Pimitespib Doubles PFS in Advanced Refractory GIST

The heat shock protein 90 (HSP90) inhibitor pimitespib led to a significant improvement in progression-free survival (PFS) and prolongation in overall survival (OS) compared with placebo in patients with advanced gastrointestinal stromal tumor (GIST) that is refractory to imatinib (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga), according to results from the phase 3 CHAPTER-GIST-301 trial (JapicCTI-184094) that were presented during the 2021 ASCO Annual Meeting.¹

Findings showed that the median PFS with pimitespib was 2.8 months (95% CI, 1.6-2.9) compared with 1.4 months (95% CI, 0.9-1.8) with placebo, leading to a 49% reduction in the risk of disease progression or death and meeting the study’s primary end point (HR, 0.51; 95% CI, 0.30-0.87; stratified log-rank P = .006).

A PFS improvement was also observed in patients with KIT exon 13/14 and 17/18 mutations (HR, 0.52).

“This trial demonstrated that pimitespib significantly improved PFS [and prolonged] OS [with] a tolerable safety profile, as an HSP90 inhibitor, for the first time,” lead study author Yoshitaka Honma, MD, of the National Cancer Center Hospital in Tokyo, Japan, said in a poster presentation on the findings. “Pimitespib represents a potential new standard treatment in patients with GIST in the salvage-line setting, with a mechanism of action [that differs] from traditional therapies.”

An estimated 90% of GIST cases harbor driver mutations in KIT and PDGFRA, which promotes continuous oncogenic signaling. Although ripretinib (Qinlock) and avapritinib (Ayvakit) are both available in the treatment of patients with GIST and target KIT or PDGFRA, they may have limited efficacy due to secondary KIT mutations, such as exon 13/14 and exon 17/18, or in those with other mutations beyond KIT or PDGFRA mutations.

Pimitespib is a novel HSP90 inhibitor that has shown prior antitumor activity in molecularly defined subgroups of solid tumors.² In a phase 2 study (JapicCTI-163182), pimitespib demonstrated a median progression-free survival of 4.4 months (95% CI, 2.8-6.0) in patients refractory to imatinib, sunitinib, and regorafenib.³

In the double-blind, placebo-controlled CHAPTER-GIST-301 study, investigators enrolled patients with histologically confirmed advanced GIST that was refractory to imatinib, sunitinib, and regorafenib. Patients had to have at least 1 measurable lesion and an ECOG performance status of 0 or 1.

Participants were randomized in a 1:2 fashion to receive pimitespib (n = 54) at 160 mg on a 5-days-on/2-days-off schedule in 21-day cycles or placebo (n = 27), also at a 5-days-on/2-days-off schedule in 21-day cycles.

Notably, those who experienced disease progression via blinded central radiological review (BCRR) were unblinded and then permitted to cross over to receive open-label pimitespib.

The primary end point of the trial was PFS by BCRR based on modified RECIST v1.1 criteria; secondary end points included OS, PFS in patients who crossed over to pimitespib (known as secondary PFS), pharmacogenomics, and safety. Crossover-adjusted OS was calculated through the rank preserving structural failure time (RPSFT) model.

Patients were stratified by the number of prior systemic anticancer therapies (3 vs 4 or more) and age (less than 65 years vs 65 years or older).

The primary analysis was planned at an estimated 70 PFS events per BCRR and was performed using a stratified log-rank test. A sample size of 81 patients was calculated to provide 90% power to detect a difference in PFS between pimitespib and placebo, with a 1-sided significance level of 0.025.

Patients were enrolled to the trial from October 2018 to April 2020 across 6 sites in Japan. The data cutoff date was June 23, 2020. Of the 58 patients who received pimitespib, 50 discontinued due to either progressive disease (PD; n = 39), adverse effects (AEs; n = 4), physician decision (n = 3), withdrawal of consent (n = 2), because they did not take the study drug for more than 21 days (n = 1), or death due to tumor hemorrhage that was unrelated to pimitespib (n = 1). One patient started open-label pimitespib but then discontinued due to PD.

Of the 28 patients who received treatment with placebo, 24 discontinued due to either PD (n = 22) or AEs (n = 2). Seventeen patients on this arm then started open-label pimitespib, 16 of whom discontinued the HSP90 inhibitor because of PD (n = 13), they didn’t take the study drug for more than 21 days (n = 2), or withdrawal of consent (n = 1)

Eight patients are on ongoing treatment with pimitespib compared with 4 patients who remain on placebo. One patient from the placebo arm is still receiving open-label pimitespib.

Baseline characteristics were similar in both arms. The median age of patients was 61.75 years, and 38.6% of patients were older than 65 years; more than half of patients were male (56.1%) and 85.1% had an ECOG performance status of 0. Moreover, 38.7% of patients had received more than 4 prior therapies.

Across both arms, 60.6% of patients had detectable KIT mutations in exon 9 (13.3%), exon 11 (49.5%), and exon 13/14 or exon 17/18 (52.7%). Moreover, 10.3% of patients had detectable PDGFRA mutations.

Additional data showed that the secondary PFS with the HSP90 inhibitor was 2.7 months (95% CI, 0.7-4.1). No complete or partial responses were reported in either arm. The stable disease rate was 62.1% on the pimitespib arm and 35.5% on the placebo arm per BCCR.

The median OS was 13.8 months (95% CI, 9.2–not reached [NR]) with pimitespib vs 9.6 months (95% CI, 5.5–NR) with placebo (HR, 0.63; 95% CI, 0.32-1.21). When adjusting the placebo OS via RPSFT, the median OS was 7.6 months (95% CI, 5.3-14.9), which translated to a 58% reduction in the risk of death with pimitespib (HR, 0.42; 95% CI, 0.21-0.85).

Regarding safety, all-grade and grade 3 or higher AEs occurred in 96.6% and 43.1% of patients on pimitespib, respectively, and in 78.6% and 28.6% of those on placebo, respectively.

Treatment-related AEs (TRAEs) that were all grade or grade 3 or higher occurred in 93.1% and 25.9% of those on the pimitespib arm, respectively, and 39.3% and 3.6% of those on the placebo arm, respectively. The grade 3 or higher TRAEs reported in those who received pimitespib included diarrhea (13.8%), decreased appetite (1.7%), malaise (1.7%), renal impairment (3.4%), and anemia (5.2%).

AEs that led to dose reductions on the pimitespib and placebo arms occurred in 38.2% and 3.6% of patients, respectively, while AEs that led to dose interruptions were reported in 67.2% and 32.1% of patients, respectively. Moreover, AEs that resulted in study discontinuation occurred in 6.9% and 7.1% of patients on the investigative and control arms, respectively.

References

1. Honma Y, Kurokawa Y, Sawaki A, et al. Randomized, double-blind, placebo (PL)-controlled, phase III trial of pimitespib (TAS-116), an oral inhibitor of heat shock protein 90 (HSP90), in patients (pts) with advanced gastrointestinal stromal tumor (GIST) refractory to imatinib (IM), sunitinib (SU) and regorafenib (REG). J Clin Oncol. 2021;39(suppl 15):11524. doi:10.1200/JCO.2021.39.15_suppl.11524
2. Garcia-Carbonero R, Carnero A, Paz-Ares L. Inhibition of HSP90 molecular chaperones: moving into the clinic. Lancet Oncol. 2013;14(9):e358-369. doi:10.1016/S1470-2045(13)70169-4
3. Doi T, Kurokawa Y, Sawaki A, et al. Efficacy and safety of TAS-116, an oral inhibitor of heat shock protein 90, in patients with metastatic or unresectable gastrointestinal stromal tumour refractory to imatinib, sunitinib and regorafenib: a phase II, single-arm trial.Eur J Cancer. 2019;121:29-39. doi:10.1016/j.ejca.2019.08.009