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Table of Contents
DRUG REVIEW
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 93-98

Ripretinib: A narrative drug review


1 Department of Pharmacy Practice, Amrita Institute of Medical Science and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
2 Department of Medical Oncology, Amrita Institute of Medical Science and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India

Date of Submission02-Oct-2020
Date of Decision30-Oct-2020
Date of Acceptance18-Jan-2021
Date of Web Publication26-Mar-2021

Correspondence Address:
Keechilat Pavithran
Department of Medical Oncology, Amrita Institute of Medical Science and Research Centre, Amrita Vishwa Vidyapeetham, Kochi - 682 041, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_308_20

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  Abstract 


Gastrointestinal stromal tumors (GISTs) are rare primary neoplasms of the gastrointestinal tract, mesentery, or omentum. In the past, for patients with resectable tumors, surgery was the only viable treatment option. However, therapy of GISTs has undergone a fundamental change with the advent of receptor tyrosine kinase inhibitors primarily targeting the tyrosine-protein kinase KIT and the platelet-derived growth factor receptor alpha (PDGFRA). Ripretinib is one such novel Type-II tyrosine switch control inhibitor which is used in the treatment of advanced KIT proto-oncogene-driven and PDGFRA-induced tumors, including GISTs. The Food and Drug Administration approved ripretinib on May 15, 2020, for the treatment of adult patients with progressive GISTs who had undergone prior treatment with three or more kinase inhibitors. A comprehensive search in PubMed and other sources were done, using the search terms, “GIST” and ripretinib. On combining all the abstracts and conference proceedings, here we present a comprehensive review on ripretinib's history, pharmacology, and clinical applications.

Keywords: Gastrointestinal stromal tumor, platelet-derived growth factor receptor, ripretinib, tyrosine kinase inhibitors, tyrosine kinase proto-oncogene


How to cite this article:
Kumar SS, Philip A, Pavithran K. Ripretinib: A narrative drug review. Cancer Res Stat Treat 2021;4:93-8

How to cite this URL:
Kumar SS, Philip A, Pavithran K. Ripretinib: A narrative drug review. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Apr 23];4:93-8. Available from: https://www.crstonline.com/text.asp?2021/4/1/93/312080




  Introduction Top


Gastrointestinal stromal tumors (GISTs) are a result of oncogenic mutations in the KIT proto-oncogene or platelet-derived growth factor receptor alpha (PDGFRA). These tumors commonly occur in the gastrointestinal tract, primarily in the small intestine or stomach and are derived from specialized cells called interstitial cells of Cajal found in the smooth muscle layer. GISTs are found most frequently in adults aged between 40 and 70 years and are relatively rare in younger adults and individuals aged below 18 years. The common symptoms of GIST include weight loss, nausea, abdominal pain, loss of appetite, tiredness, weakness, vomiting, black and tarry stools, and bleeding which may lead to anemia (general).[1],[2],[3],[4],[5]

The development of small-molecule inhibitors against receptor tyrosine kinases has radically changed the treatment paradigm for KIT/PDGFRA-mutant GISTs.[6] Ripretinib, a novel, type-II tyrosine switch control inhibitor, was developed for the treatment of KIT/PDGFRA-driven tumors. Ripretinib mainly inhibits both wild and mutant forms of KIT and PDGFRA, as well as other kinases such as platelet-derived growth factor receptor beta (PDGFRB), tyrosine-protein kinase receptor 2 (TIE2), vascular endothelial growth factor receptor 2 (VEGFR2), and the BRAF proto-oncogene. It was first approved by the US Food and Drug Administration (FDA) in 2020 for the treatment of adult patients with advanced GISTs who had progressed on at least three prior lines of therapy with conventional tyrosine kinase inhibitors (TKIs). However, development of resistance to the approved KIT/PDGFRA inhibitors poses a clinical challenge. Ripretinib is currently being tested in various ongoing clinical trials, and the growing evidence of its effectiveness in several trials suggests that it may significantly improve the outcomes with no additional toxicity in patients with advanced GIST.[7],[8],[9],[10],[11] Ripretinib is also being investigated in the treatment of systemic mastocytosis and gliomas. Avapritinib is another TKI that targets PDGFRA and KIT, in addition to other proteins. It was the first drug approved for the treatment of advanced GISTs that harbor mutations in the exon 18 (including D842V) of the PDGFRA gene.[12] The aim of this review is to provide an update regarding the most recently approved treatment of GIST. Here, we briefly cover the mechanism of action, indications, and toxicities of ripretinib and the major pivotal trials. A summary of the key features of ripretinib is presented in [Table 1].
Table 1: Key features of ripretinib

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  Methods Top


We searched the PubMed database and the proceedings of the meetings of the American Society of Clinical Oncology, European Society for Medical Oncology, and American Association for Cancer Research. We searched for articles that were published between 2005 and 2020. We used the search terms “GIST” and “Ripretinib.” We limited our search to articles published in the English language. A flowchart of the search strategy adopted is presented in [Figure 1]. All the articles and abstracts were first screened by two authors (S. S. K and A. P). Drug approval news, case reports, case series, and retrospective studies were excluded. After the database search, S. S. K and A. P. identified 21 articles. Thereafter, S. S. K and K. P. separately screened the titles and abstracts of 23 articles to identify the eligible studies. After assessing the quality of the potentially eligible articles and abstracts, 21 were selected, and their data are presented in this review.
Figure 1: Flowchart illustrating the search methodology

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  Overview of Clinical Trials Top


  • Several studies are underway for determining the effectiveness and safety of ripretinib in adult patients with GISTs. Its FDA approval was based on the INVICTUS study, a randomized, international, multi-center, double-blind, placebo-controlled, Phase III clinical trial. The aim of this trial was to test the drug as a fourth-line therapeutic agent (after imatinib, sunitinib, and regorafenib) in GISTs. In this trial, the efficacy of ripretinib was tested in 129 patients with advanced GISTs who had received at least three prior lines of therapy. Patients were randomized in a 2:1 ratio to receive either ripretinib (n = 85) 150 mg or placebo (n = 44) orally once a day until disease progression or the development of unbearable toxic effects. The primary outcome was progression-free survival (PFS) based on a blinded-independent central review (BICR). The study endpoints were objective response rate (ORR) determined using the modified response evaluation criteria in solid tumors (mRECIST) and overall survival (OS). In this trial, the median PFS in the ripretinib arm was 6.3 months, while that for patients in the placebo arm was 1 month. Ripretinib decreased disease progression or the risk of death by 85%. The ORR was 9% in the ripretinib arm and 0 in the placebo arm. The updated results showed that the median OS in the ripretinib arm was not reached (95% confidence interval [CI], 13.1–NE), whereas it was 6.3 (95% CI 4.1–10.0) months in the placebo arm. The drug lowered the mortality rate by 57%. The adverse effects of the drug were alopecia, vomiting, nausea, abdominal pain, fatigue, myalgia, diarrhea, constipation, reduced appetite, and the palmar-plantar erythrodysesthesia syndrome[13],[14],[15],[16],[17]
  • The Phase I study of ripretinib consisted of a dose-escalation phase followed by an expansion phase with a recommended phase-II dose (RP2D). Patients included in this study had advanced GISTs that were intolerant to or had progressed on one or more lines of therapy and other advanced tumors. A total of 258 patients (n = 184 with GIST) were enrolled in the study, of which 68 were in the dose-escalation phase. The maximum tolerated dose was not reached, and 150 mg daily was established as the R2PD. On combining the safety and efficacy data of the patients from the dose-escalation and expansion phases, ripretinib was found to be well tolerated. Ripretinib resulted in an ORR of 11.3% (ranging from 7.2% in the fourth line to 19.4% in the 2nd line). The median PFS achieved from the use of ripretinib ranged from 5.5 months in the fourth line to 10.7 months in the 2nd line setting.[18],[19]
  • The phase III trial, INTRIGUE is an ongoing randomized, open-label study comparing the effectiveness of ripretinib and sunitinib in patients with GISTs who have progressed on or are intolerant to the first-line agent, imatinib. The primary endpoint of this trial is PFS as evaluated by a BICR using mRECIST. This pivotal trial will explore the role of ripretinib as a 2nd-line therapy compared to the standard 2nd-line drug, sunitinib. The study is expected to close by June 2021.[20]


The details of the clinical trials comparing placebo with ripretinib in patients with advanced GISTs are summarized in [Table 2].
Table 2: Clinical trials evaluating the role of ripretinib in advanced gastrointestinal stromal tumor

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  History Top


Ripretinib was designated as an orphan drug for GIST in 2014, and Phase I studies were initiated in 2015. It is the first novel medication officially approved as a 4th-line agent for GIST. It was approved by the FDA on May 15, 2020, for use in adult patients with advanced GIST beyond the third line.


  Chemistry Top


Ripretinib is a kinase inhibitor of both the wild type and mutated forms of the tumor-associated antigen, mast/stem cell factor receptor KIT, and PDGFRA with possible antineoplastic activity.

IUPAC name: N-{4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl}-N'-phenylurea.

Molecular formula: C24H21BrFN5O2.

Molecular weight: 510.4 g/mol.

The chemical structure of ripretinib is shown in [Figure 2].
Figure 2: Chemical structure of Ripretinib (Source: National center for biotechnology information. Pubchem database. Ripretinib, CID = 71584930. https://pubchem.ncbi.nlm.nih.gov/compund/ripretinib

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  Physical Properties Top


  • White to off-white colored crystalline solid
  • Lipophilic
  • Weak base
  • Insoluble in aqueous media.



  Dosage Forms and Strength Top


  • 50 mg oval tablet.



  Mechanism of Action Top


Ripretinib is a switch control inhibitor of the KIT proto-oncogene and PDGFRA. In vitro studies have shown that ripretinib can also inhibit other kinases such as PDGFRB, TIE2, VEGFR2, and BRAF. KIT and PDGFRA have an inhibitory switch in the intracellular juxtamembrane domain and an activation switch in the kinase domain. Ripretinib serves as a functional substitute for the inhibitory switch by binding to the inhibitory switch pocket. This prevents the switch pocket from being accessed by the activation loop, thereby locking the kinase into an inactive state. In addition, ripretinib binds to the activation loop further preventing its access to the switch pocket and blocking the kinase activity. This dual mechanism of action ensures that KIT and PDGFRA remain inactive, resulting in the inhibition of cell proliferation. Due to the heterogeneous nature of the KIT and PDGFRA mutants in GIST, ripretinib was developed mainly to inhibit the drug-resistant KIT mutations found in metastatic GIST.[9],[20]


  Pharmacodynamics Top


Exposure-response relationship of ripretinib and its pharmacodynamics time course have not been completely described in the published literature.


  Pharmacokinetics Top


Ripretinib is absorbed in the gastrointestinal tract. The maximum serum concentration of ripretinib is achieved in 4 h. The mean volume of distribution (Vd) is about 307 L.

Protein binding: Over 99% of ripretinib is bound to albumin and α-1 acid glycoprotein.


  Metabolism Top


Ripretinib is primarily metabolized by the CYP3A4 subfamily of enzymes and to a lesser extent by the BCRP/ABCG2, CYP2C8, CYP2D6, and CYP2E1 subfamily of enzymes. It is excreted in the feces (34%) and urine (<1%). The elimination half-life of ripretinib is 14.8 h. The clearance is about 15.3 L/h.


  Indication with Recommended Doses Top


Advanced gastrointestinal stromal tumor

An oral daily dose of 150 mg should be taken with or without food by adults who have received previous lines of therapy with three or more kinase inhibitors, including imatinib, until the progression of the disease or unacceptable toxicity.


  Contraindications Top


There are no contraindications.


  Adverse Drug Reactions Top


The most common adverse effect of ripretinib is alopecia (52%). The other adverse reactions are as follows:

  • Cardiovascular: Peripheral edema (17%), hypertension (14%), ventricular hypertrophy or left ventricular failure (2%), and cardiac failure (1%)
  • Dermatological: Palmar-plantar erythrodysesthesia (21%), xeroderma (13%), and pruritus (11%)
  • Endocrine and metabolic: Decreased serum phosphate (26%), increased serum triglycerides (26%), decreased serum calcium (23%), weight loss (19%), decreased serum sodium (17%)
  • Gastrointestinal: Nausea (39%), abdominal pain (36%), constipation (34%), increased serum lipase (32%), diarrhea (28%), decreased appetite (27%), vomiting (21%), increased serum amylase (13%), and stomatitis (11%)
  • Hematologic: Prolonged partial thromboplastin time (35%), international normalized ratio (21%; grades 3/4 - 4%), and neutropenia (10%),
  • Oncologic: Squamous cell carcinoma of the skin (5% to 7%), anemia (4%), keratoacanthoma (2%), and malignant melanoma (≤2%)
  • Hepatic: Increased serum bilirubin (22%) and increased serum alanine aminotransferase (12%)
  • Nervous system: Fatigue (42%) and headache (19%)
  • Neuromuscular and skeletal: Myalgia (32%), increased creatine phosphokinase in blood (21%), arthralgia (18%), and muscle spasm (15%)
  • Respiratory: Dyspnea (13%).[10],[21]



  Warnings Top


  • Palmar-plantar erythrodysesthesia occurred in about 21% of the patients during the clinical trial. If severe, ripretinib should be withheld and recommenced at the same or a decreased dose if the symptoms get clinically better within 7 days
  • There are the chances of new primary cutaneous malignancies in patients receiving ripretinib. Therefore, dermatologic evaluations should be performed before initiating ripretinib and also routinely during follow-up
  • Grade 1–3 hypertension may occur in patients receiving ripretinib. If the patient is symptomatic, ripretinib should be withheld until the symptoms have resolved and the blood pressure (BP) is controlled. Once the BP is under control, ripretinib can be restarted at a reduced dose. Ripretinib should not be started in patients with uncontrolled hypertension
  • Ripretinib should be permanently discontinued if the patient has cardiac dysfunction, which includes cardiac failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy
  • As there is a risk of delayed wound healing, ripretinib should not be administered for a minimum of 2 weeks following a major surgery or until there is adequate wound healing
  • If the patient has arthralgia or myalgia, ripretinib should be withheld until it resolves and then resumed at a reduced dose



  Drug Overdose and Reversal Top


Information regarding ripretinib overdose is limited. Overdose with ripretinib may result in hematological toxicity, skin toxicity, as well as muscle, liver, and gastrointestinal toxicity.


  Drug Interactions Top


  • Ripretinib is a substrate of cytochrome P450 3A4 (CYP3A4). Therefore, the concurrent use of ripretinib with a strong CYP3A4 inhibitor such as conivaptan, fusidic acid, or idelalisib should be avoided as it will increase the adverse effects of ripretinib. Other CYP3A4 inhibitors such as aprepitant, clofazimine, duvelisib, erdafitinib, fosaprepitant, fosnetupitant, larotrectinib, mifepristone, netupitant, palbociclib, simeprevir, and stiripentol may increase the serum concentrations of CYP3A4 substrates, and hence, more frequent monitoring is advised.
  • Co-administration of ripretinib with strong CYP3A4 inducers can diminish the exposure of ripretinib and its active metabolite (DP-5439), which in turn would result in decreased anti-tumor activity of ripretinib. Therefore, the concomitant use of ripretinib with strong CYP3A4 inducers should be avoided. Moderate CYP3A4 inducers such as dabrafenib, deferasirox, ivosidenib, sarilumab, siltuximab, and tocilizumab may decrease the serum concentration of the CYP3A4 substrates.



  Use in Patients With Renal Impairment Top


No dose adjustment is needed.


  Use in Patients With Hepatic Impairment Top


No dose adjustment is necessary for patients with mild hepatic impairment with a total bilirubin ≤ the upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or in those with a total bilirubin of 1–1.5 times ULN and any AST. For the patients with moderate or severe hepatic impairment, a recommended dose has not been established.


  Use of Ripretinib in Pregnant Women Top


Based on the studies in animal models and its mechanism of action, ripretinib may cause fetal harm if given to pregnant women. Therefore, there is a need to advise pregnant women about the potential risks to the fetus.


  Carcinogenic and Mutagenic Potential Top


Carcinogenicity studies have not been conducted with the drug. Ripretinib was not reported to be mutagenic in any of the assays.


  Effect on Fertility Top


Results of studies in animal models suggest that ripretinib may cause impaired fertility in men.


  Special Instructions and Warnings Top


  • In patients having uncontrolled hypertension, treatment with ripretinib should not be initiated and BP should be monitored during the therapy
  • For at least a week before an elective surgery and at least 2 weeks post a major surgery, treatment should be withheld until wound healing is satisfactory
  • In case of grade 4 hypertension, grade 3/4 left-ventricular systolic dysfunction, and recurrence of other grade 3/4 adverse reactions, treatment should be permanently stopped
  • Withholding treatment, dose reduction, and dose re-escalation can be done for other adverse reactions such as palmar-plantar erythrodyesthesia, arthralgia or myalgia, cutaneous malignancies, and embryofetal toxicity
  • For grade 2 adverse reactions, ripretinib should be withheld until the severity reduces to grade ≤1 or baseline. If the symptoms resolve within 7 days, it should be resumed at the same dose; otherwise, it should be resumed at a reduced dose. If the severity of the adverse reactions is maintained at grade ≤1 or baseline for at least 28 days, dose re-escalation may be considered. In case of grade 3 adverse reactions, ripretinib should be withheld for at least 7 days or until the severity reduces to grade ≤1 or baseline (maximum 28 days) and then resumed at a reduced dose. If the severity of the adverse reactions is maintained at grade ≤1 for at least 28 days, dose re-escalation may be considered.



  Conclusion Top


The treatment landscape of metastatic GISTs has changed dramatically over the last few years with the introduction of various novel KIT and PDGFRA inhibitors. Ripretinib is a newly approved fourth-line tyrosine kinase II inhibitor which might become a cornerstone in the treatment of advanced GIST. The growing evidence of its effectiveness in several clinical trials suggests that ripretinib may significantly improve the outcomes with no added toxicity in patients with advanced GISTs and may become an option in the earlier stages too.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet 2007;369:1731-41.  Back to cited text no. 1
    
2.
Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813-25.  Back to cited text no. 2
    
3.
Miettinen M, Lasota J. Gastrointestinal stromal tumors: Review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 2006;130:1466-78.  Back to cited text no. 3
    
4.
Nilsson B, Bümming P, Meis-Kindblom JM, Odén A, Dortok A, Gustavsson B, et al. Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era–a population-based study in western Sweden. Cancer 2005;103:821-9.  Back to cited text no. 4
    
5.
Din OS, Woll PJ. Treatment of gastrointestinal stromal tumor: Focus on imatinib mesylate. Ther Clin Risk Manag 2008;4:149-62.  Back to cited text no. 5
    
6.
Martin-Broto J, Moura DS. New drugs in gastrointestinal stromal tumors. Curr Opin Oncol 2020;32:314-20.  Back to cited text no. 6
    
7.
Serrano C, George S. Gastrointestinal stromal tumor: Challenges and opportunities for a new decade. Clin Cancer Res 2020;26:5078-85.  Back to cited text no. 7
    
8.
Mazzocca A, Napolitano A, Silletta M, Spalato Ceruso M, Santini D, Tonini G, et al. New frontiers in the medical management of gastrointestinal stromal tumours. Ther Adv Med Oncol 2019;11:1-13.  Back to cited text no. 8
    
9.
Smith BD, Kaufman MD, Lu WP, Gupta A, Leary CB, Wise SC, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell 2019;35:738-51000000000.  Back to cited text no. 9
    
10.
Blay JY, Serrano C, Heinrich MC, Zalcberg J, Bauer S, Gelderblom H, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:923-34.  Back to cited text no. 10
    
11.
George S, Heinrich MC, Zalcberg JR, Bauer S, Gelderblom H, Schoffski P, et al. Safety profile of ripretinib, including impact of alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES) on patient-reported outcomes (PROs), in ≥ fourth-line advanced gastrointestinal stromal tumors (GIST): Analyses from INVICTUS. J Clin Oncol 2020;38:11539.  Back to cited text no. 11
    
12.
Dhillon S. Avapritinib: First approval. Drugs 2020;80:433-9.  Back to cited text no. 12
    
13.
Mehren MV, Serrano C, Bauer S, Gelderblom H, George S, Heinrich M, et al. LBA87-INVICTUS: A phase III, interventional, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as ≥ 4th-line therapy in patients with advanced gastrointestinal stromal tumors (GIST) who have received treatment with prior anticancer therapies (NCT03353753). Ann Oncol 2019;30:925-26.  Back to cited text no. 13
    
14.
George S, Heinrich M, Chi P, Razak A, Mehren MV, Gordon M, et al. Initial results of phase I study of DCC-2618, a broad-spectrum KIT and PDGFRa inhibitor, in patients (PTS) with gastrointestinal stromal tumor (GIST) by number of prior regimens. Ann Oncol 2018;29:576-95.  Back to cited text no. 14
    
15.
Heinrich MC, George S, Zalcberg JR, Bauer S, Gelderblom H, Schoffski P, et al. Quality of life (QoL) and self-reported function with ripretinib in ≥4th-line therapy for patients with gastrointestinal stromal tumors (GIST): Analyses from INVICTUS. J Clin Oncol 2020;38:11535.  Back to cited text no. 15
    
16.
Zalcberg JR, Heinrich M, George S, Bauer S, Gelderblom H, Schöffski P, et al. Clinical benefit with ripretinib as ≥4th line treatment in patients with advanced gastrointestinal stromal tumors (GIST): Update from the phase III INVICTUS study. Ann Oncol 2020;31:S973-4.  Back to cited text no. 16
    
17.
Serrano C, Heinrich M, George S, Zalcberg J, Bauer S, Gelderblom H, et al. Efficacy and safety of ripretinib as ≥4th-line therapy for patients with gastrointestinal stromal tumor following crossover from placebo: Analyses from INVICTUS. Ann Oncol 2020;31:236.  Back to cited text no. 17
    
18.
Janku F, Abdul Razak AR, Chi P, Heinrich MC, von Mehren M, Jones RL, et al. Switch control inhibition of KIT and PDGFRA in patients with advanced gastrointestinal stromal tumor: A phase I study of ripretinib. J Clin Oncol 2020;38:3294-303.  Back to cited text no. 18
    
19.
Janku F, Chi P, Heinrich M, von Mehren M, Jones RL, Ganjoo K, et al. Ripretinib intra-patient dose escalation (IPDE) following disease progression provides clinically meaningful progression-free survival (PFS) in gastrointestinal stromal tumor (GIST) in phase I study. Ann Oncol 2020;31:S974-S975.  Back to cited text no. 19
    
20.
Nemunaitis J, Bauer S, Blay JY, Choucair K, Gelderblom H, George S, et al. Intrigue: Phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib. Future Oncol 2020;16:4251-64.  Back to cited text no. 20
    
21.
Farag S, Smith MJ, Fotiadis N, Constantinidou A, Jones RL. Revolutions in treatment options in gastrointestinal stromal tumours (GISTs): The latest updates Curr Treat Options Oncol 2020;21:55.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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  In this article
Abstract
Introduction
Methods
Overview of Clin...
History
Chemistry
Physical Properties
Dosage Forms and...
Mechanism of Action
Pharmacodynamics
Pharmacokinetics
Metabolism
Indication with ...
Contraindications
Adverse Drug Rea...
Warnings
Drug Overdose an...
Drug Interactions
Use in Patients ...
Use in Patients ...
Use of Ripretini...
Carcinogenic and...
Effect on Fertility
Special Instruct...
Conclusion
References
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