Avapritinib Falls Short in Third- and Fourth-Line Gastrointestinal Stromal Tumors


"While we are disappointed by the outcome of the VOYAGER trial, we are deeply grateful to the patients, investigators, and clinical site staff who contributed to the completion of this global study."

Avapritinib (Ayvakit) monotherapy did not improve progression-free survival (PFS) in patients with locally advanced unresectable or metastatic gastrointestinal stromal tumor (GIST) compared with regorafenib (Stivarga), missing the primary end point of the phase III VOYAGER trial, according to top-line results announced by Blueprint Medicines, Inc, in a press release.1

"While we are disappointed by the outcome of the VOYAGER trial, we are deeply grateful to the patients, investigators, and clinical site staff who contributed to the completion of this global study. We hope these data will reveal important insights to improve the scientific understanding of the disease and inform future innovations in GIST, and we are committed to sharing the results at a future medical meeting," said Jeff Albers, chief executive officer, Blueprint Medicines, in a statement.

A total of 240 patients were treated with avapritinib in the study and the remaining 236 received regorafenib. The median PFS observed with avapritinib was 4.2 months compared with 5.6 months in the regorafenib group. The difference between the arms was not statistically significant. The overall response rate (ORR) was 17% with avapritinib versus 7% for the control.

Top-line safety results showed that avapritinib was well-tolerated in patients. Most of the adverse events observed with the drug were grades 1 or 2. Additionally, the safety profile of avapritinib was similar to prior data on the drug with no new safety signals.

In the international, multicenter, open-label, randomized VOYAGER study, avapritinib was administered at 300 mg once daily and the comparator, regorafenib was administered at 160 mg once daily for three weeks. The secondary end point of the study included ORR, overall survival, and quality of life.

Top-line results from this study are a downward dive for the efficacy of avapritinib. Previously, the agent showed promise in patients with GIST in the phase I NAVIGATOR study (NCT02508532). In the study avapritinib demonstrated clinical activity in patients KIT- and PDGFRA-mutant GIST that was resistant to all available therapies, and the VOYAGER study was launched based on the NAVIGATOR findings.2

According to data presented at the 2020 Gastrointestinal Cancers Symposium (GI 2020), avapritinib achieved an 86% ORR in 43 evaluable patients with PDGFRA-mutant GIST, which included 3 complete responses (CRs) and 34 partial responses (PRs) with 1 response pending. Stable disease (SD) was seen in 52 patients. The median duration of response (DOR) was not reached in the PDGFRA-mutated patients, but it was notable that 78% of patients had continued responses at the time of data cutoff.

In the 111 evaluable patients with fourth-line GIST, the median ORR was 22%. Of the responses in this subgroup, there was 1 CRs and 23 PRs with 1 response pending. Five patients in this group had SD. The median DOR was not reached in the PDGFRA-mutated patients, but, in the fourth-line group, the median DOR was 10.2 months with a median follow-up of 10.8 months.

The safety analysis showed that avapritinib was tolerable at both the 300 mg and 400 mg dose level, and most adverse events (AEs) observed were grades 1 and 2. Twenty-five percent of patients experienced treatment-emergent AEs, of which the most common were nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (29%). Grade 3 or 4 AEs occurred in about 2% of patients, and the most common were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Overall, 8.3% of patients discontinued treatment as a result of an AE.

Based on NAVIGATOR, experts hypothesized that avapritinib had the potential to change the treatment landscape for patients with advanced GIST. The study results later served as the basis for the FDA approval of avapritinib as treatment of adults with unresectable or metastatic GIST who harbor a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. Avapritinib was the first precision medicine therapy for the treatment of a genomically-altered population of patients with GIST.3

Further analyses from the VOYAGER study, which may include OS, ORR, and quality of life reports, are ongoing and will be presented at an upcoming medical meeting.1


1. Blueprint Medicines announces top-line results from phase 3 VOYAGER trial of avapritinib versus regorafenib in patients with advanced gastrointestinal stromal tumor [news release]. Cambridge, Massachusetts: Blueprint Medicines, Inc; April 28, 2020. https://bit.ly/2zDRORC. Accessed April 28, 2020.

2. Heinrich MC, Jones EL, von Mehren M, et al. Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST). J Clin Oncol. 2020; 38 (4). Abstract 826.

3. Medicines announces FDA approval of Ayvaki (avapritinib) for the treatment of adults with unresectable or metastatic PDGFRA exon 18 mutant gastrointestinal stromal tumor [news release]. Cambridge, Massachusetts: Blueprint Medicines, Inc; January 9, 2020. https://bit.ly/35blWiS. Accessed April 28, 2020.

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