Standard versus personalized schedule of regorafenib in metastatic gastrointestinal stromal tumors: a retrospective, multicenter, real-world study

Abstract

Background Despite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off). Patients and methods Institutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan–Meier method was used to estimate survival and the log-rank test to make comparisons. Results Of a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months [95% confidence interval (CI) 3.73-11.0 months] versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively [hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052]. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16). Conclusions Regorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy.

Exploring the Dynamic Crosstalk between the Immune System and Genetics in Gastrointestinal Stromal Tumors

“…GISTs with c-KIT exon 9 mutation are, instead, more sensitive to an increased dose of imatinib of 800 mg/die [14,18,21]. For patients with metastatic GIST progressing on IM, sunitinib, regorafenib, and ripretinib as second-, third-and fourth-line treatments, respectively, clinically improve objective response and PFS [22][23][24][25][26][27][28]. For PDGFRA exon 18 D842V-mutated GIST, which results in primary resistance to IM, avapritinib is a valid therapeutic option [29].…”

The Role of Regorafenib in the Management of Advanced Gastrointestinal Stromal Tumors: A Systematic Review

“…A prospective Taiwanese study of 28 patients revealed an mPFS of 4.44 months and an OS of 29.34 months [ 27 ]. Nannini et al (2021) compared the standard versus personalized dosing regimens for advanced GIST in a retrospective multicenter study, resulting in mPFS of 5.6 months (95% CI 3.73-11.0 months) versus 9.7 months (95% CI 7.9-14.5 months), respectively (HR 0.51; 95% CI 0.34-0.75; P = 0.00052), and a mOS of 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16) [ 30 ]. The latest Japanese study by Teranishi et al (2022) demonstrated 23.8 months of median OS and an 80% rate of one-year OS, along with 7.1 months of mPFS and a 40.2% rate of one-year PFS [ 33 ].…”

“…ROBINS-I: Risk of Bias In Non-randomised Studies -of InterventionsStudy CharacteristicsThe standard treatment regimen in all studies was the same: regorafenib 160 mg/daily in four-week cycles with three weeks on medication and one week off of it Nannini et al (2021). assessed the effect of personalized dose reductions and temporary interruptions to control and prevent drug-related adverse events[30].…”

“…ROBINS-I: Risk of Bias In Non-randomised Studies -of InterventionsStudy CharacteristicsThe standard treatment regimen in all studies was the same: regorafenib 160 mg/daily in four-week cycles with three weeks on medication and one week off of it Nannini et al (2021). assessed the effect of personalized dose reductions and temporary interruptions to control and prevent drug-related adverse events[30]. The second phase III RCT performed byKang et al (2021) evaluated the avapritinib vs. regorafenib for patients with locally advanced, unresectable, and/or metastatic GIST previously treated with imatinib and one or two other TKIs (excluding avapritinib and regorafenib)[24].…”

Neuropsychiatric Adverse Drug Reactions with Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors: An Analysis from the European Spontaneous Adverse Event Reporting System

“…Considering their different mechanisms of action, including the development of secondary resistance mutations, TKIs differ in their effectiveness and safety profile [ 20 ] and in some adverse events (AEs) such as skin and gastrointestinal toxicity with IM [ 21 ]; anemia, hand foot syndrome, and hypertension with SU [ 22 ]; anemia, cognitive effects, and periorbital edema with AVA [ 23 ]; hand-foot skin reaction, hepatotoxicity, and hypertension with REG [ 24 ]; myalgia, palmar-plantar erythrodysesthesia syndrome (PPES), and weight loss with RIP [ 25 ].…”