Khagi, Simon

Introduction: Glioblastoma is a fatal intracranial neoplasm that is refractory to treatment, with inevitable disease recurrence and progression to death. Marine-derived compounds, including those found in nutraceutical products, may provide therapeutic benefit in the setting of glioblastoma. We present two patient cases whose courses demonstrate a compelling role for marine-derived products in the management of glioblastoma. Cases: Case 1 describes a patient with MGMT promoter unmethylated glioblastoma who went on to complete standard of care chemoradiation along with concurrent use of a majority sea cucumber (MSC) blend known as SeaCare® (SeaCare, Torrington, CT, USA). Her survival of over 2 years significantly exceeds the recognized median survival time of glioblastoma. Case 2 describes a patient with a complicated course who experienced dramatic improvement after the initiation of the MSC blend, with an exceptional survival time of over 4 years post-diagnosis. Discussion: The mechanisms of marine-derived products that underlie these dramatic clinical effects are likely multifaceted but may hinge on the modification of the tumor immune microenvironment and suppression of tumorigenic effects. Specifically, the change in tumor-associated macrophages (TAMs) within the tumor microenvironment is central to this complex interplay. Conclusions: Ultimately, the use of marine products in the treatment of glioblastoma may present a novel and promising therapeutic strategy that warrants further investigation.

Abstract BACKGROUND Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and METHODS Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results. RESULTS 331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p < 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine. CONCLUSION Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.

Abstract Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as “recruiting” or “not yet recruiting” as of February 2021.

With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel–novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel–novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel–novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel–novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel–novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.