Ripretinib intrapatient dose escalation after disease progression provides clinically meaningful outcomes in advanced gastrointestinal stromal tumour

• Published in: European journal of cancer (1990) 2021-09, Vol.155, p.236-244
• Main Authors: George, Suzanne, Chi, Ping, Heinrich, Michael C., von Mehren, Margaret, Jones, Robin L., Ganjoo, Kristen, Trent, Jonathan, Gelderblom, Hans, Razak, Albiruni A., Gordon, Michael S., Somaiah, Neeta, Jennings, Julia, Meade, Julie, Shi, Kelvin, Su, Ying, Ruiz-Soto, Rodrigo, Janku, Filip
• Format: Article
• Language: English
• Subjects: Adverse events; Disease Progression; Dosage; Enzyme inhibitors; Female; Gastrointestinal cancer; Gastrointestinal Stromal Tumors - drug therapy; Gastrointestinal Stromal Tumors - mortality; Gastrointestinal Stromal Tumors - pathology; Gastrointestinal stromal tumours; Growth factors; Humans; Kinases; Male; Metabolic response; Naphthyridines - pharmacology; Naphthyridines - therapeutic use; Patients; Pharmacology; Platelet-derived growth factor; Positron emission; Positron emission tomography; Progression-Free Survival; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Ripretinib; Solid tumors; Therapy; Treatment Outcome; Tumors; Tyrosine; Urea - analogs & derivatives; Urea - pharmacology; Urea - therapeutic use
• ISSN: 0959-8049; 1879-0852; 1879-0852
• DOI: 10.1016/j.ejca.2021.07.010

Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and platelet-derived growth factor receptor α kinase signalling. Ripretinib showed preliminary efficacy in patients with advanced gastrointestinal stromal tumour (GIST) in a phase I study across a range of doses. Results were confirmed in the phase III INVICTUS study, and ripretinib 150 mg once daily (QD) was subsequently approved as a ≥fourth-line therapy. Here, we report the phase I study results of intrapatient dose escalation (IPDE) in patients with GIST treated across second, third and later lines of therapy. Patients with advanced GIST who experienced disease progression (PD) at ripretinib 150 mg QD could dose escalate to 150 mg twice daily (BID). Progression-free survival (PFS) 1 was calculated from the date of the first dose of ripretinib 150 mg QD to PD (as per Response Evaluation Criteria in Solid Tumours 1.1); PFS2 was from the date of IPDE (150 mg BID) to PD or death. Treatment-emergent adverse events (TEAEs) were summarised by dosing periods and compared descriptively. Of 142 patients with GIST receiving ripretinib 150 mg QD, 67 underwent IPDE. IPDE provided benefit across all lines of therapy; the median PFS2 was 5.6, 3.3 and 4.6 months for patients on second-, third- and ≥fourth-line therapy, respectively. A partial metabolic response after IPDE was demonstrated in 13 of 37 patients with available positron emission tomography scans. TEAEs reported at both doses were similar. Ripretinib IPDE after PD provided continued clinical benefit in advanced GIST across second, third and later lines of therapy with a similar safety profile to that observed with the QD regimen. •Treatment options are limited for advanced gastrointestinal stromal tumour (GIST).•Ripretinib is a novel oral switch-control tyrosine kinase inhibitor.•Ripretinib is approved for patients with advanced GIST in the fourth line and beyond.•Ripretinib dose escalation at progression provides clinical benefit in advanced GIST.