GLIAVAX: A stratified phase II clinical trial of avelumab and axitinib in patients with recurrent glioblastoma.

Neyns, Bart; Salama, Laila Ben; Awada, Gil; Cremer, Jennifer; Schwarze, Julia Katharina; Seynaeve, Laura; Four, Stephanie Du; Fischbuch, Lydia; Vanbinst, Anne‐Marie; Everaert, Hendrik; Michotte, Alex; Rogiers, Anne; Theuns, Peter; Duerinck, Johnny

doi:10.1200/jco.2019.37.15_suppl.2034

Cited by 9 publications

(6 citation statements)

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“…GLIAVAX, a phase II trial of 54 patients with recurrent GBM treated with avelumab and axitinib demonstrated favorable tolerability but did not meet the primary endpoint goal with a 6-month progression-free survival (PFS-6) of only 18%. 79 The addition of pembrolizumab to bevacizumab, a VEGF inhibitor, also did not improve PFS-6. 80 Other TKI combinations being studied with PD-1 blockade include TTAC-001 (VEGFR-2/KDR) and lenvatinib (VEGFR1/2/3).…”

Section: Ctla-4mentioning

confidence: 99%

T lymphocyte-targeted immune checkpoint modulation in glioma

Kelly

Giles

Gilbert

2020

J Immunother Cancer

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Immunomodulatory therapies targeting inhibitory checkpoint molecules have revolutionized the treatment of solid tumor malignancies. Concerns about whether systemic administration of an immune checkpoint inhibitor could impact primary brain tumors were answered with the observation of definitive responses in pediatric patients harboring hypermutated gliomas. Although initial clinical results in patients with glioblastoma (GBM) were disappointing, recently published results have demonstrated a potential survival benefit in patients with recurrent GBM treated with neoadjuvant programmed cell death protein 1 blockade. While these findings necessitate verification in subsequent studies, they support the possibility of achieving clinical meaningful immune responses in malignant primary brain tumors including GBM, a disease in dire need of additional therapeutic options. There are several challenges involved in treating glioma with immune checkpoint modulators including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselective blood brain barrier impairing the ability for peripheral lymphocytes to traffic to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response. To this end, there are now several novel agents targeting more recently uncovered “second generation” checkpoint molecules. Given the multiplicity of drugs being considered for combination regimens, an increased understanding of the mechanisms of action and resistance combined with more robust preclinical and early clinical testing will be needed to be able to adequately test these agents. This review summarizes our current understanding of T lymphocyte-modulating checkpoint molecules as it pertains to glioma with the hope for a renewed focus on the most promising therapeutic strategies.

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Section: Ctla-4mentioning

confidence: 99%

T lymphocyte-targeted immune checkpoint modulation in glioma

Kelly

Giles

Gilbert

2020

J Immunother Cancer

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“…Anderson Cancer Center, 2021). However, avelumab has not seen a similar level of success in GBM, having failed to meet the threshold for justifying further investigation in the GLIAVAX trial testing axitinib and avelumab combination use in rGBM patients following SOC (Neyns et al, 2019). Durvalumab has been FDA approved for bladder cancer and non-small cell lung cancer (NSCLC) and is currently being tested in a phase II trial for newly diagnosed unmethylated GBM patients (Ludwig Institute for Cancer Research, 2021).…”

Section: Anti-pd1/pdl1mentioning

confidence: 99%

Immunotherapy Resistance in Glioblastoma

Wang¹,

Chen²,

Jain³

et al. 2021

Front. Genet.

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Glioblastoma is the most common malignant primary brain tumor in adults. Despite treatment consisting of surgical resection followed by radiotherapy and adjuvant chemotherapy, survival remains poor at a rate of 26.5% at 2 years. Recent successes in using immunotherapies to treat a number of solid and hematologic cancers have led to a growing interest in harnessing the immune system to target glioblastoma. Several studies have examined the efficacy of various immunotherapies, including checkpoint inhibitors, vaccines, adoptive transfer of lymphocytes, and oncolytic virotherapy in both pre-clinical and clinical settings. However, these therapies have yielded mixed results at best when applied to glioblastoma. While the initial failures of immunotherapy were thought to reflect the immunoprivileged environment of the brain, more recent studies have revealed immune escape mechanisms created by the tumor itself and adaptive resistance acquired in response to therapy. Several of these resistance mechanisms hijack key signaling pathways within the immune system to create a protumoral microenvironment. In this review, we discuss immunotherapies that have been trialed in glioblastoma, mechanisms of tumor resistance, and strategies to sensitize these tumors to immunotherapies. Insights gained from the studies summarized here may help pave the way for novel therapies to overcome barriers that have thus far limited the success of immunotherapy in glioblastoma.

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“…Besides PD-1, preliminary results are available from the first two single-arm phase II studies which tested PD-L1 inhibitors in glioblastoma patients using efficacy as primary endpoints. In the first study conducted in recurrent glioblastoma, the combination of anti-PD-L1 antibody avelumab and axitinib (a tyrosine kinase inhibitor selective for VEGF receptors) did not meet the study threshold for activity (six-mo PFS being 18%) [19]. In the second study, the addition of PD-L1 inhibitor durvalumab to SOC resulted in a modest increase of OS for patients with newly diagnosed MGMT-unmethylated glioblastoma (durvalumab 15.1 mo vs. historical controls 12.7 mo) [20].…”

Section: Pd-l1 Inhibitor Trialsmentioning

confidence: 99%

Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives

Weenink

French

Smitt

et al. 2020

Cancers

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Glioblastomas are aggressive, fast-growing primary brain tumors. After standard-of-care treatment with radiation in combination with temozolomide, the overall prognosis of newly diagnosed patients remains poor, with a 2-year survival rate of less than 20%. The remarkable survival benefit gained with immunotherapy in several extracranial tumor types spurred a variety of experimental intervention studies in glioblastoma patients. These ranged from immune checkpoint inhibition to vaccinations and adoptive T cell therapies. Unfortunately, almost all clinical outcomes were universally disappointing. In this perspective, we provide an overview of immune interventions performed to date in glioblastoma patients and re-evaluate their performance. We argue that shortcomings of current immune therapies in glioblastoma are related to three major determinants of resistance, namely: low immunogenicity; immune privilege of the central nervous system; and immunosuppressive micro-environment. In this perspective, we propose strategies that are guided by exact shortcomings to sensitize glioblastoma prior to treatment with therapies that enhance numbers and/or activation state of CD8 T cells.

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GLIAVAX: A stratified phase II clinical trial of avelumab and axitinib in patients with recurrent glioblastoma.

Cited by 9 publications

References 0 publications

T lymphocyte-targeted immune checkpoint modulation in glioma

T lymphocyte-targeted immune checkpoint modulation in glioma

Immunotherapy Resistance in Glioblastoma

Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives

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