Avapritinib Shows Potential for Patients With PDGRFA D842V-Mutant Gastrointestinal Stromal Tumors
Avapritinib showed anti-tumor activity and was well tolerated among Chinese patients with gastrointestinal stromal tumors (GISTs) who had platelet-derived growth factor receptor alpha (PDGFRA) D842V mutations, according to results from a phase 1/2 trial. There was also notable efficacy seen from avapritinib as a fourth- or later-line treatment for patients with GISTs without this mutation.
Avapritinib, a potent and selective small-molecule inhibitor targeting KIT proto-oncogene receptor tyrosine kinase (KIT) exon 17 and PDGFRA exon 18 mutations was approved by the Food and Drug Administration in the US in 2020 for unresectable or metastatic GISTs with PDGFRA exon 18 mutations. In the global, phase 1 NAVIGATOR study, Dr Jian Li, MD, Beijing Cancer Hospital & Institute, Beijing, China, and colleagues wrote, “the safety and preliminary clinical efficacy of avapritinib for PDFRA D842V-mutant GISTs were demonstration.” The current results are from the individual, open-label phase 1/2 bridging study.
This study enrolled 65 patients with unresectable/metastatic GISTs, all were treated with oral avapritinib once daily, with 6 patients receiving an initial dose of 200 mg and 59 patients receiving 300 mg. Patients with PDGFRA D842V mutations were eligible under any line setting while patients without the mutation had to have been treated with ≥3 prior lines of treatment. The primary end points of phase 1 were the recommended phase 2 dose, incidence of dose-limited toxicities, and safety. The primary end point of phase 2 was overall response rate (ORR).
The recommended phase 2 dose was determined to be 300 mg of avapritinib once daily orally. At the data cutoff date of January 8, 2021, 65 patients had received ≥1 dose of avapritinib. The Independent Radiology Review Committee (IRRC)-assessed ORR was 75% and the investigator-assess ORR was 49%. The clinical benefit rate was determined to be 86%, by both bodies. Neither the median duration of response nor progression free survival were reached. For patients in the fourth- or later-line setting, the ORR was 22% as assessed by IRRC and 35% as assessed by investigators, and both bodies found the median PFS of this group to be 5.6 months.
In both dose groups, the median treatment duration was 36 weeks. There were no dose-limited toxicities observed in the 10 patients included in the phase 1 dose-determining set (200 mg, n = 6; 300 mg, n = 4). Among all 65 patients, 100% of those in the 200 mg dose group and 98% of those in the 300 mg group experienced a treatment-related adverse event. There were 50.8% of patients who had a dose reduction, all from the 300 mg group, and 86.2% experienced a dose interruption. Discontinuation due to treatment-emergent adverse events occurred in 5% of patients, though none were determined to be related to avapritinib.
Grade ≥3 treatment-related adverse events were reported in 72% of all patients, with the most common, across both groups, being anemia (35%). In the 300 mg group, the most common grade ≥3 adverse events were decreased white blood cell count (19%), increased blood bilirubin levels (14%), and decreased neutrophil count (12%). There were 2 patients who experienced grade 4 treatment-related adverse events, both from the 300 mg dose group, and no grade 5 events were reported.
“Avapritinib had manageable safety and tolerability, consistent with NAVIGATOR. It demonstrated clinical benefit in Chinese patients with GIST bearing PDGFRA D842V mutation and promising preliminary anti-tumor activity as fourth- or later-line monotherapy,” concluded Dr Li, et al.
Source:
Li J, Zhang X, Den Y, et al. Efficacy and safety of avapritinib in treating unresectable or metastatic gastrointestinal stromal tumors: Phase I/II open-label, multicenter study. The Oncologist. Published online: December 7, 2022. doi:10.1093.oncolo/oyac242
