Phase III Study of Avapritinib in Patients With Advanced GIST Reaches Target Enrollment

Frank Jiang, PhD

Frank Jiang, PhD

The target number of patients with advanced gastrointestinal stromal tumors (GIST) have been enrolled in the phase III VOYAGER study in China, which is evaluating the safety and efficacy investigational drug avapritinib (BLU-285) in the third- or fourth-line settings, according to a press release from CStone Pharmaceuticals.¹

Top-line results from the VOYAGER study will be reported in the second quarter of 2020 by avapritinib developer, Blueprint Medicines. The United States FDA had accepted a new drug application (NDA) for the agent as a treatment for adults with PDGFRα exon 18—mutant GIST, regardless of prior therapy, and GIST in the fourth line. Contingent upon and an initial approval, a supplemental NDA for third-line avapritinib is also planned for submission to the FDA by the drug developer for the second half of 2020. A submission to the China National Medical Products Administration is also planned for that time.

Prior to the VOYAGER study, avapritinib had shown potential in this patient population in the phase I NAVIGATOR study. The overall response rate (ORR) observed in this study was 86% in the overall population of patients with PDGFRα exon 18—mutant GIST, and 22% when used in the fourth-line setting or later.²Prior reports from the NAVIGATOR trial in subjects who were regorafenib (Stivarga) naïve showed an ORR of 26% in both the third- and fourth-line settings, and 25% in the second-line setting.³

In patients with PDGFRα D842V-driven GIST the duration of response (DOR) not reached,³and those with heavily pretreated GIST in the fourth-line had a 10.2-month DOR.²

The median progression-free survival (PFS) in patients with PDGFRα exon 18 mutations was not reached. In patients who received treatment in the fourth-line or later setting, the median PFS was 3.7 months.³Those who were regorafenib-naïve in the third- or fourth-line setting had a median PFS of 8.6 months, according to previously reported data.²

Investigators determined that avapritinib was a tolerable drug for the study patient population, with the safety profile showing mostly grade 1 and 2 adverse events (AEs). The most common all-grade treatment-related adverse events (TRAEs) were nausea (59.3 %), fatigue (47.1%), anemia (36.3 %), cognitive effects (41.2 %), periorbital edema (40.2 %), vomiting (31.9%), decreased appetite (28.4 %), diarrhea (31.9 %), and increased lacrimation

(30.4%).²

The most common grade 3 and 4 TEAEs observed in patients included, anemia (16.2 %), fatigue (6.4 %), cognitive effects (3.9%), and diarrhea (2.9%). Treatment with avapritinib was discontinued by 8.3% of patients on the study, and 2% of those patients experienced cognitive effects.²

To date, the open-label, first-in-human NAVIGATOR study (NCT02508532) is active with a target completion date of January 2021.

Although patients with GIST do have a standard third-line option of regorafenib, which has a PFS of 4.8 months and an ORR of 5%, there is currently no option for patients who fail standard of care in the third-line setting. Avapritinb, therefore, can serve an unmet need if it is found to be safe and effective in the VOYAGER study.¹

“We are pleased that in China, the global phase III VOYAGER trial has completed its enrollment target sooner than planned, and this rapid progress reaffirms the urgent clinical needs of GIST patients in China,” said Frank Jiang, PhD, chairman and chief executive officer of CStone.

The phase III VOYAGER study (NCT03465722) randomizes patients to avapritinib 300 mg once daily, continuously, or comparator regorafenib 160 mg once daily for 3 out of every 4 weeks. The overall goal of the study is to determine if avapritinib prolongs PFS compared with regorafenib in patients with advanced GIST.

The co-secondary end points are ORR, overall survival, and treatment of cancer quality of life.

The study is currently active, but no longer enrolling patients. To be eligible, patients had to be aged 18 years or older with histologically confirmed metastatic or unresectable GIST and have an ECOG performance status of 0 or 1. These patients had to have receive prior treatment with imatinib (Gleevec) and 1 or 2 other tyrosine kinase inhibitors (TKIs). Patients who demonstrated intolerance to prior TKI treatment were required to have an objective disease progression prior to enrolling in the study.

Some of the exclusion criterion for the study included prior treatment with either drug used in the study, prior treatment with 3 or more TKIs, clinically significant cardiovascular disease, brain metastases, poor organ function, and several bleeding disorders.

The estimated completion date for the phase III VOYAGER study is April 2023.

References

1. CStone announces enrollment target reached in the global Phase III VOYAGER trial of avapritinib in Chinese patients with third-line GIST [press release]. Cstone Pharaceuticals: Suzhou, China; December 10, 2019.https://prn.to/38QnEYB. Accessed December 19, 2019.
2. Heinrich MC, Jones RL, von Mehren M, et al, Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST). Presented at: 2019 American Society of Oncology Annual Meeting; May 31- July 4, 2019; Chicago, Illinois. Abstract 11022.
3. Blueprint Medicines Announces Updated NAVIGATOR Trial Results in Patients with Advanced Gastrointestinal Stromal Tumors Supporting Development of Avapritinib Across All Lines of Therapy [press release]. Blueprint Medicines Corporation: Cambrige, Massachusetts; November 15, 2019.https://bit.ly/2Z3isMi. Accessed December 19, 2019.