Michael C. Heinrich, MD

As reported inThe Lancet Oncology by Michael C. Heinrich, MD, of the VA Portland Health Care System and the Oregon Health & Science University Knight Cancer Institute, and colleagues, the phase I NAVIGATOR trial showed that the PDGFRA and KIT kinase inhibitor avapritinib produced a high response rate in patients with PDGFRA D842V–mutant gastrointestinal stromal tumor (GIST).¹ The study supported the January 2020 approval of avapritinib at 300 mg/d for treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations.

Study Details

The international study encompassed 46 patients with unresectable GIST, including 20 with PDGFRA D842V-mutant disease, in a dose-escalation phase. An additional 36 patients with PDGFRA D842V-mutant disease were included during a dose-expansion phase.

In the dose-escalation phase, during which patients received avapritinib at 30 to 600 mg/d, the maximum tolerated dose was 400 mg/d. This was initially 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/d. 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, median age was 62 years. A total of 87% had received at least one previous tyrosine kinase inhibitor and 21% had received at least five.

Responses

As of data cutoff (November 2018), the median follow-up was at 15.9 months. At this time, 66% of patents remained on treatment. Among all 56 patients with D842V mutation who were 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 demonstrating an 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.

Among the 28 patients who received a starting dose of 300 mg, an objective response was observed in 26 (93%), with a 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 at 600 mg/d, consisting of grade 2 hypertension, dermatitis acneiform, and memory impairment in one patient, and grade 2 hyperbilirubinemia in one patient.

Most treatment-related adverse events were grade 1 or 2. Among 32 patients treated with a starting dose of 300 mg/d, the most common 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 common 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 of 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, consisting of worsening dizziness, acute psychotic episode, worsening cognitive disorder, multifocal brain hemorrhage, memory impairment, frontolobal encephalopathy, gastric hemorrhage, intracranial bleeding, hyperbilirubinemia, and encephalopathy. 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 D842V-mutated gastrointestinal stromal tumours. 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, including dose interruptions with or without dose reductions; two (2%) of 82 patients discontinued treatment because of intracranial bleeding. Overall, we found that avapritinib had clinical activity and a manageable safety profile in patients with advanced, PDGFRA D842V-driven gastrointestinal stromal tumours.” 

DISCLOSURE: The study was funded by Blueprint Medicines. Dr. Heinrich holds stock or other ownership interests in MolecularMD; has received honoraria from Novartis; has served in a consulting or advisory role for Blueprint Medicines, Deciphera, MolecularMD, and Novartis; holds an institutional patent for the treatment of GIST; and has provided expert testimony on behalf of Novartis.

REFERENCE

1. Heinrich MC, Jones RL, von Mehren M, et al: Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): A multicentre, open-label, phase I trial. Lancet Oncol 21:935-946, 2020.