In a phase Ib/IIa trial reported in JAMA Oncology, Wagner et al found that the combination of a type I KIT inhibitor, PLX9486, with the type II inhibitor sunitinib produced clinical benefit and improved progression-free survival rates in patients with refractory gastrointestinal stromal tumors (GIST).
As related by the investigators, type II KIT inhibitors (eg, imatinib and sunitinib) bind to the inactive conformation of tyrosine kinase. Type I inhibitors such as PLX9486 are conformation-complementary, active-state inhibitors.
Study Details
In the U.S. multicenter trial, 39 patients received PLX9486 alone at 250, 350, 500, or 1,000 mg daily (part 1, n = 21) or at 500 and 1,000 mg combined with sunitinib at 25 or 37.5 mg daily (part 2, n = 18) continuously in 28-day cycles until disease progression or treatment discontinuation. The primary efficacy endpoints were clinical benefit rate and progression-free survival.
Efficacy Outcomes
The recommended phase II dose of PLX9486 was 1,000 mg daily. Among patents (n = 7) receiving PLX9486 at ≤ 500 mg, no objective responses were observed, and the clinical benefit rate was 14% (95% confidence interval [CI] = 0%–58%). At the 1,000-mg dose (n = 12), partial response was observed in one patient (duration = 7.4 months) and the clinical benefit rate was 50% (95% CI = 21%–79%). Among 15 patients receiving PLX9486 and sunitinib, one complete and two partial responses were observed (durations = 18.4, 18.3, and 12.3 months, respectively), and the clinical benefit rate was 80% (95% CI = 52%–96%).
KEY POINTS
- The combination of the type I inhibitor PLX9486 with sunitinib was associated with a clinical benefit rate of 80% and a median progression-free survival of 12.1 months.
- Combination treatment was associated with an acceptable safety profile.
Median progression-free survival was 1.74 months (95% CI = 1.55–1.84 months) among patients receiving PLX9486 alone at ≤ 500 mg, 5.75 months (95% CI = 0.99–11.0 months) among those receiving PLX9486 alone at 1,000 mg (hazard ratio [HR] vs ≤ 500 mg = 0.35, 95% CI = 0.12–1.0, P = .051), and 12.1 months (95% CI = 1.35 months–not estimable) among those receiving PLX9486 at 500 or 1,000 mg plus sunitinib (HR = 0.14, 95% CI = 0.04–0.44, P < .001 vs ≤ 500 mg; HR = 0.40, 95% CI = 0.16–0.99, P = .048 vs 1,000 mg).
Median overall survival in the three groups was 2.96, 11.34, and 18.11 months, respectively.
Adverse Events
Adverse events seen with PLX9486 monotherapy were mostly grade 1 or 2, with the most common being fatigue, increased aspartate aminotransferase (AST), diarrhea, and nausea; the most common grade ≥ 3 events were anemia (16.5%) and hyperuricemia (12.5%). With combination treatment, the most common adverse events of any grade were diarrhea, increased AST/alanine aminotransferase, nausea, and vomiting; the most common grade ≥ 3 events were anemia (27.8%), hypophosphatemia (16.7%), and diarrhea, fatigue, hypertension, and lymphopenia (11.1% each).
The investigators concluded, “In this phase Ib/IIa nonrandomized clinical trial, [the] type I and type II KIT inhibitors PLX9486 and sunitinib were safely coadministered at the recommended dose of both single agents in patients with refractory GIST. Results suggest that cotargeting two complementary conformational states of the same kinase was associated with clinical benefit with an acceptable safety profile.”
Jonathan C. Trent, MD, PhD, of Sylvester Comprehensive Cancer Center, University of Miami, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by National Cancer Institute grants and by Plexxikon Inc, a wholly owned subsidiary of Daiichi Sankyo Group. For full disclosures of the study authors, visit jamanetwork.com.
