Pimitespib a potential new standard treatment for GIST?

The pivotal phase III CHAPTER-GIST-301 trial presented at ASCO 2021 demonstrated the potential of pimitespib, a novel oral inhibitor of heat shock protein 90 (HSP90), for the treatment of individuals with advanced gastrointestinal stromal tumours (GISTs) refractory to standard treatment (ie, imatinib, sunitinib, and regorafenib).

All standard treatments for GIST are tyrosine kinase inhibitors (TKIs) specifically targeting KIT or PDGFRA. However, these are sometimes ineffective owing to secondary KIT mutations, other mutations (ie, BRAF), or absence of KIT and PDGFRA mutations. [Lancet Oncol 2020;21:864-865]

“[As such, there] remains an unmet clinical need for advanced GIST refractory to standard treatments,” said Dr Yoshitaka Honma from the National Cancer Center Hospital, Tokyo, Japan.

With KIT and PDGFRA being clients of HSP90 for their functional stability, HSP90 appears to be a rational therapeutic target in GIST patients with resistance to TKIs, he added. “Pimitespib is a selective HSP90 inhibitor [that has shown] antitumour effects with reduced levels of client proteins, including KIT, PDGFRA, and BRAF.”

Eighty-six participants (median age 62 years, 56 percent male) with histologically confirmed advanced GIST were randomized 2:1 to receive either pimitespib 160 mg QD (5 days on/2 days off) or placebo. Seventeen placebo recipients crossed over to open-label pimitespib. KIT mutations were detected in more than half of participants (59 percent and 63 percent in the respective pimitespib and placebo arms). [ASCO 2021, abstract 11524]

Median progression-free survival (PFS) was twofold longer with pimitespib vs placebo (2.8 vs 1.4 months), yielding a hazard ratio (HR) of 0.51 (95 percent confidence interval, 0.30–0.87; p for stratified log-rank test=0.006). “The primary endpoint of this trial was met,” said Honma.

A similar PFS trend favouring pimitespib was also seen in patients with KIT Exon 13/14, 17/18 mutations (HR, 0.52). Among placebo recipients who crossed over to pimitespib, secondary PFS was 2.7 months.

Median overall survival (OS) was also longer with pimitespib vs placebo (13.8 vs 9.6 months; HR, 0.63; p=0.081). Crossover-adjusted median OS using the rank preserving structural failure time model for placebo was 7.6 months (adjusted HR, 0.42; p=0.007).

Safety-wise, grade ≥3 adverse event (AE; 43 percent vs 29 percent) and treatment-related AE rates (26 percent vs 4 percent) were higher with pimitespib vs placebo. Nonetheless, the study drug was generally well-tolerated with manageable grade ≥3 adverse events (AEs), the most common being diarrhoea (14 percent), anaemia (7 percent), and decreased appetite (7 percent).

“[AEs were] temporary and manageable by dose interruption or reduction,” said Honma. Four pimitespib recipients withdrew from the study owing to AEs.

“[F]or the first time, an HSP90 inhibitor significantly improved PFS with OS prolongation in patients with advanced GIST refractory to [standard treatments],” said Honma. “With a mechanism of action different from traditional therapies … pimitespib has the potential to be a new standard treatment in GIST in the salvage line setting.”