It is not good news when gastrointestinal stromal tumors (GIST) are progressed and are resistant to tyrosine kinase inhibitors (TKIs). In advanced GIST that was resistant to conventional TKIs, researchers, for a randomized, placebo-controlled, phase III study assessed the effectiveness and safety of pimitespib, a brand-new heat shock protein 90 inhibitor.

Patients with histologically proven GIST who had not responded to imatinib, sunitinib, or regorafenib underwent a 2:1 randomization to receive oral pimitespib 160 mg/day or a placebo for 5 days in a row, every week, over the course of 21 days. Cross-over to open-label pimitespib was allowed after blinded central radiological review (BCRR) determined that the illness had progressed. Progression-free survival (PFS) by BCRR in the complete analysis set was the main outcome. Overall survival (OS), which was modified using the rank-preserving structural failure time (RPSFT) approach to lessen the predicted confounding effect of cross-over, was one of the secondary endpoints.

A total of 86 participants were randomization to pimitespib (n = 58) or a placebo (n=28) from October 31, 2018, to April 30, 2020. The median PFS with pimitespib was 2.8 months (95% CI: 1.6-2.9 months), compared to 1.4 months (95% CI: 0.9-1.8 months) for placebo (hazard ratio (HR): 0.51; one-sided P=0.006). In contrast to placebo, pimitespib had a better cross-over-adjusted OS [HR 0.42 (0.21-0.85), one-sided P=0.007]. The median PFS following cross-over was 2.7 months (95% CI 0.7-4.1 months), with 17 patients (60.7%) who were receiving placebo switching to pimitespib. Diarrhea (74.1%) and loss of appetite (31.0%) were the most frequent (≥30%) adverse reactions (AEs) to pimitespib treatments, while diarrhea (13.8%) was the most frequent (≥10%) grade more or around 3 AE. Pimitespib was discontinued in three (5.2%) individuals due to treatment-related adverse events (AEs).

In patients with advanced GIST who were resistant to conventional TKIs, pimitespib exhibited an acceptable safety profile and dramatically improved PFS and cross-over-adjusted OS when compared to placebo.