As reported in The Lancet Oncology by Heinrich et al, the phase I NAVIGATOR trial showed that the PDGFRA and KIT kinase inhibitor avapritinib produced a response in patients with PDGFRA D842V–mutant gastrointestinal stromal tumors (GIST).
The study supported the January 2020 approval of avapritinib at 300 mg/d for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations.
Study Details
The international study included 46 patients with unresectable GIST (including 20 with PDGFRA D842V–mutant disease) in a dose-escalation phase, with an additional 36 patients with PDGFRA D842V–mutant disease being added in a dose-expansion phase.
In the dose-escalation phase, in which patients received 30 mg to 600 mg of avapritinib daily, the maximum tolerated dose was determined to be 400 mg daily. This dose was initially used as the starting dose in the dose-expansion phase, but due to toxicity (primarily an excess of grade 3 cognitive events and a frequent need for dose reduction), the starting dose was subsequently reduced to 300 mg once daily.
Overall, starting doses were < 300 mg/d in 30 patients, 300 mg/d in 32, 400 mg/d in 17, and 600 mg/d in 3. Treatment was given in continuous 28-day cycles until disease progression or unacceptable toxicity.
Among all 82 patients, the median age was 62 years. A total of 87% had received one or more previous tyrosine kinase inhibitors, and 21% had received five or more.
Responses
As of data cutoff (November 2018), median follow-up was 15.9 months. At this time, 66% of patents remained on treatment. Among all 56 patients with a D842V mutation treated with any dose, objective response on central review using modified Response Evaluation Criteria in Solid Tumors version 1.1 was observed in 49 (88%), with complete response in 5 (9%); an additional 7 patients (13%) had stable disease. Median duration of response was not reached, with 70% of responders having ongoing response at 12 months.
Progression-free survival was 100% at 3 months, 94% at 6 months, and 81% at 12 months. Overall survival was estimated at 100% at 6 months, 91% at 12 months, and 81% at 24 months.
KEY POINTS
- Treatment with avapritinib produced an objective response rate of 88%, with stable disease observed in the remainder of patients.
- Cognitive adverse events occurred in 40% of patients, and were grade 1 in most.
Among the 28 patients who received a starting dose of 300 mg, objective response was observed in 26 (93%), with complete response in 1 (4%); an additional 2 patients (7%) had stable disease.
Adverse Events
In the dose-escalation phase, dose-limiting toxicities occurred in two patients receiving 600 mg of avapritinib per day, consisting of grade 2 hypertension, dermatitis acneiform, and memory impairment in one patient, and grade 2 hyperbilirubinemia in the other.
Most treatment-related adverse events were grade 1 or 2. Among 32 patients treated with a starting dose of 300 mg/d, the most commonly reported treatment-related grade 1 or 2 adverse events were nausea (69%), diarrhea (41%), decreased appetite (38%), and fatigue (38%). Among 17 patients receiving a starting dose of 400 mg/d, the most commonly reported treatment-related grade 1 or 2 adverse events were nausea (71%), vomiting (47%), fatigue (47%), and periorbital edema (47%).
Across all doses, treatment-related grade 3 or 4 adverse events occurred in 47 (57%) of all 82 patients receiving avapritinib, with the most common being anemia (17%). Grade 3 or 4 events occurred in 65% of patients with a starting dose of 300 mg/d, with the most common being anemia (22%; all grade 3), and in 53% of those with a starting dose of 400 mg, with the most common being diarrhea (18%; all grade 3).
Among all 84 patients, treatment-related serious adverse events of any grade occurred in 26%, with the majority being grade 3; the most common of any grade were anemia (4%), pleural effusion (4%), diarrhea (2%), and vertigo (2%). Treatment was discontinued due to adverse events in 15 patients (18%); 10 adverse events were considered treatment-related. No treatment-related deaths were reported.
Cognitive effects and intracranial bleeding were considered adverse events of special interest. Cognitive adverse events irrespective of causality attribution occurred in 33 patients (40%; grade 1 in 19) and included memory impairment (30%), cognitive disorder (10%), confusional state (9%), and encephalopathy (2%). Intracranial bleeding occurred in two patients (2%, grade 3 in both).
The investigators concluded, “Our data show that avapritinib is clinically active in patients with PDGFRA D842V–mutated GIST. Most adverse events associated with avapritinib were grade 1–2; these adverse events were generally proportional to dose and exposure. Although cognitive effects are a concern, these effects were manageable for most patients through dose modifications…Overall, we found that avapritinib had clinical activity and a manageable safety profile in patients with advanced, PDGFRA D842V–driven GIST.”
Michael C. Heinrich, MD, of the VA Portland Health Care System and Oregon Health & Science University Knight Cancer Institute, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Blueprint Medicines. For full disclosures of the study authors, visit thelancet.com.
