ripretinib
Regulatory sources consulted
Approved indications
- In adults with advanced gastrointestinal stromal tumor who previously received three or more kinase inhibitors, including imatinib.
Contraindications
Absolute
- Hypersensitivity to ripretinib or its excipients.
Clinical warnings
- Major warning · It can cause palmar-plantar erythrodysesthesia. Withhold and restart at the same or reduced dose according to grade, recovery time, and recurrence. — CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001
- Major warning · It can cause new primary cutaneous malignancies. Perform dermatologic evaluation at treatment start and routinely during treatment; excise and evaluate suspicious lesions. — DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78d
- Major warning · Control blood pressure before and during treatment; do not start with uncontrolled hypertension. Assess ejection fraction before and during treatment as clinically indicated and permanently discontinue for Grade 3–4 left ventricular systolic dysfunction. — DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78d
- Major warning · Withhold for at least 1 week before elective surgery and do not administer for at least 2 weeks after major surgery or until adequate wound healing. Limit ultraviolet exposure during treatment and for 1 week afterward. — DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78d
Drug interactions
- ModerateStrong CYP3A inhibitors
Mechanism: They increase exposure to ripretinib and its active metabolite.
Recommendation: If combined, monitor adverse reactions more frequently.
DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78dhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f18e462-03dd-4296-a02a-a0577e3ee78d
- HighStrong or moderate CYP3A inducers
Mechanism: They reduce exposure and may decrease antitumor activity.
Recommendation: Avoid the combination. If a moderate inducer is unavoidable, use 150 mg twice daily with monitoring.
DailyMed, QINLOCK set_id 9f18e462-03dd-4296-a02a-a0577e3ee78dhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f18e462-03dd-4296-a02a-a0577e3ee78d
- ModerateBCRP inhibitors
Mechanism: They may increase ripretinib or active-metabolite concentrations.
Recommendation: Use the combination cautiously and monitor adverse reactions.
CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001https://cima.aemps.es/cima/dochtml/ft/1211569001/FT_1211569001.html
- ModerateNarrow-therapeutic-index CYP3A, CYP1A2, or UGT1A substrates
Mechanism: Ripretinib may increase exposure to these substrates.
Recommendation: Use the combination cautiously and monitor substrate concentration, efficacy, and toxicity.
CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001https://cima.aemps.es/cima/dochtml/ft/1211569001/FT_1211569001.html
- ModerateNarrow-therapeutic-index CYP2B6 substrates
Mechanism: CYP2B6 induction may reduce their exposure and efficacy.
Recommendation: Monitor substrate response and coordinate adjustments if efficacy is lost.
CIMA/AEMPS, ficha técnica QINLOCK 50 mg, registro 1211569001https://cima.aemps.es/cima/dochtml/ft/1211569001/FT_1211569001.html
Adverse events
Common (≥1%)
alopecia · fatigue · nausea · abdominal pain · constipation · myalgia · diarrhea · decreased appetite · palmar-plantar erythrodysesthesia · vomiting
Rare but serious
melanoma · cardiac failure
Pregnancy and lactation
It can cause embryo-fetal harm. Verify pregnancy before starting. Females and males with partners who can become pregnant must use effective contraception during treatment and for 1 week afterward. If systemic hormonal contraceptives are used, add a barrier method. It may impair male fertility. Do not breastfeed during treatment or for 1 week afterward.
Recent literature (PubMed)
Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.
To provide an accessible, comprehensive overview of past, present, imminent, and future therapies for systemic mastocytosis. Based on recent trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved two drugs for treating advanced systemic mastocytosis: avapritinib and midostaurin. The FDA also approved imatinib for selected cases of aggressive systemic mastocytosis without the D816V c-Kit mutation. Moreover, for the first time, a cytoreductive molecule, avapritinib, has been approved for patients with indolent systemic mastocytosis. Despite the considerable therapeutic progress in recent years, systemic mastocytosis is an incurable disease. In the last 20 years, the management of systemic mastocytosis has transformed from a one-size-fits-all approach, characterized by nonspecific cytoreductive drugs, to a tailored strategy focused on increasingly precise molecular targets, with the most notable example being the KIT inhibitors. Recently, the FDA and EMA have approved two drugs for treating systemic mastocytosis: avapritinib and midostaurin. Moreover, numerous trials are currently assessing the efficacy of new molecules: most are testing new-generation KIT inhibitors (ripretinib, bezuclastinib, elenestinib, masitinib, nintedanib), others focusing on Bruton's kinase (TL-895), interleukin-6 (sarilumab), sialic acid-binding immunoglobulin-like lectin-8 (lirentelimab), mTOR and CD33, among others. Real-life data are needed to confirm preliminary preclinical results.
This review discusses the current and future landscape of advanced gastrointestinal stromal tumor (GIST) treatment. It covers the role of tyrosine kinase inhibitors (TKIs), specifically imatinib, and further treatment options, such as sunitinib, regorafenib, and ripretinib, as well as avapritinib for platelet-derived growth factor receptor alpha D842V mutations. In addition, this review emphasizes individualized treatment strategies within multidisciplinary expert teams, including surgery and other locoregional therapies, together with the importance of mutation-guided approaches, particularly for wild-type GISTs. Finally, it explores the potential of next-generation KIT inhibitors, combination therapies, and other investigational approaches.
Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501). Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib (KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability. Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ri