A 2/1 Sunitinib Dosing Schedule Provides Superior Antitumor Effectiveness and Less Toxicity Than a 4/2 Schedule for Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis

Abstract

Background: The standard sunitinib schedule to treat metastatic renal cell carcinoma (mRCC) is 4 weeks on/2 weeks off (4/2). However, some studies revealed intolerable adverse events (AEs) in patients on this schedule. An alternative schedule, 2 weeks on/1 week off (2/1), may overcome this issue. This meta-analysis was performed to compare the effectiveness and toxicity between the 2/1 and 4/2 sunitinib dosing schedules. Methods: We acquired relevant studies by searching PubMed, ScienceDirect, the Cochrane Library, Scopus, Ovid MEDLINE, Embase, Web of Science, and Google Scholar. Our main endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and AEs. Results: We identified 9 medium-and high-quality studies. Both schedules were effective for mRCC, with comparable OS and similar ORR. However, the 2/1 schedule had better PFS (hazard ratio (HR) = 0.81, 95% confidence interval [CI]: 0.66-0.99, P = 0.04), higher DCR [risk rate (RR) = 1.22, 95% CI: 1.01-1.47, P = 0.04] and fewer dosage interruptions (RR = 0.60, 95% CI: 0.43-0.84, P = 0.003). Additionally, the 2/1 schedule elicited fewer specific severe AEs, including thrombocytopenia/platelet disorder, hand-foot syndrome, hypertension, and fatigue. In our subanalysis, PFS was better among East Asians using the 2/1 schedule than among other populations (HR= 0.75, 95% CI: 0.58-0.98, P = 0.03), and patients administered an initial dosage of 50 mg/d on the 2/1 schedule had superior PFS (HR = 0.76, 95% CI: 0.59-0.97, P = 0.03) than those others. Conclusions: These findings suggest that the 2/1 schedule is more suitable for mRCC than 4/2, due to superior PFS, better DCR and fewer AEs. Nevertheless, more large-scale studies with good quality are needed.

Balancing the Risk-Benefit Ratio of Immune Checkpoint Inhibitor and Anti-VEGF Combination Therapy in Renal Cell Carcinoma: A Systematic Review and Meta-Analysis

“…Since renal disorder is an independent risk factor for cardiovascular disease ( 46 ), combination therapy may increase the burden on the kidney, resulting in direct damage to renal tubules because podocytes and tubular cells widely express VEGF, leading to continuous drug accumulation and hypertension ( 15 , 47 ). A significantly increased risk of developing hypertension was detected among RCC patients with continuous daily dosing compared with the intermittent dosing schedule ( 48 , 49 ). Recently, anti-VEGF treatment was recognized as a potential trigger for an increased incidence of cardiovascular toxicity ( 50 ).…”

Systematic review and cost-effectiveness of pharmacokinetically guided sunitinib individualized treatment for patients with metastatic renal cell carcinoma

“…Based on the available evidence, the 2/1 schedule is relatively more effective and safer than the 4/2 schedule, and is feasible way to maintain drug level. 29,30 Comparison of intermittent versus continuous dosing regimens revealed that CDD does not have any advantage over 4/2 schedule in terms of the incidence or severity of AEs or patient-reported outcomes. 18…”

Bruton’s Tyrosine Kinase (BTK) Inhibitor RN486 Overcomes ABCB1-Mediated Multidrug Resistance in Cancer Cells

“…Furthermore, the cytotoxicity experiments excluded RN486 is a substrate of ABCB1. In addition, even though some ABCB1 inhibitors were identified as stimulators in ATPase assay of ABCB1, ABCB1 overexpression might not necessarily cause drug resistance to those inhibitors ( Cui et al, 2019a ; Wu et al, 2020 ). The reasons for unchanged ATPase activity with 0-10 μM RN486 may vary included additional interactions between RN486 with inhibitor binding site.…”