Refractory gastrointestinal stromal tumors can potentially be treated by using a KIT inhibitor combination of PLX9486 and sunitinib.
By co-administering type I and II KIT inhibitors PLX9486 and sunitinib (Sutent) and co-targeting complimentary, confirmational states of the same kinase, it is possible that patients with refractory gastrointestinal stromal tumors (GIST) may achieve a clinical benefit, according to data from a nonrandomized phase 1b/2 trial (NCT02401815).
Patients who were treated with 500 mg or less of PLX9486 monotherapy had a median progression-free survival (PFS) of 1.74 months (95% CI, 1.55-1.84), as well as 5.75 months (95% CI, 0.99-11.0) at 1000 mg (HR, 0.35; 95% CI, 0.12-1.0; log rank test P =.051). Patients who were treated with the PLX9486 and sunitinib combination achieved a median PFS of 12.1 months (95% CI, 1.35–not reached). Patients also had a clinical benefit rate of 14% (95% CI, 0%-58%) at 500 mg of PLX9486 or lower, 50% (95% CI, 21%-79%) at 1000 mg, and 80% (95% CI, 52%-96%) with the PLX9486 and sunitinib combination.
A total of 39 patients with solid tumors enrolled into this study, 89.7% (n = 35) of whom had GIST. Of these patients, 24 were enrolled into part 1 of the study, and 15 were enrolled into part 2e, with 3 patients from part 1 subsequently enrolling in part 2e. All patients who were PLX9486-naïve (n =35) received imatinib (Gleevec), 86% (n = 30) received sunitinib, and 77% (n = 27) received all 3 standard lines of therapy. After circulating tumor DNA was analyzed, 20 patients had detectable KIT exon 9 and 11 mutations.
During part 1 of the study, the mean duration of treatment with PLX9486 was 148 days. During part 2e of the study, the mean duration of treatment with PLX9486 was 337 days and sunitinib was 307 days.
Additional findings from the trial indicated that no objective response was observed with PLX9486 monotherapy at dose of 500 mg or lower. Among the 12 patients who received a 1000 mg daily dose of PLX9486, 1 patient achieved a confirmed partial response (PR) with a duration of 7.4 months. With the combination of PLX9486 and sunitinib, there was 1 confirmed complete response and 2 confirmed PRs. The median overall survival was 2.96 months for 500 mg or less of PLX9486, 11.34 months for 1000 mg, and 18.11 months for the PLX9486 and sunitinib combination.
As a decrease in exon 17 and 18 mutations levels was noted among patients who achieved clinical benefit early on after receiving PLX9486 , it is possible that the therapy may suppress tumor subclones dependent on A-loop mutations. When combining PLX9486 and sunitinib, a decrease in exon 13-mutant and exon 14-mutant alleles was noted.
Common treatment-emergent adverse effects (TEAEs) of grade 3 or higher in part 1 included anemia (16.5%; n = 4), and hyperuricemia (12.5%; n = 3). The most common TEAEs of grade 3 or higher in part 2e were anemia (27.8%; n = 5) of patients, hypophosphatemia in (16.7%; n = 3), as well as diarrhea, hypertension, and lymphopenia (11.1%).
“In this study, a combination of type I, PLX9486, and type II, sunitinib, KIT inhibitors was well tolerated in patients with advanced GIST. Moreover, a broad spectrum of conformationally distinct oncogenic resistance mutations may be targeted by this combination,” the investigators concluded..
Wagner AJ, Severson PL, Shields AF, et al. Association of combination of conformation-specific KIT inhibitors with clinical benefit in patients with refractory gastrointestinal stromal tumors: A phase 1b/2a nonrandomized clinical trial. JAMA Oncol. 2021;7(9):1343-1350. doi:10.1001/jamaoncol.2021.2086