Background: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. Methods: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O⁶-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. Results: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. Conclusions: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. Trial registration: NCT00977431 (first posted September 15, 2009).

2023^ Background: Bv plus 1st-line standard of care (SoC; T+RT) achieved a PFS benefit in the AVAglio phase III, randomized, double-blind, placebo [P]-controlled trial in patients (pts) with newly diagnosed GBM. AVAglio includes BM evaluation to identify pts benefiting most from Bv. Analysis of plasma VEGF-A and VEGFR-2 was prioritized based on encouraging findings in Bv trials in several tumor types. Methods: AVAglio includes an optional, exploratory correlative BM analysis; participating pts provided informed consent for BMs. Baseline (BL) plasma samples were analyzed using the Roche IMPACT platform, based on multiplex ELISA technology. Pts were dichotomized according to BM levels using either Q1, median or Q3 cut-offs. Potential interactions between BL BM levels and PFS were tested using Cox regression analyses. Results: Of 921 patients enrolled, 571 (62%) were evaluable in the BM study. Baseline characteristics and PFS outcome were comparable in the ITT and BM-evaluable populations. Median BL VEGF-A and VEGFR-2 levels were 77.0 pg/mL and 12.6 ng/mL, respectively. No significant interaction for PFS was seen at α=0.025. Conclusions: The potential predictive (VEGF-A, VEGFR-2) and prognostic (VEGF-A) value seen in breast, pancreatic and gastric cancers was not apparent in BL BM samples from AVAglio using a median, Q1 or Q3 cut-off. Additional plasma and tumor BM analyses are ongoing. Clinical trial information: NCT00943826. [Table: see text]

Glioblastoma (GB), a prevalent and highly malignant primary brain tumour with a very high mortality rate due to its resistance to conventional therapies and invasive nature, resulting in 5-year survival rates of only 4–17%. Despite recent advancements in cancer management, the survival rates for GB patients have not significantly improved over the last 10–20 years. Consequently, there exists a critical unmet need for innovative therapies. One promising approach for GB is Targeted Alpha Therapy (TAT), which aims to selectively deliver potentially therapeutic radiation doses to malignant cells and the tumour microenvironment while minimising radiation exposure to surrounding normal tissue with or without conventional external beam radiation. This approach has shown promise in both pre-clinical and clinical settings. A review was conducted following PRISMA 2020 guidelines across Medline, SCOPUS, and Embase, identifying 34 relevant studies out of 526 initially found. In pre-clinical studies, TAT demonstrated high binding specificity to targeted GB cells, with affinity rates between 60.0% and 84.2%, and minimal binding to non-targeted cells (4.0–5.6%). This specificity significantly enhanced cytotoxic effects and improved biodistribution when delivered intratumorally. Mice treated with TAT showed markedly higher median survival rates compared to control groups. In clinical trials, TAT applied to recurrent GB (rGB) displayed varying success rates in extending overall survival (OS) and progression-free survival. Particularly effective when integrated into treatment regimens for both newly diagnosed and recurrent cases, TAT increased the median OS by 16.1% in newly diagnosed GB and by 36.4% in rGB, compared to current standard therapies. Furthermore, it was generally well tolerated with minimal adverse effects. These findings underscore the potential of TAT as a viable therapeutic option in the management of GB.

Randomised control trial data support the use of stereotactic radiosurgery (SRS) in up to 4 brain metastases (BMs), with non-randomised prospective data complementing this for up to 10 BMs. There is debate in the neuro-oncology community as to the appropriateness of SRS in patients with >10 BMs. We present data from a large single-centre cohort, reporting survival in those with >10 BMs and in a >20 BMs subgroup. A total of 1181 patients receiving SRS for BMs were included. Data were collected prospectively from the time of SRS referral. Kaplan–Meier graphs and logrank tests were used to compare survival between groups. Multivariate analysis was performed using the Cox proportional hazards model to account for differences in group characteristics. Median survival with 1 BM (n = 379), 2–4 BMs (n = 438), 5–10 BMs (n = 236), and >10 BMs (n = 128) was 12.49, 10.22, 10.68, and 10.09 months, respectively. Using 2–4 BMs as the reference group, survival was not significantly different in those with >10 BMs in either our univariable (p = 0.6882) or multivariable analysis (p = 0.0564). In our subgroup analyses, median survival for those with >20 BMs was comparable to those with 2–4 BMs (10.09 vs. 10.22 months, p = 0.3558). This study contributes a large dataset to the existing literature on SRS for those with multi-metastases and supports growing evidence that those with >10 BMs should be considered for SRS.

Summary: Proton Beam Therapy (PBT) has the potential to improve paediatric cancer care by reducing radiation exposure and thus long‐term toxicities. Ethical concerns and debates surrounding the treatment, such as eligibility and accessibility, are ongoing in Australia. The Australian Bragg Centre for Proton Therapy and Research (ABCPTR) (named after Sir William Henry Bragg who described the Bragg peak in his laboratory at the University of Adelaide in 1903) aims to increase access to PBT in Australasia and offer a patient‐centred care approach. Research is underway to assess PBT's safety and cost‐effectiveness, using tools including Normal Tissue Complication Probability (NTCP) models. Collaborative efforts are focused on developing tailored survivorship clinics to enhance patient follow‐up and quality of life. With the anticipated opening of the ABCPTR, Australia is preparing to take a significant step in radiation oncology, offering new research opportunities and creating a publicly funded treatment centre. The initiative aims to balance treatment efficacy with patient care, setting the stage for a future in which radiation therapy will reduce long‐term side effects compared to the current standard of care. The implementation of PBT in Australia represents a complex and promising approach to paediatric oncology. This article provides an overview of the current landscape, highlighting the potential benefits and challenges of a treatment that could redefine the quality of survivorship and contribute to global research and best clinical practice.