Gliomas - Emerging treatments | BMJ Best Practice

Dordaviprone

Dordaviprone is a small molecular protease activator that activates the enzyme CIpP (mitochondrial caseinolytic protease P) and inhibits the dopamine D2/3 receptor. Dordaviprone is approved by the US Food and Drug Administration (FDA) (accelerated approval) for the treatment of patients aged ≥1 year with diffuse midline glioma harbouring an H3 K27M mutation with progressive disease following prior therapy.[21][60] Approval was based on positive results from five open-label clinical studies of 50 patients with recurrent H3 K27M-mutant diffuse midline glioma, which found dordaviprone monotherapy to be well tolerated, and demonstrating lasting and clinically meaningful efficacy.[70] The ACTION trial, a phase 3 randomised controlled trial (RCT) to assess the safety and efficacy of dordaviprone in patients with newly diagnosed H3 K27M-mutant diffuse glioma, is ongoing.[71]

Tovorafenib

Tovorafenib is an oral type II RAF kinase inhibitor that has central nervous system penetration. It inhibits mutant BRAF V600, wild-type BRAF, and wild-type CRAF kinases. It inhibits signalling through RAF-mediated pathways, such as the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, which regulate cell proliferation. Somatic mutations in BRAF, which affect signalling through this pathway, are common in pilocytic astrocytomas. As a result of the phase 2 FIREFLY-1 trial, tovorafenib is approved by the USFDA (accelerated approval) for the treatment of patients ≥6 months of age with relapsed or refractory paediatric low-grade glioma harbouring a BRAF fusion or rearrangement, or BRAF V600E mutation. The FIREFLY-1 trial assessed the response to tovorafenib monotherapy in patients aged 1-24 years with BRAF-altered relapsed or refractory paediatric low-grade glioma. The overall response rate was 67%; median duration of response was 16.6 months; and median time to response was 3 months. The most common treatment-related adverse events were hair colour changes (76%), elevated creatinine phosphokinase (56%), and anaemia (49%). Seven percent of patients discontinued tovorafenib therapy due to treatment-related adverse events.[72] Tovorafenib has been granted orphan drug designation by the EMA.

Trametinib plus dabrafenib

The combination of trametinib (a mitogen-activated extracellular kinase [MEK] inhibitor) and dabrafenib (a BRAF kinase inhibitor) is approved by the USFDA and EMA for the treatment of patients ≥1 year of age with low-grade glioma with a BRAF V600E mutation who require systemic therapy. The combination is also approved by the EMA (but not the USFDA) for the treatment of patients ≥1 year of age with high-grade glioma with a BRAF V600E mutation who have received at least one prior radiation and/or chemotherapy treatment. The safety and efficacy of trametinib plus dabrafenib for low-grade glioma was evaluated in a multicentre, open-label trial in patients with BRAF V600E mutation-positive low-grade glioma aged 1 to <18 years. The overall response rate was 47%; median duration of response was 24 months; and median progression-free survival was 20 months. The most common treatment-related adverse events were pyrexia and fatigue.[73]

Other isocitrate dehydrogenase inhibitors

Along with vorasidenib (which is already recommended for the treatment of gliomas in select patients), other isocitrate dehydrogenase (IDH) inhibitors, such as ivosidenib, safusidenib, and olutasidenib are being investigated as potential treatments for IDH-mutant gliomas.[7][74] In a phase 1 dose escalation and expansion study, ivosidenib was given to 66 patients with IDH1-mutant advanced gliomas. The drug was well tolerated with no dose-limiting toxicities, and was associated with prolonged disease control and reduced growth of non-enhancing tumours.[75] Subsequently, retrospective studies into real world use of ivosidenib in patients with IDH1-mutant gliomas of different grades have shown favourable results, with patients without enhancing disease generally having a better response.[74][76]

Other targeted molecular therapies

These therapies are based on specific tumour molecular markers. Regorafenib, an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases, was associated with increased survival compared with lomustine in patients with recurrent glioblastoma in one phase 2 RCT.[27][77] Cyclin-dependent kinase (CDK) inhibitors such as abemaciclib, palbociclib, ribociclib, and zotiraciclib are undergoing clinical trials for the treatment (alone and in combination with other agents) of newly diagnosed and recurrent glioma.[7][27][78] The proteasome inhibitor marizomib is being evaluated, alone and in combination with bevacizumab, for the treatment of recurrent grade 4 glioblastoma.[27][79][80]

Therapies targeting DNA damage response pathways

Several inhibitors of the DNA damage response are being evaluated, alone and in combination with other agents (e.g., temozolomide). These include poly(ADP-ribose) polymerase inhibitors such as olaparib, pamiparib (BGB-290), and niraparib.[7][27][81]

Immunotherapies

Immunotherapies being investigated for treating glioma include immune checkpoint inhibitors, viral therapies, vaccines, and cellular therapies.[7][27] One phase 3 trial comparing nivolumab (an anti-programmed cell death protein 1 [PD1] antibody) with bevacizumab in patients with recurrent glioblastoma showed no difference in median overall survival.[82] Other anti-PD1 checkpoint inhibitors with effectiveness in treating other cancers that are being assessed for glioma include avelumab, pembrolizumab, and durvalumab.[7][27] Anti-epidermal growth factor receptor (EGFR) therapies for glioblastoma (e.g, rindopepimut, an EGFRvIII peptide vaccine) have not proved effective so far.[27][83] [ ] Ongoing trials with ipilimumab, an antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), are focused on combining it with other immunotherapy agents.[27][84] Viral therapies include vocimagene amiretrorepvec (Toca 511) combined with flucytosine; however, in one randomised, open-label phase 2/3 trial with patients with recurrent glioblastoma, vocimagene amiretrorepvec/flucytosine did not improve overall survival or other efficacy end points compared with standard of care (lomustine, temozolomide, or bevacizumab).[85] One phase 3 non-RCT reported that treatment with autologous tumour lysate-loaded dendritic cell vaccination was associated with improved overall survival in patients with newly diagnosed or recurrent glioblastoma compared with standard of care.[86] Vaccines are also being evaluated for IDH-mutant gliomas, with vaccine-induced immune responses observed in 93.3% of patients in one phase 1 trial.[87] Other vaccine trials are ongoing.[7][27] Cellular therapies being explored include chimeric antigen receptor (CAR) T-cell therapy and the natural killer (NK) cell therapy CYNK-001.[27][88][89]

Other therapies

It is estimated that around 100 therapies are under evaluation for diffuse gliomas.[27] These include cytotoxic agents such as lisavanbulin (BAL101553) and VAL-083; agents that may augment temozolomide activity, such as ibudilast; and demethylating agents such as ASTX727 (oral decitabine and cedazuridine) and 5-azacytidine.[7][27][90][91][92][93] Various combination approaches are also being investigated.[7][27]