Phase II, Open-Label, Randomized, Multicenter Trial (HERBY) of Bevacizumab in Pediatric Patients With Newly Diagnosed High-Grade Glioma

Abstract

Purpose Bevacizumab (BEV) is approved in more than 60 countries for use in adults with recurrent glioblastoma. We evaluated the addition of BEV to radiotherapy plus temozolomide (RT+TMZ) in pediatric patients with newly diagnosed high-grade glioma (HGG). Methods The randomized, parallel group, multicenter, open-label HERBY trial ( ClinicalTrials.gov identifier: NCT01390948) enrolled patients age ≥ 3 years to ≤ 18 years with localized, centrally neuropathology-confirmed, nonbrainstem HGG. Eligible patients were randomly assigned to receive RT + TMZ (RT: 1.8 Gy, 5 days per week, and TMZ: 75 mg/m per day for 6 weeks; 4-week treatment break; then up to 12 × 28-day cycles of TMZ [cycle 1: 150 mg/m per day, days 1 to 5; cycles 2 to 12: 200 mg/m per day, days 1 to 5]) with or without BEV (10 mg/kg every 2 weeks). The primary end point was event-free survival (EFS) as assessed by a central radiology review committee that was blinded to treatment. We report findings of EFS at 12 months after the enrollment of the last patient. Results One hundred twenty-one patients were enrolled (RT+TMZ [n = 59]; BEV plus RT+TMZ [n = 62]). Central radiology review committee-assessed median EFS did not differ significantly between treatment groups (RT+TMZ, 11.8 months; 95% CI, 7.9 to 16.4 months; BEV plus RT+TMZ, 8.2 months; 95% CI, 7.8 to 12.7 months; hazard ratio, 1.44; P = .13 [stratified log-rank test]). In the overall survival analysis, the addition of BEV did not reduce the risk of death (hazard ratio, 1.23; 95% CI, 0.72 to 2.09). More patients in the BEV plus RT+TMZ group versus the RT+TMZ group experienced one or more serious adverse events (n = 35 [58%] v n = 27 [48%]), and more patients who received BEV discontinued study treatment as a result of adverse events (n = 13 [22%] v n = 3 [5%]). Conclusion Adding BEV to RT+TMZ did not improve EFS in pediatric patients with newly diagnosed HGG. Our findings were not comparable to those of previous adult trials, which highlights the importance of performing pediatric-specific studies.

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies

“…More recently, an international randomized phase II clinical trial (HERBY) evaluated the concomitant and adjuvant temozolomide with/without bevacizumab, a recombinant humanized monoclonal anti‐VEGF antibody, in children with newly diagnosed HGG . The addition of bevacizumab did not improve the median EFS and was associated with increased toxicity and treatment discontinuation.…”

“…However, this has not been clearly defined in pHGG, where there have been inconsistent results among different studies: in the CCG‐945 and ACNS0126 cohorts, patients with MGMT‐overexpressing tumors had higher relapse rates, whereas in the ACNS0423 there was no significant difference in EFS or OS based on MGMT expression . In the HERBY trial, the methylation status of the MGMT promoter was not associated with significant differences in survival either . These discrepancies may partly stem from the fact that the use of MGMT immunohistochemistry is not as robust as other methods, such as methylation‐specific PCR and genome‐wide methylation arrays .…”

“…Historically, pHGGs have been classified for data subanalyses in clinical trials as “glioblastomas,” “anaplastic astrocytomas,” and “others”; or, less frequently, as WHO grade IV, III, and mixed grading (II‐III and/or III‐IV). But these distinctions did not provide a good rationale to apply different therapeutic approaches for each subgroup . Advances in the understanding of the molecular biology of pHGG have shown considerable diversity within this group of tumors .…”

“…In the first instance, it is encouraging to find successful examples of pharma‐sponsored academia‐driven pediatric trials directed toward HGG, DIPG, and other advanced/high‐risk solid tumors, such as HERBY, BIOMEDE (NCT02233049), and E‐SMART (NCT02813135). Further collaborations between academia, industry, regulatory agencies, and parent/patient stakeholders, such as the existing international ACCELERATE Platform, will be crucial to help overcome these hurdles.…”

Integrated analysis of long‐term growth and bone development in pediatric and adolescent patients receiving bevacizumab

“…However, in two phase II trials, the addition of bevacizumab to standard therapy for children and adolescents with untreated metastatic soft tissue sarcoma or osteosarcoma did not significantly improve event‐free survival (EFS); its safety profile was consistent with the known safety profile in adults. Similarly, in a phase II trial in pediatric patients with newly diagnosed high‐grade glioma, the addition of bevacizumab to radiotherapy‐temozolomide failed to prolong EFS . Sustained disease control was, however, reported with bevacizumab and irinotecan in children with recurrent low‐grade gliomas in an earlier phase II study …”