements)

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“…A detailed gene expression analysis of the cohort from the AVAGlio study corroborates this impression; patients with an IDH1 wild-type proneural glioblastoma exhibited an increase in OS of 4.3 months (38). Our previous studies in a relevant number of patients with glioblastoma identified radiological biomarkers suggesting that bevacizumab may exhibit antitumor activity (23,24).…”

Section: Discussionsupporting

confidence: 55%

Bevacizumab as a last-line treatment for glioblastoma following failure of radiotherapy, temozolomide and lomustine

et al. 2017

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Abstract. In previous trials, bevacizumab failed to prolong the overall survival time in newly diagnosed glioblastoma and at the first recurrence. Randomized clinical trials at the second or further recurrence following the failure of radiotherapy, temozolomide and lomustine, and retrospective analyses focusing on this specific cohort, are not yet available. A total of 62 patients with glioblastoma who received bevacizumab after the failure of standard care, including radiotherapy, temozolomide and lomustine, were retrospectively identified. Patient characteristics, previous treatment details, concomitant therapy, response based on the Response Assessment in Neuro-Oncology criteria, and progression-free survival (PFS) and overall survival (OS) times and rates were evaluated. Furthermore, the PFS and OS times and rates were analyzed for responders and non-responders. Of the patients, 54.8% (n=34) responded to treatment [complete response (CR) 3.2%, n=2; partial response (PR) 51.6%, n=32]. The median PFS time was 3.5 months and the median OS time was 7.5 months. The PFS rate at 6 months was 21.5% and the OS rate at 12 months was 11.5%. Responders (CR or PR) experienced a superior median PFS time compared with non-responders (i.e. stable or progressive disease; 5.4 vs. 1.9 months; P<0.0001) and a superior PFS rate at 6 months (34.9 vs. 7.1%; P<0.0001). The median OS time (8.6 vs. 6.4 months; P<0.0001) and OS rate at 12 months (21.3 vs. 0%; P<0.0001) were also superior in patients who exhibited a response to bevacizumab treatment. In conclusion, the objective response rate and the PFS and OS times and rates indicate that bevacizumab has activity in patients with glioblastoma following the failure of radiotherapy, temozolomide, and lomustine. A randomized trial comparing bevacizumab with best supportive care in these patients is advised.

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Section: Discussionsupporting

confidence: 55%

Bevacizumab as a last-line treatment for glioblastoma following failure of radiotherapy, temozolomide and lomustine

et al. 2017

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“…Moreover, the baseline health-related quality of life and performance status were maintained longer and glucocorticoid use was lower in the bevacizumab arm in the AVAglio trial but with more grade 3 and 4 adverse events (66.8% vs. 51.3%). The retrospective analysis of molecular biomarkers in the AVAglio trial showed that patients with both isocitrate dehydrogenase 1 (IDH1) wild-type tumors and proneural pattern of gene expression may have derived 4.3 months of OS benefit with the addition of bevacizumab to a standard regimen (92). Because of the post-hoc nature of this analysis, the predictive effect in relation to bevacizumab treatment must be interpreted with caution.…”

Section: Inhibition Of Angiogenesis In Gbmmentioning

confidence: 99%

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

et al. 2017

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Abstract. Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single antiangiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed.Glioblastoma multiforme (GBM) belongs to the largest group of primary central nervous system (CNS) tumors, so-called gliomas, which are formed from supporting glial cells in the brain parenchyma (1, 2). GBM represents the most common and most malignant tumor in this class, with an incidence of 3-4/100,000/year (3, 4). GBM is an extremely invasive and difficult to treat tumor, characterized by intense and aberrant vascularization and high resistance to radiotherapy (RT) and chemotherapy (CHT). The current standard of care for patients with newly-diagnosed GBM comprises of neurosurgery and subsequent concomitant chemoradiotherapy by fractionated external-beam RT and systemic temozolomide followed by systemic temozolomide in the adjuvant setting (5). There are only very limited possibilities for the treatment of subsequent recurrences, generally with minimal clinical efficacy (6). Despite intensive multimodal treatment strategies, the median survival of patients with GBM is still 12.1-14.6 months and only 3-5% of patients survive longer than 3 years (7).Enormous progress has been made in the genetics and epigenetics of GBM during the past decade. The Cancer 21Τhis article is freely accessible online.Correspondence to: Jiri Polivka, Department of Neurology, Faculty Hospital Plzen, alej Svobody 80, 304 60, Plzen, Czech Republic. E-mail: polivka@fnplzen.cz Key Words: Glioblastoma multiforme, GBM, targeted therapy, immunotherapy, immune checkpoint inhibitors, PD1 inhibition, CTLA4 inhibition, clinical trials, personalized medicine, review. ANTICANCER RESEARCH 37: 21-34 (2017) [8][9][10][11][12]. The most important genetic...

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“…Key molecular signatures defining specific subtypes of glioblastoma proposed and validated by The Cancer Genome Atlas (TCGA) project include Proneural, Neural, Classical and Mesenchymal, based on copy number alterations and expression characteristics of 840 genes, including EGFR, TP53, PDGFRA, IDH1 and [25]. A recently reported analysis in patient tumors from the AVAglio trial showed a statistically significant PFS and OS benefit in patients with Proneural wild-type IDH1 GBM, when bevacizumab was added to standard therapy (17.1 vs 12.8 months with placebo), thus identifying a predictive marker of response to bevacizumab in the newly diagnosed setting [26]. This finding will need to be further validated, ideally in samples from RTOG 0825, and it has practice changing potential.…”

Section: Angiogenesis Inhibition In Newly Diagnosed Gbmmentioning

confidence: 99%

What Next for Newly Diagnosed Glioblastoma?

Domingo-Musibay

Galanis

2015

Future Oncol.

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Glioblastoma is the most common primary brain tumor in adults. Despite current multimodality treatment including surgical resection and temozolomide-based chemoradiotherapy, median survival is only 14-16 months. Characterization of molecular alterations in glioblastoma has identified prognostic subgroups and therapeutic opportunities for clinical trials across glioblastoma subsets. Following a number of negative Phase III trials testing temozolomide dose intensification and angiogenesis inhibition, recent interim analysis data indicate survival prolongation with use of a device (Optune™) delivering alternating electrical field therapy in newly diagnosed glioblastoma patients. In this review, we present an overview of the data supporting the current standard of care and discuss novel experimental therapies in early and late phase clinical testing including devices, small molecule drugs, angiogenesis inhibitors, oncolytic virotherapy and immunotherapy. KEYWORDSGlioblastoma (grade IV astrocytoma) is the most common primary brain tumor in adults. Median survival is 14-16 months after diagnosis, and survival following progression is on average only 6-8 months [1]. The WHO classification of grade IV astrocytomas also includes gliosarcoma, which shares clinical and genetic similarities with glioblastoma, and giant cell glioblastoma, which represents a distinct subset with comparatively better prognosis [2][3][4]. A new version of WHO c lassification incorporating molecular markers is expected to be released in spring 2016.In the past decade, there have been important gains in our understanding of genetic alterations associated with gliomagenesis, although this knowledge to date has not been translated into significant survival improvements. Better understanding of key pathways driving tumor growth and development and the role of the tumor microenvironment extends the promise of further improvements in therapy. Surgery, radiation and chemotherapy have established roles with some room for refinement, but new devices, small molecule cell cycle inhibitors, biologic and immune-based therapies have started yielding promising results in Phase II and early readings of Phase III trials and create optimism for future changes in the treatment landscape and standard of care. Standard-of-care therapyThe standard backbone in the treatment of newly diagnosed glioblastoma is surgical resection, when feasible, followed by radiation therapy (RT) administered concurrently with oral temozolomide (TMZ), followed by six cycles of adjuvant TMZ therapy. RT for glioblastoma has formed the basis of postoperative therapy for decades [5]; developments in radiation delivery techniques have led to the current standard of involved field RT at a dose of 60 Gy delivered in 30 fractions. Increasing RT dose up to 90 Gy has been studied, and it provides no additional benefit regardless of the For reprint orders, please contact: reprints@futuremedicine.com

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Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial

Cited by 251 publications

References 32 publications

Bevacizumab as a last-line treatment for glioblastoma following failure of radiotherapy, temozolomide and lomustine

Bevacizumab as a last-line treatment for glioblastoma following failure of radiotherapy, temozolomide and lomustine

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

What Next for Newly Diagnosed Glioblastoma?

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