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Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind,
Y Kurokawa1, Y Honma2, A Sawaki3
1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Background:
Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs.
Patients And Methods:
Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over.
Results:
From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months [95% confidence interval (CI) 1.6-2.9 months] with pimitespib versus 1.4 months (0.9-1.8 months) with placebo [hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006]. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo [HR 0.42 (0.21-0.85), one-sided P = 0.007]. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients.
Conclusions:
Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.
Insights
Pimitespib significantly improved progression-free survival and overall survival in patients with advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs). This novel heat shock protein 90 inhibitor demonstrated an acceptable safety profile in the trial.
Area of Science:
- Oncology
- Pharmacology
Background:
- Advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) have a poor prognosis.
- Novel therapeutic strategies are needed for these patients.
Purpose of the Study:
- To evaluate the efficacy and safety of pimitespib, a heat shock protein 90 inhibitor, in advanced GIST.
- To compare pimitespib with placebo in patients refractory to standard TKIs.
Main Methods:
- A randomized, placebo-controlled, phase III trial was conducted.
- Patients received oral pimitespib or placebo, with cross-over permitted upon disease progression.
- Progression-free survival (PFS) and overall survival (OS) were primary and secondary endpoints, respectively.
Main Results:
- Pimitespib significantly improved median PFS (2.8 vs. 1.4 months) and cross-over-adjusted OS compared to placebo.
- The hazard ratio for PFS was 0.51 (P=0.006) and for OS was 0.42 (P=0.007).
- Common adverse events included diarrhea and decreased appetite; treatment-related AEs led to discontinuation in 5.2% of patients.
Conclusions:
- Pimitespib demonstrated significant efficacy in improving PFS and OS in advanced GIST patients refractory to TKIs.
- Pimitespib has an acceptable safety profile for this patient population.
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