This study is the first meta-analysis to comprehensively evaluate the effectiveness and safety of IDH inhibitors as a treatment option for cancer. We included a total of four RCTs involving 751 patients with IDH-mutated cancers.

The results of our meta-analysis revealed significant improvements in PFS, ORR, and DCR in the experimental group compared to the control group. However, there was no significant difference in OS and TRAEs between the two groups. The lack of difference in OS outcomes suggests that IDH inhibitors may not confer a survival advantage over other treatment options. However, it is important to note that IDH inhibitors demonstrated remarkable benefits in terms of PFS, ORR, and DCR when compared to alternative therapies.

In terms of safety, over half of the patients receiving IDH inhibitors reported treatment-related adverse events grade 3 or higher (TRAEs ≥ 3), although the incidence was lower than that in the usual care group. Nonetheless, the odds ratios for TRAEs and TRAEs ≥ 3 were not significantly different between the IDH inhibitors group and the conventional treatment group. This suggests that while IDH inhibitors may be associated with a higher incidence of adverse events, the severity of these events is comparable to conventional treatments. Among the most common treatment-related adverse events reported across the included studies, nausea had the highest combined incidence of 30% (105/349) in patients receiving IDH inhibitors. Other common adverse events included increased serum bilirubin, thrombocytopenia, loss of appetite, vomiting, and diarrhea. However, it is important to note that these adverse events can be managed through dose adjustments or discontinuation of IDH inhibitors, glucocorticoid treatment, and supportive care. To ensure early detection and management of adverse events, active monitoring and assessment of patients’ signs and symptoms are crucial. Helpful assessments to consider include high-resolution computed tomography scans, consultations with appropriate specialists, oxygen saturation testing, and any other necessary diagnostic procedures.

While this study aimed to comprehensive evaluation of the effectiveness and safety of IDH inhibitors as a treatment option for cancer patients, it does have some limitations. Firstly, the small number of included articles limited our ability to conduct further subgroup analyses. Secondly, the limited number of patients in the four included studies may affect the reliability of the outcomes. Lastly, the high heterogeneity observed in the analysis results, even with the use of a random effects model, raises concerns about its potential impact on the findings.

In addition, I noticed that when I refer to literature, IDH research is now a lot of practice. For example, in the phase I study using ivosidenib, the researchers observed that patients in the enhanced disease cohort, who had gadolinium contrast material present on their MRI scans, had a longer duration of treatment and better progression-free survival compared to the nonenhanced group. Additionally, a significant proportion of patients in the nonenhanced group achieved remission. It was also noted that after treatment with ivosidenib, there was a decrease in the estimated tumor growth rate in patients with nonenhancing disease [20]. In regards to the role of IDH inhibitors in glioma treatment, there is still ongoing research to fully understand their effectiveness. Results from the ivosidenib study showed that patients treated with this inhibitor experienced prolonged stable disease and a reduction in the growth of non-enhancing tumors. On the other hand, vorasidenib demonstrated an overall response rate of 18% specifically in non-enhancing gliomas.In another recent study, called a phase 1b/2 study, olutasidenib, a selective mutant isocitrate dehydrogenase (mIDH) 1 inhibitor, was tested on 26 patients with recurrent mIDH1 gliomas, which mainly consisted of enhancing tumors. The study reported that the inhibitor was well-tolerated by patients and showed some promising early clinical activity in a group of patients who had received extensive prior treatment. Furthermore, there are ongoing clinical investigations exploring the potential of other mIDH inhibitors such as BAY1436032, DS-1001, LY3410738, and many more. These studies aim to further expand our understanding of IDH inhibitors and their potential role in the treatment of gliomas [21, 22].

Several groups have identified and characterized mutations in the IDH gene in intrahepatic cholangiocarcinoma (iCCA). These mutations occur more frequently in IDH1 than IDH2, and they are known as “hotspot” mutations because they occur at specific points in the gene, specifically the arginine 132 (R132) residue in IDH1 and the arginine 172 (R172) residue in IDH2. These mutations are found at higher rates in iCCA compared to extrahepatic cholangiocarcinoma (CCA) cases. The mutant IDH protein loses its normal enzymatic activity and gains a new ability to produce a metabolite called 2-hydroxyglutarate (2-HG). This oncometabolite can be detected in both the tumor tissue and the bloodstream. Researchers have developed pharmacologic inhibitors that specifically target the mutant forms of IDH, such as IDH1-R132 and IDH2-R172. These inhibitors can effectively block the function of the mutant IDH enzymes at very low concentrations, resulting in a decrease in 2-HG levels. In laboratory studies, IDH inhibitors have shown the ability to inhibit tumor growth in cell lines harboring specific IDH mutations. One such inhibitor, AG-120 (ivosidenib), is a potent oral drug that targets mutant IDH1.

In addition to ivosidenib, other IDH1 and IDH2 inhibitors are currently being evaluated in clinical trials enrolling patients with CCA. These trials aim to further explore the potential of IDH inhibitors as a targeted therapy for this type of cancer. However, it is important to conduct further research in a larger study population to fully understand the effectiveness and safety of these inhibitors.

It is widely believed that the development of AML caused by IDH mutation may be associated with widespread hypermethylation of the entire genome. Consequently, the clinical treatment of AML typically involves the use of chemotherapy, targeted therapy, and hematopoietic stem cell transplantation. Extensive research has revealed that a considerable percentage (ranging from 38 to 86%) of chondrosarcoma cases involve IDH mutations.Furthermore, investigations have demonstrated the high frequency of IDH1 gene mutations (ranging from 60 to 80%) in oligodendroglioma, astroglioma, and secondary glioblastoma. Surprisingly, these mutations are almost entirely absent in primary glioblastoma tumors. Therefore, IDH inhibitors are highly likely to be used in the study of these lesions.

In addition, many new IDH inhibitors are currently under investigation. In 2015, Novartis announced the development of a new compound called IDH305, which is an oral inhibitor currently undergoing Phase I clinical trials. The drug has shown promising results, with an IC50 of 18 nM, indicating its potency in inhibiting the target enzyme. What makes IDH305 particularly impressive is its nearly 200-fold selectivity for mIDH1 R132H mutation over the wild-type IDH1. This selectivity ensures that the drug specifically targets cancer cells with the mutated enzyme while minimizing potential side effects on healthy cells. Prior to the clinical trials, preclinical tests were conducted to evaluate IDH305’s efficacy. These tests demonstrated that the drug effectively reduces the level of 2-HG, a metabolite associated with tumor growth, in tumors. These positive results, combined with the compound’s favorable pharmacokinetic properties, prompted researchers to move forward with the first clinical trial in 2016, registered under the identification code NCT02381886. However, despite the initial clinical trial, there have been no new updates or findings regarding IDH305 in recent years. It is unclear whether the lack of new research data is due to ongoing trials that have not yet released results or if the development of this specific compound has been halted.

In contrast to Novartis’ IDH305, Agios Pharmaceuticals has developed a dual inhibitor called AG-881, targeting both IDH1 and IDH2 mutations. This drug has demonstrated effectiveness against various mutations, including IDH1 R132C, IDH1 R132L, IDH1 R132H, and IDH1 R132S, with IC50 values ranging from 0.04 to 22 nM. Currently, AG-881 is undergoing a Phase 1 trial for solid tumors, including gliomas, with encouraging outcomes for 93 patients. Additionally, clinical trials focusing on advanced hematological malignancies are also underway, indicating AG-881’s potential in treating a broader range of cancers.

Similarly, Bayer has developed a highly selective and potent mIDH1 inhibitor called BAY1436032. This compound shows great promise in the treatment of AML [NCT03127735] and advanced solid tumors [NCT024746081]. However, there is a lack of available clinical reports or updates regarding the outcomes of these trials, leaving the current status and efficacy of BAY1436032 uncertain.

GSK321, another promising mIDH1 inhibitor, has shown high potency in preclinical studies. This compound has the ability to induce myeloid differentiation in IDH1 mutant cells, helping to restore normal cellular function. However, GSK321 is still in the preclinical stage and has yet to enter clinical trials.

Finally, Daiichi Sankyo has reported the development of a mIDH1 inhibitor called DS-1001b, specifically intended for the treatment of chondrosarcoma. Currently, DS-1001b is being studied in clinical trials to assess its effectiveness in treating recurrent or progressive gliomas [NCT03030066]. The results of these trials will shed light on whether DS-1001b can be a viable treatment option for these types of cancers.