Ripretinib for the treatment of adult patients with advanced gastrointestinal stromal tumors

Sargsyan, Amalya; Kucharczyk, Monika A; Jones, Robin L.; Constantinidou, Anastasia

doi:10.1080/17474124.2023.2167711

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…The adverse effect profile of ripretinib is different from that of avapritinib but also found more frequently with increased dose [ 30 ]. In the phase 1 study that included dose escalation and expansion ( n = 179), 13% of the patients ( n = 24) had to discontinue treatment due to treatment-emergent adverse events, with increased lipase level, anemia, hypertension, and abdominal pain being the more common (>5%) of the grade 3/4 adverse events found [ 34 , 35 ]. In the phase 3 INTRIGUE study, comparing ripretinib 150 mg to sunitinib in the second-line setting, only 3.6% of the patients ( n = 223) experienced treatment-emergent adverse events, leading to study treatment discontinuation, while 41.3% of those patients had any grade 3/4 adverse events [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Outcomes of Late-Line Systemic Treatment in GIST: Does Sequence Matter?

Thirasastr,

Sutton,

Joseph

et al. 2024

Cancers

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Ripretinib and avapritinib have demonstrated activity in the late-line treatment of gastrointestinal stomal tumors (GISTs). We investigated whether patients previously treated with ripretinib benefit from avapritinib, and vice versa. Patients diagnosed with metastatic/unresectable GIST and treated with both drugs at two institutions in 2000–2021 were included. Patients were grouped by drug sequence: ripretinib–avapritinib (RA) or avapritinib–ripretinib (AR). Radiographic response was evaluated using RECIST 1.1. Kaplan–Meier and log-rank tests were used to compare time-to-progression (TTP) and overall survival (OS). Thirty-four patients (17 per group) were identified, with a median age of 48 years. The most common primary site was the small bowel (17/34, 50%), followed by the stomach (10/34, 29.4%). Baseline characteristics and tumor mutations were not significantly different between groups. Response rates (RRs) for ripretinib were 18% for RA and 12% for AR; RRs for avapritinib were 12% for AR and 18% for RA. Median TTPs for ripretinib were 3.65 months (95%CI 2–5.95) for RA and 4.73 months (1.87–15.84) for AR. Median TTPs for avapritinib were 5.39 months (2.86–18.99) for AR and 4.11 months (1.91–11.4) for RA. Median OS rates following RA or AR initiation were 29.63 (95%CI 13.8–50.53) and 33.7 (20.03–50.57) months, respectively. Both ripretinib and avapritinib were efficacious in the late-line treatment of GIST, with no evidence that efficacy depended on sequencing.

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Section: Discussionmentioning

confidence: 99%

Outcomes of Late-Line Systemic Treatment in GIST: Does Sequence Matter?

Thirasastr,

Sutton,

Joseph

et al. 2024

Cancers

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“…In the gastrointestinal stromal tumor with an incidence of ~ 1 case per 100,000 per year the proto-oncogenes KIT and PDGFRα are important. For the treatment of advanced and metastatic stages, the tyrosine kinase inhibitor imatinib is indicated [ 55 ]. However, this drug, the first tyrosine kinase inhibitor at all [ 46 ], is not active in all patients since the tumor shows a primary resistance or undergoes secondary resistance due to mutations of the KIT and PDGFRα genes.…”

Section: New Multi-target Drugs In 2022mentioning

confidence: 99%

“…Ripretinib (#2; Fig. 6 i) is a safe and effective new kinase inhibitor, targeting KIT and PDGFRα mutations and resistance (Table 3 ) [ 55 ].…”

Section: New Multi-target Drugs In 2022mentioning

confidence: 99%

Polypharmacology: promises and new drugs in 2022

Ryszkiewicz,

Malinowska,

Schlicker

2023

Pharmacol. Rep

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Polypharmacology is an emerging strategy of design, synthesis, and clinical implementation of pharmaceutical agents that act on multiple targets simultaneously. It should not be mixed up with polytherapy, which is based on the use of multiple selective drugs and is considered a cornerstone of current clinical practice. However, this ‘classic’ approach, when facing urgent medical challenges, such as multifactorial diseases, increasing resistance to pharmacotherapy, and multimorbidity, seems to be insufficient. The ‘novel’ polypharmacology concept leads to a more predictable pharmacokinetic profile of multi-target-directed ligands (MTDLs), giving a chance to avoid drug-drug interactions and improve patient compliance due to the simplification of dosing regimens. Plenty of recently marketed drugs interact with multiple biological targets or disease pathways. Many offer a significant additional benefit compared to the standard treatment regimens. In this paper, we will briefly outline the genesis of polypharmacology and its differences to polytherapy. We will also present leading concepts for obtaining MTDLs. Subsequently, we will describe some successfully marketed drugs, the mechanisms of action of which are based on the interaction with multiple targets. To get an idea, of whether MTDLs are indeed important in contemporary pharmacology, we also carefully analyzed drugs approved in 2022 in Germany: 10 out of them were found multi-targeting, including 7 antitumor agents, 1 antidepressant, 1 hypnotic, and 1 drug indicated for eye disease.

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