Krawczyk Kinga, Śladowska Katarzyna, Holko Przemysław, Kawalec Paweł
Faculty of Health Sciences, Institute of Public Health, Jagiellonian University Medical College, Krakow, Poland.
Department of Nutrition and Drug Research, Faculty of Health Sciences, Institute of Public Health, Jagiellonian University Medical College, Krakow, Poland.
Front Pharmacol. 2023 Sep 7;14:1223929. doi: 10.3389/fphar.2023.1223929. eCollection 2023.
This study aimed to compare the safety profile of tyrosine kinase inhibitors (TKIs) approved for use as monotherapy or combination therapy for the first-line treatment of adult patients with metastatic clear cell renal cell carcinoma (RCC). A systematic review with frequentist network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomized controlled trials (RCTs) investigating the use of: cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib, cabozantinib + nivolumab, lenvatinib + pembrolizumab, axitinib + avelumab, and axitinib + pembrolizumab in previously untreated adult patients with metastatic clear cell RCC. Eligible studies were identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane Library. The risk of bias for RCTs was assessed using the Cochrane Collaboration tool. The P score was used to determine the treatment ranking. The mean probability of an event along with the relative measures of the NMA was considered with the treatment rankings. A total of 13 RCTs were included in the systematic review and NMA. Sorafenib and tivozanib used as monotherapy were the best treatment options. Sorafenib achieved the highest P score for treatment discontinuation due to adverse events (AEs), fatigue, nausea, vomiting of any grade, and hypertension of any grade or grade ≥3. Tivozanib achieved the highest P score for AEs, grade ≥3 AEs, dose modifications due to AEs, and grade ≥3 diarrhea. Sunitinib was the best treatment option in terms of diarrhea and dysphonia of any grade, while cabozantinib, pazopanib, and axitinib + pembrolizumab-in terms of grade ≥3 fatigue, nausea, and vomiting. TKIs used in combination were shown to have a poorer safety profile than those used as monotherapy. Lenvatinib + pembrolizumab was considered the worst option in terms of any AEs, grade ≥3 AEs, treatment discontinuation due to AEs, dose modifications due to AEs, fatigue of any grade, nausea, vomiting, and grade ≥3 nausea. Axitinib + avelumab was the worst treatment option in terms of dysphonia, grade ≥3 diarrhea, and hypertension, while cabozantinib + nivolumab was the worst option in terms of grade ≥3 vomiting. Interestingly, among the other safety endpoints, cabozantinib monotherapy had the lowest P score for diarrhea and hypertension of any grade. The general safety profile, including common AEs, is better when TKIs are used as monotherapy vs. in combination with immunological agents. To confirm these findings, further research is needed, including large RCTs.
本研究旨在比较已获批用于一线治疗成年转移性透明细胞肾细胞癌（RCC）患者的单药治疗或联合治疗的酪氨酸激酶抑制剂（TKIs）的安全性。根据系统评价和Meta分析的首选报告项目指南，进行了一项采用频率论网络Meta分析（NMA）的系统评价。我们纳入了随机对照试验（RCTs），这些试验研究了卡博替尼、帕唑帕尼、索拉非尼、舒尼替尼、替沃扎尼、卡博替尼+纳武单抗、乐伐替尼+帕博利珠单抗、阿昔替尼+阿维鲁单抗以及阿昔替尼+帕博利珠单抗在既往未接受治疗的成年转移性透明细胞RCC患者中的应用。两名评审员在MEDLINE（通过PubMed）、EMBASE和Cochrane图书馆中确定了符合条件的研究。使用Cochrane协作工具评估RCTs的偏倚风险。P值用于确定治疗排名。将事件的平均概率以及NMA的相对测量值与治疗排名一起考虑。系统评价和NMA共纳入了13项RCTs。索拉非尼和替沃扎尼单药治疗是最佳治疗选择。索拉非尼在因不良事件（AEs）、任何级别的疲劳、恶心、呕吐以及任何级别或≥3级高血压导致的治疗中断方面获得了最高的P值。替沃扎尼在AEs、≥3级AEs、因AEs导致的剂量调整以及≥3级腹泻方面获得了最高的P值。舒尼替尼在任何级别的腹泻和声音嘶哑方面是最佳治疗选择，而卡博替尼、帕唑帕尼以及阿昔替尼+帕博利珠单抗在≥3级疲劳、恶心和呕吐方面是最佳治疗选择。联合使用的TKIs显示出比单药治疗更差的安全性。乐伐替尼+帕博利珠单抗在任何AEs、≥3级AEs、因AEs导致的治疗中断、因AEs导致的剂量调整、任何级别的疲劳、恶心、呕吐以及≥3级恶心方面被认为是最差的选择。阿昔替尼+阿维鲁单抗在声音嘶哑、≥3级腹泻和高血压方面是最差的治疗选择，而卡博替尼+纳武单抗在≥3级呕吐方面是最差的选择。有趣的是，在其他安全终点中，卡博替尼单药治疗在任何级别的腹泻和高血压方面的P值最低。当TKIs作为单药治疗而非与免疫制剂联合使用时，包括常见AEs在内的总体安全性更好。为了证实这些发现，需要进一步的研究，包括大型RCTs。
