Tenosynovial Giant Cell Tumor Treatment Revolution: Vimseltinib's Edge Over Pexidartinib

This paper compares vimseltinib and pexidartinib in treating TGCT, highlighting key differences in their efficacy and safety, with vimseltinib showing better tumor reduction. Vimseltinib is more selective for CSF1R, leading to fewer side effects and no liver toxicity, whereas pexidartinib carries a higher risk of hepatotoxicity. Overall, vimseltinib offers better effectiveness and safety. Dear Editor, Tenosynovial giant cell tumor (TGCT) is a locally aggressive soft tissue tumor that can cause lumps and painful swelling. Overexpression of “colony-stimulating factor 1” in tumor cells leads to the disease, which induces the overproduction of macrophages, cytokine production, and tumor growth [1]. The major treatment approach for TGCT is surgery. However, because of disease recurrence, patients require several operations throughout their lives, which can reduce their quality of life and increase the likelihood of death. Therefore, emphasis has been placed on non-surgical treatment methods, such as “colony-stimulating factor 1 receptor (CSF1R)” inhibitors [2]. CSF1R inhibitors have proven to be effective for treating TGCT patients. These drugs target CSF1R, which can promote TGCT growth. There are two promising medications in this class: Romvimza (vimseltinib) and Turalio (pexidartinib). Pexidartinib was the first CSF1R inhibitor that the U.S. Food and Drug Administration approved for TGCT. It could effectively shrink the tumor but was determined to be associated with a risk of severe liver toxicity. Therefore, vimseltinib was developed as a newer and more selective CSF1R inhibitor with a stronger safety profile and fewer liver-related issues. A comparative analysis of vimseltinib and pexidartinib is needed to determine their relative advantages and guide clinical decision-making for TGCT patients. Vimseltinib was developed through structure-guided drug design and conventional medicinal chemistry methods to suppress CSF1R with little interference with the “kinase insert domain receptor (KIT),” “fms-like tyrosine kinase 3 (FLT3),” and “platelet-derived growth factor receptor (PDGFR)” kinases. In a preclinical study, vimseltinib was shown to be 500-fold more selective for CSF1R, which supported the continuous peripheral inhibition of this target. Although pexidartinib can effectively block CSF1R signaling, it also suppresses KIT, PDGFR, and FLT3, which diminishes its selectivity for CSF1R and elevates side effect risks [3]. When used as a monotherapy, vimseltinib (30 mg) is taken two times per week, at least 72 h apart. Conversely, pexidartinib is taken at a more substantial dose (250 mg) twice per day during the duration of the treatment. This disparity in dosing regimens is also reflective of a substantial difference in price. From the distributor AbMole's website, pexidartinib costs approximately $2700 per week, while vimseltinib is relatively cheaper at approximately $1700 per week [4]. A number of clinical trials have been performed to compare the efficacy and safety of these two medications. ENLIVEN, a clinical trial conducted in 2020, showed that 39% of individuals treated with pexidartinib had at least a 30% reduction in tumor size after taking the drug as prescribed for 24 weeks. However, this trial also showed some negative facts about the drug. Numerous individuals reported nausea, joint pain, and change in taste after taking it. Hair depigmentation was also one of the most frequent side effects of pexidartinib, noted in 83% of individuals. Severe side effects, such as hepatotoxicity, which can prove to be fatal in certain cases, were also observed in some individuals who received the drug [5]. The MOTION Phase 3 trial, which was conducted to examine the effectiveness of vimseltinib, revealed that 40% of the participants receiving the drug had at least a 30% decrease in tumor size at the 25th week of taking the medication. More importantly, the trial revealed that vimseltinib was not associated with any hepatotoxicity, as was seen with pexidartinib. Furthermore, the drug caused fewer side-effects compared with pexidartinib, with reports of people generally suffering from mild-to-moderate periorbital edema, fatigue, and pruritus (itchy skin) [6]. Both vimseltinib and pexidartinib have similar risks when administered in specific patient subgroups. First, animal research has suggested that these medications can potentially cause embryo-fetal injury, as well as pregnancy loss, if taken by pregnant women. Hence, there is a need to advise pregnant women on these risks before initiating the therapy. Second, breastfeeding is highly not recommended while undergoing treatment with these drugs. Moreover, animal studies have also indicated some cases of impaired fertility in both males and females [7]. The comparison between vimseltinib and pexidartinib has also identified key differences in selectivity and safety. Vimseltinib's higher specificity for CSF1R reduces off-target activity against KIT, FLT3, and PDGFR. The MOTION Phase 3 trial reported a slightly higher tumor reduction rate using vimseltinib (40%) compared with using pexidartinib (39%) in the ENLIVEN trial, alongside a significantly reduced risk of hepatotoxicity. Therefore, the better safety profile and higher tumor reduction rate suggest that vimseltinib is a more appropriate drug for treating TGCT. However, because these recent clinical trials only represent short-term treatment data, long-term trials and studies need to be conducted to fully evaluate the extended effects of the drug. Treatment with vimseltinib can significantly improve the quality-of-life of non-surgical candidates. The healthcare community should continue to evaluate these therapies to optimize TGCT management and enhance patient outcomes. Muhammad Affan Abid: conceptualization (equal), formal analysis (equal), resources (equal), supervision (equal), writing – original draft (equal), writing – review and editing (equal). Syed Azfar Hussain: methodology (equal), writing – original draft (equal), writing – review and editing (equal). Muhammad Ali Kamal: investigation (equal), visualization (equal), writing – original draft (equal). The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. Data are openly available in a public repository that issues datasets with DOIs.