Combining Type I and Type II KIT Inhibitors Yields Clinical Benefit in Refractory GIST

Stomach cancer, computer illustration.
Investigators assessed the effects of a combination of type I and type II KIT inhibitors on mutation and disease control in patients with advanced gastrointestinal stromal tumors.

A combination of type I, PLX9486, and type II, sunitinib, KIT inhibitors was well tolerated in patients with advanced gastrointestinal stromal tumors (GIST), according to a study in JAMA Oncology.

The multicenter, 2-part, open-label, phase 1b/2a, nonrandomized clinical trial investigated the safety and pharmacokinetics of PLX9486 and established the maximum tolerated dose/recommended phase 2 dose for patients with advanced solid tumors. Extension part 2e evaluated the safety and preliminary activity of PLX9486 in combination with sunitinib among patients with refractory GIST (ClinicalTrials.gov Identifier: NCT02401815).

The participants received 250, 350, 500, and 1000 mg of PLX9486 alone (part 1) or 500 and 1000 mg of PLX9486 with 25 or 37.5 mg of sunitinib (part 2e) continuously, in 28-day dosing cycles, until disease progression, treatment discontinuation, or withdrawal.

A total of 39 patients with solid tumors (median age, 57 years; range, 39-79 years; 56.4% men), 35 of whom had GIST (89.7%), were included in part 1 (n=24) and part 2e (n=15) from March 2015 to February 2019. In addition, 3 patients from part 1 were also included in part 2e, expanding the safety population to 18 patients.

In part 1, participants had a mean duration of PLX9486 treatment of 148 (range, 14-670) days. Monotherapy with PLX9486 was well tolerated, with grades 1 to 2 adverse events occurring most frequently. Common treatment-emergent adverse events (TEAEs) were fatigue, aspartate aminotransferase increase, diarrhea, and nausea.

In part 2e, the mean duration of PLX9486 and sunitinib treatment was 337 (range, 27-825) days and 307 (range, 28-825) days, respectively. Study authors noted the combination of PLX9486 with sunitinib was associated with an expected adverse events profile for each of the single agents.

The top doses of both agents (1000 mg/d PLX9486 and 37.5 mg/d sunitinib, continuously) were well tolerated. Diarrhea, aspartate aminotransferase/alanine aminotransferase increase, nausea, and vomiting were common TEAEs observed in the combination of PLX9486 with sunitinib.

In part 1, PLX9486 had a modest increase in exposure at steady state between 250- and 1000-mg/d doses. In part 2e, sunitinib coadministration was associated with improved oral uptake of PLX9486. In addition, sunitinib had a dose-proportional increase in steady-state exposure from 25 to 37.5 mg.

The median progression-free survival (PFS) was 1.74 (95% CI, 1.55-1.84) months for patients with GIST who received 500 mg or less of PLX9486 monotherapy, and 5.75 (95% CI, 0.99-11.0) months for those who received daily doses of 1000 mg. The hazard ratio (HR) for progression was 0.35 (95% CI, 0.12-1.0; log-rank test P =.051) in favor of the 1000-mg daily dose.

The addition of sunitinib (25 or 37.5 mg) to PLX9486 (500 or 1000 mg) was associated with a median PFS of 12.1 (95% CI, 1.35-not available) months. The HRs were 0.14 (95% CI, 0.04-0.44; P <.001) and 0.40 (95% CI, 0.16-0.99; P =.048) vs 500-mg or less and 1000-mg PLX9486, respectively.

The investigators noted that the small sample size and the heterogeneous nature of GIST limits the interpretation of the findings.

“We showed that KIT mutations can be detected in the [circulating tumor] DNA of patients with GIST, and the level of change in mutant reads may indicate disease activity,” stated the investigators. “In conjunction with radiographic measurement, [circulating tumor] DNA analysis supports that the PLX9486-sunitinib combination may provide broad inhibition of KIT mutant receptors in patients with refractory GIST.”

Disclosure: The study was sponsored by Plexxikon Inc, a wholly owned subsidiary of Daiichi Sankyo Group. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

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. Published online July 8, 2021. doi: 10.1001/jamaoncol.2021.2086