Rindopepimut

Historically, the central nervous system (CNS) was considered an immune-privileged organ. However, recent studies have shown that the immune system plays a significant role in the CNS. Thus, there is renewed interest in applying cancer immunotherapy to CNS malignancies with the hope of generating a robust anti-tumor immune response and creating long-lasting immunity in patients. There has been some work with non-specific immunotherapy such as IL-2 for brain metastasis. Unfortunately, the results from non-specific immunotherapy studies were lackluster, so the focus has shifted to more specific CNS immunotherapies including cancer vaccines, immune checkpoint inhibitors, oncolytic virus therapy, and chimeric antigen receptor (CAR) T cell therapy. With respect to cancer vaccines, rindopepimut has been well-studied in glioblastoma (GBM) patients with the EGFRvIII mutation, with early results from phase II trials showing possible efficacy in carefully selected GBM patients. Other antigen-specific CNS tumor vaccines are still in the early stages. Immune checkpoint inhibitors are amongst the most promising and widely studied CNS immunotherapy strategies. Anti-PD-1 showed promising results in many non-CNS solid tumors, however, results from early clinical trials show poor efficacy for anti-PD-1 in GBM patients. Anti-PD-1 is also under investigation for CNS metastasis and showed some efficacy in non-small cell lung cancer and renal cell carcinoma patients. Anti-PD-1 is under early stage investigation for other CNS tumors such as chordoma. Oncolytic virus therapy is the strategy of infecting tumor cells with a virus that in turn triggers an innate immune response leading to tumor cell lysis. Oncolytic viruses currently under investigation include several adenovirus-based therapies and a herpes simplex virus-based therapy. Phase I studies have demonstrated the safety of oncolytic virus therapies in GBM patients. Current studies are evaluating the efficacy of these therapies both alone and in combination with other immunotherapy approaches such as checkpoint inhibition in patients with CNS tumors. CAR T cell therapy is a newer immunotherapy approach. CAR T cell therapies, directed against EGFRvIII mutation and HER-2 mutation, demonstrate an acceptable safety profile, although there is no conclusive evidence of the survival benefit of these therapies in early trials. Studies are currently underway to determine optimal tumor-specific antigen selection and modality of administration for CAR T cell therapy. Overall, the prognosis is generally poor for patients with CNS malignancies. The promising results of cancer immunotherapy for non-CNS tumors have created significant interest in applying these therapies for CNS malignancies. Preliminary results have not demonstrated robust efficacy for CNS immunotherapy. However, it is important to keep in mind that the field is still in its infancy and many clinical trials are still early-phase. Several, clinical trials are currently underway to further explore the role of immunotherapy for CNS malignancies.

Despite the fact that bevacizumab (Bev) has been approved to treat recurrent glioblastoma, patients have failed to demonstrate a significant overall survival (OS) advantage. In recent years, the advent of more Bev combination regimens seems to bring new hope for patients; nevertheless, there is still a lack of intuitive comparison among these therapies.

To explore the efficacy and safety of various Bev combination regimens in patients with recurrent glioblastoma and to further explore the differences in the efficacy of each treatment in randomized controlled trials (RCTs) and nonrandomized controlled trials (non-RCTs).

We comprehensively searched the PubMed, Cochrane Library, and OVID databases for relevant RCTs and non-RCTs of Bev in combined regimens for recurrent glioblastoma. The Cochrane quality assessment method was used to assess the quality of RCTs, and the Newcastle-Ottawa scale was used to assess the quality of non-RCTs. Excel software was used to extract data from the literature, and a network meta-analysis was performed using RevMan 5.3 and Stata 16 statistical software.

In patients with recurrent glioblastoma, the 6-month OS of patients receiving bevacizumab combination therapy was ranked from high to low as follows: Bev + rindopepimut, Bev + lomustine (CCNU), CCNU, tumor treating fields + Bev, Bev, Bev + irinotecan (Iri), Bev + temozolomide (TMZ), Bev + vorinostat, Bev + onartuzumab, Bev + dasatinib, Bev + carboplatin, Bev + trebananib, Bev + VB-111, TMZ, PCV, VB-111, and carboplatin. The 6-month progression-free survival from high to low was ranked as follows: Bev + CCNU, Bev + rindopepimut, Bev + dasatinib, Bev + vorinostat, Bev, Bev + Iri, Bev + TMZ, CCNU, Bev + carboplatin, TMZ, Bev + VB-111, PCV, Bev + trebananib, carboplatin, and VB-111. We compared the total incidence of serious adverse events (≥3) and found that Bev + vorinostat and Bev + trebananib were safer than Bev, while other regimens were not as safe as Bev. A descriptive analysis showed that Bev + rindopepimut also appeared to be safer than Bev. In subgroup analysis, among RCTs, Bev + CCNU therapy had the highest 6-month OS and 6-month progression-free survival. Among non-RCTs, Bev + Iri therapy showed the highest 6-month OS and good 6-month progression-free survival.

Both Bev + CCNU and Bev + rindopepimut could be considered as effective therapies for treating the recurrent glioblastoma according to the network meta-analysis results. Among them, Bev + rindopepimut therapy seems to be safer and more effective. Moreover, we found that Bev + Iri also appeared to be an effective therapy in a retrospective study.