The European Commission has granted a conditional marketing authorization to avapritinib for single agent use in adult patients with unresectable or metastatic gastrointestinal stromal tumors that harbor a PDGFRA D842V mutation.
The European Commission has granted a conditional marketing authorization to avapritinib (Ayvakyt) for single agent use in adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) that harbor a PDGFRA D842V mutation.1
The regulatory decision is based on efficacy data from the phase 1 NAVIGATOR trial (NCT02508532), along with combined safety findings from the NAVIGATOR and phase 3 VOYAGER trials. Altogether, avapritinib was found to showcase deep and durable clinical activity with an acceptable safety profile in previously treated and untreated patients with PDGFRA D842V–mutant GIST.
A total of 38 patients with PDGFRA D842V–mutant GIST were enrolled on the NAVIGATOR trial and received a starting dose of 300 mg or 400 mg of avapritinib once daily. Results presented during the 2020 ESMO Virtual Congress showed that avapritinib elicited an overall response rate (ORR) with the agent was 95% (95% CI, 82.3%-99.4%); 13% of patients experienced a complete response (CR), and the median duration of response (DOR) was 22.1 months (95% CI, 14.1–not estimable).2 Moreover, the median progression-free survival (PFS) reported with avapritinib in these patients was 24 months, while the median overall survival (OS) had not yet been reached.
“There have historically been no treatments offering hope for patients with PDGFRA D842V–mutant GIST. [Avapritinib] represents the first major therapeutic breakthrough for patients with GIST harboring this mutation, defining a new standard of care,” Sebastian Bauer, MD, medical oncologist at the West German Cancer Center, stated in a press release.
In the open-label, first-in-human, phase 1 NAVIGATOR trial, investigators set out to examine the safety and efficacy of avapritinib at the recommended phase 2 dose and maximum-tolerated dose in patients with unresectable or metastatic GIST.
To be eligible for inclusion on the dose-escalation portion of the trial, patients had to have unresectable disease and have progressed after imatinib (Gleevec) and 1 or more other TKIs or have a PDGFRA D842V mutation. Twenty-three patients had KIT-mutant GIST, while 23 had PDGFRA-mutant GIST; 3 patients had tumors that harbored mutations beyond D842V and 20 patients had PDGFRA D842V–mutated disease.
The dose-expansion portion of the trial enrolled patients with unresectable GIST. The total population of patients with PDGFRA D842V–mutated disease was 56; group 2 was comprised of 36 patients. Patients without D842V mutations who were treated with 2 or more prior lines of TKIs comprised group 1 (n = 126) and those without the mutations who were only treated with 1 prior line of TKI treatment comprised group 3 (n = 42). The safety population was comprised of a total of 250 participants.
With regard to safety, the most commonly reported adverse effects (AEs) that occurred in 30% or more of participants included nausea (64% in the safety population), anemia (54%), diarrhea (45%), fatigue (63%), memory impairment (32%), periorbital edema (44%), decreased appetite (40%), increased lacrimation (35%), vomiting (42%), peripheral edema (32%), abdominal pain (26%), increased blood bilirubin (22%), and hypokalemia (19%).
AEs of special interest included cognitive effects (46%), such as memory impairment (32%), confusional state (7%), cognitive disorder (11%), and encephalopathy (2%). Intracranial bleeding was also reported in 3% of patients, with 1% experiencing intracranial hemorrhage, less than 1% having cerebral hemorrhage, and 1% reporting subdural hematoma.
Overall, 34% (n = 13) of participants with PDGFRA D842V–mutant disease who received 300 mg or 400 mg of avapritinib discontinued treatment because of any-cause toxicities. Twenty-one percent of participants (n = 8) discontinued treatment because of treatment-related AEs.
Earlier results from NAVIGATOR helped to support the FDA approval of the agent for use in patients with PDGFRA exon 18–mutant GIST. Results demonstrated that avapritinib elicited an ORR of 84% (95% CI, 69%-93%) in that specific patient population; this was comprised of a 7% CR rate and a 77% partial response rate.3
“The NAVIGATOR trial confirmed that almost all patients with PDGFRA D842V–mutant GIST achieved tumor shrinkage and clinical responses were durable. These patients have lived longer than what is expected based on historical outcomes, and [adverse] effects have been well tolerated in most patients,” Bauer added. “With this approval, it is more important than ever to conduct mutational testing prior to first-line treatment, so that patients with PDGFRA D842V–mutant GIST may begin therapy with [avapritinib], the only effective treatment for their tumor type.”
Topline results from the phase 3 VOYAGER trial (NCT03465722) showed that the agent did not improve PFS compared with regorafenib (Stivarga) in previously treated patients with locally advanced unresectable or metastatic GIST, missing the primary end point.4 Avapritinib led to a median PFS of 4.2 months versus 5.6 months with regorafenib; this difference was not determined to be of statistical significance. The ORR with avapritinib was 17% versus 7% with regorafenib.
In the open-label trial, participants with third- or fourth-line GIST were randomized to avapritinib (n = 240) or regorafenib (n = 236). To be eligible for inclusion, patients had to have locally advanced unresectable or metastatic GIST and had previously been treated with imatinib and 1 or 2 other TKIs. In the trial, participants were given oral avapritinib at a daily dose of 300 mg or oral regorafenib at a daily dose of 160 mg on a 3-weeks-on/1-week-off schedule. The primary end point of the trial was PFS, while key secondary end points included ORR, OS, and quality of life.
In May 2020, the FDA issued a complete response letter to Blueprint Medicines Corporation stating that it would not approve the new drug application for avapritinib for the treatment of adult patients with unresectable or metastatic fourth-line GIST.5
The company plans to initiate its first commercial launch of avapritinib in Germany following the European approval. The timing of accessibility to the agent will vary for other countries depending on local reimbursement and access pathways. The agent will be available in different doses, including 100 mg, 200 mg, and 300 mg, with 300 mg being the recommended starting dose for use once daily.
In accordance with the marketing authorization, the company will conduct an observational long-term study examining avapritinib in patients with PDGFRA D842V–mutated GIST.