Preliminary safety and activity in a first-in-human phase 1 study of BLU-285, a potent, highly-selective inhibitor of KIT and PDGFRa activation loop mutants in advanced gastrointestinal stromal tumor (GIST)

• Published in: European journal of cancer (1990) Vol. 69; p. S4
• Main Authors: Heinrich, M, Jones, R, Schoffski, P, Bauer, S, vonMehren, M, Eskens, F, Cassier, P, Mir, O, Shi, H, Alvarez-Diez, T, Healy, ME, Wolf, B, George, S
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science Ltd 01-12-2016
• Subjects: Activation; Anticancer properties; Antitumor agents; Ascites; Clinical trials; Constipation; Deoxyribonucleic acid; Digestive system; DNA; Dosage; Edema; Fatigue; Gastrointestinal cancer; Imatinib; Inhibitors; Lesions; Medical treatment; Mutants; Mutation; Nausea; Reduction; Safety; Shrinkage; Toxicity; Tumors; Vomiting
• ISSN: 0959-8049; 1879-0852

Background: Activating mutations in KIT or PDGFRα are genetic drivers in >85% of GIST. However, primary and acquired mutations in the activation loop of PDGFRα and KIT are not effectively treated by approved therapies. A phase 1 study (NCT02508532) was initiated in advanced GIST to assess the safety, PK and preliminary clinical activity of BLU-285. a potent, highly-selective oral inhibitor that targets KIT Exon 17 and PDGFRα D842 activation loop mutants. Methods: Adult patients (pts) with unresectable GIST, who had received ≥2 kinase inhibitors including imatinib, or who had a primary PDGFRα D842 mutation regardless of prior therapy were given BLU-285 once daily on a 4-week cycle following a 3+3 escalation design, which allowed enrichment of dose levels demonstrated to be safe. Adverse events (AEs) per CTCAE, PK and plasma/tumor mutant DNA levels were assessed. Response was determined by RECIST 1.1 every 8 weeks. Results: At a 23-SEP-2016 cutoff, 32 pts (17 PDGFRα [16 D842-mutant], 15 KIT [Exon 17 mutation confirmed in 8 of 10 with results]) have been treated with BLU-285 at doses of 30 to 400 mg/day. The median number of prior kinase inhibitors was 3 (range 0-6). Although still in dose escalation, anti-tumor activity was seen across all dose levels. This included a reduction in tumor burden per RECIST 1.1 in 11 of 12 PDGFRα D842-mutant pts with ≥1 radiographic assessment (6 PR [4 confirmed; -33; -36; -42; -45; -51; -54%] and 6 SD [0; -5; -13; -21; -25; -30%]) and in 5 of 13 KIT pts (1 confirmed PR [-62%] and 4 SD [-2; -6%; -18%; -24%]). 3 of the 5 KIT pts had Exon 17 mutation in plasma and/or tumor (data pending for the other 2). Marked reductions in non-target lesions, including ascites and diffuse omental disease, were also observed. ≥10-fold reduction in circulating PDGFRα D842-mutanI DNA levels were observed at C1D15, prior to radiographic response. All pts with radiographic tumor shrinkage remain on study. BLU-285 is rapidly absorbed (Tmax 2-4 h), exposure increases linearly with dose, and half-life is >24h supporting once daily dosing. No dose limiting toxicities or Grade 4 or 5 BLU-285-related AEs have been reported and dose escalation continues. Most AEs were CTCAE grade 1 or 2 and the most common were nausea (38%), fatigue, peripheral edema (31% each), vomiting (28%), and constipation (22%). 8 pts discontinued treatment, all due to progressive disease; 24 remain on study with treatment durations of 2-12 cycles. Conclusion: Current therapies do not effectively target KIT and PDGFRa activation loop mutants. BLU-285, a potent, highly-selective inhibitor of these mutants has been well tolerated and demonstrates clinical activity, including objective response in both PDGFRα D842- and KIT Exon 17-mutant GIST. These encouraging phase 1 data support expanded clinical testing of BLU-285 in both GIST subtypes.