Novel Drug Significantly Improves Survival in Rare Gastrointestinal Cancer

The novel drug pimitespib was associated with significant survival outcome improvements in patients with advanced gastrointestinal stromal tumor (GIST) whose disease stopped responding to Gleevec (imatinib), Sutent (sunitinib) and Stivarga (regorafenib), compared to treatment with placebo.

The data, which were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrated that treatment with the study drug led to a 49% reduction in the risk of disease progression or death. Moreover, pimitespib was also associated with improved survival in patients whose disease harbors KIT exon 13/14 and 17/18 mutations.

“This trial demonstrated that pimitespib significantly improved (progression-free survival and prolonged overall survival with) a tolerable safety profile, (with) an HSP90 inhibitor, for the first time,” lead study author Dr. Yoshitaka Honma, of the National Cancer Center Hospital in Tokyo, Japan, said in during a presentation of 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 Qinlock (ripretinib) and Ayvakit (avapritinib) are both available in the treatment of patients with GIST and target those driver mutations, they may have limited efficacy.

Pimitespib, a novel HSP90 inhibitor, has shown prior antitumor activity in molecularly defined subgroups of solid tumors.

Here, the authors presented results from the CHAPTER-GIST-301 study, which enrolled patients with histologically confirmed advanced GIST whose disease did not respond to treatment with Gleevec, Sutent and Stivarga.

Participants were randomized to receive either study drug (54 patients) or placebo (27 patients).

Of note, patients whose disease progressed during the “blinded” portion of the study were “unblinded” and permitted to cross over and receive study drug.

Measuring progression-free survival (time during and after treatment when the patient lives without disease progression) was the main goal of the study. Other goals included assessing overall survival (length of time from either diagnosis or start of treatment that a patient is still alive), as well as progression-free survival in patients who crossed over to receive pimitespib and safety.

Patients across six treatment sites in Japan were enrolled onto the trial from October 2018 to April 2020. The data cut-off date was June 23, 2020. Of the 58 patients who received pimitespib, 50 discontinued treatment due to either progressive disease (39 patients), side effects (4 patients), physician decision (3 patients), withdrawal of consent (2 patients), because they did not take the study drug for more than 21 days (1 patient), or death due to tumor hemorrhage that was unrelated to pimitespib (1 patient).

Of the 28 patients who received treatment with placebo, 17 switched over to treatment with pimitespib. Sixteen discontinued the HSP90 inhibitor because of progressive disease (13 patients), they didn’t take the study drug for more than 21 days (2 patients), or withdrawal of consent (1 patient).

Eight patients are on ongoing treatment with pimitespib compared with four patients who remain on placebo. One patient from the placebo group is still receiving treatment with pimitespib.

Findings showed that the median progression-free survival with pimitespib was 2.8 months compared with 1.4 months with placebo.

Additional data showed that the secondary progression-free survival — in individuals who switched from placebo to study drug — was 2.7 months. No complete or partial responses were reported in either treatment group.

The median overall survival was 13.8 months with pimitespib versus 9.6 months with placebo.

Regarding safety, any severity and serious or severe side effects occurred in 96.6% and 43.1% of patients receiving pimitespib, respectively, and in 78.6% and 28.6% of those on placebo, respectively.

Treatment-related side effects that were any severity or serious or severe occurred in 93.1% and 25.9% of those in the pimitespib group, respectively, and 39.3% and 3.6% of those in the placebo group, respectively. The most common serious or severe treatment-related side effects 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%).

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

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