A phase III trial evaluated the efficacy and safety of pimitesib in patients with advanced GIST refractory to standard treatments, whose medical requirements remain unmet, presented at the 2021 ASCO Annual Meeting.

Pimitespib (PIM), an oral inhibitor of heat shock protein, (n=58), or placebo PL(n=28), were administered to 86 randomized patients with advanced GIST refractory to standard treatments, whose medical requirements remain unmet. To note, eligible patients had histologically confirmed advanced GIST refractory to IM, SU, and REG, ≥1 measurable lesion, and ECOG performance status 0 or 1.

During October 2018-April 2020, patients were randomized 2:1 to receive either PIM 160 mg once daily on a 5-days-on/ 2-days-off schedule or PL. Patients eligible for unblinding (at the time of progressive disease) were permitted to crossover to open-label PIM.

The primary endpoint was PFS by blinded central radiological review based on modified RECIST 1.1. Secondary endpoints included OS, PFS in the patients crossed over to PIM (secondary PFS), and safety. In addition, crossover-adjusted OS was derived by means of the RPSFT model. Exploratory endpoints included pharmacogenomics (PGx). Data reports baseline characteristics were well balanced between the two arms.

Median PFS was 2.8 months (mo) (95% CI: 1.6–2.9) for PIM vs. 1.4 mo (95% CI: 0.9–1.8) for PL. The hazard ratio (HR) for PFS was 0.51 (95% CI: 0.30–0.87) (p = 0.006, stratified log-rank test). Moreover, the stated median OS was 13.8 months.

Furthermore, the results following the PGx analysis implied PIM was also found effective in patients with secondary KIT mutation detected from blood samples. The most common ( > 5%) adverse reactions in PIM/PL included diarrhea, anemia, decreased appetite, and tumor hemorrhage. Adverse events prior to the PIM/PL study were observed in 4/2 pts respectively.

Conclusively, the results of this phase III trial demonstrate that PIM significantly improved PFS with OS prolongation in patients with advanced GIST refractory to IM, SU, and REG, as a HSP90 inhibitor for the first time. PIM was tolerated and AEs were manageable. With a mechanism of action different from that of standard therapies, PIM has the potential to be a new standard treatment in GIST. -Alexis Hyams