Switch Control Inhibition of KIT and PDGFRA in Patients With Advanced Gastrointestinal Stromal Tumor: A Phase I Study of Ripretinib.

Abstract

PURPOSE:

In advanced gastrointestinal stromal tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations.

PATIENTS AND METHODS:

This first-in-human, to our knowledge, phase I study of ripretinib (ClinicalTrials.gov identifier: NCT02571036) included a dose-escalation phase and subsequent expansion phase at the recommended phase II dose (RP2D). Eligible patients included those with advanced GIST, intolerant to or experienced progression on ≥ 1 line of systemic therapy, and other advanced malignancies. Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and preliminary antitumor activity were evaluated.

RESULTS:

At data cutoff (August 31, 2019), 258 patients (n = 184 GIST) were enrolled, with 68 patients in the dose-escalation phase. Three DLTs were reported: grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). MTD was not reached (maximum dose evaluated, 200 mg twice a day); 150 mg once daily was established as the RP2D. The most frequent (> 30%) treatment-emergent adverse events in patients with GIST receiving ripretinib 150 mg once daily (n = 142) were alopecia (n = 88 [62.0%]), fatigue (n = 78 [54.9%]), myalgia (n = 69 [48.6%]), nausea (n = 65 [45.8%]), palmar-plantar erythrodysesthesia (n = 62 [43.7%]), constipation (n = 56 [39.4%]), decreased appetite (n = 48 [33.8%]), and diarrhea (n = 47 [33.1%]). Objective response rate (confirmed) of 11.3% (n = 16/142) ranging from 7.2% (n = 6/83; fourth line or greater) to 19.4% (n = 6/31; second line) and median progression-free survival ranging from 5.5 months (fourth line or greater) to 10.7 months (second line), on the basis of investigator assessment, were observed.

CONCLUSION:

Ripretinib is a well-tolerated, novel inhibitor of KIT and PDGFRA mutant kinases with promising activity in patients with refractory advanced GIST.

• Authors: Filip Janku, Albiruni R Abdul Razak, Ping Chi, Michael C Heinrich, Margaret von Mehren, Robin L Jones, Kristen Ganjoo, Jonathan Trent, Hans Gelderblom, Neeta Somaiah, Simin Hu, Oliver Rosen, Ying Su, Rodrigo Ruiz-Soto, Michael Gordon, Suzanne George
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 38 Issue 28 Pg. 3294-3303 (10 01 2020) ISSN: 1527-7755 [Electronic] United States
• PMID: 32804590 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Naphthyridines
• Urea
• ripretinib
• KIT protein, human
• Proto-Oncogene Proteins c-kit
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Adolescent
• Adult
• Aged
• Dose-Response Relationship, Drug
• Female
• Gastrointestinal Neoplasms (drug therapy, genetics, metabolism)
• Gastrointestinal Stromal Tumors (drug therapy, genetics, metabolism)
• Humans
• Male
• Middle Aged
• Naphthyridines (administration & dosage, adverse effects, pharmacokinetics)
• Progression-Free Survival
• Proto-Oncogene Proteins c-kit (antagonists & inhibitors, genetics, metabolism)
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors, genetics, metabolism)
• Urea (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Young Adult