Assessment, Analysis, and Discussion
GIST, confusional, anemia, liver injury, memory impairment, cognitive disorder
ADVERSE EVENTS, ANEMIA, ENCEPHALOPATHY, GIST, EVENTS
The present phase I/II bridging study showed that avapritinib had a generally tolerable safety profile in patients with advanced GIST in China. Most treatment-emergent adverse events (TEAEs) were grade 1 or 2 and were manageable. In the 300-mg (RP2D) dose group, 25% of patients experienced serious TRAEs. The most frequent TRAEs included anemia (80%) and blood bilirubin increased (75%). Based on clinical observation, treatment could have contributed to a further decrease in hemoglobin for patients with anemia at baseline. Concerning another common AE, bilirubin increase, we found that this AE was primarily associated with indirect bilirubin increase, but not direct bilirubin increase. Additionally, symptomatic liver injury was not observed simultaneously in these patients. Similarly, although creatine kinase increase was also a common AE in this study, none of the events resulted in significant clinical symptoms.The AESIs observed in the study are consistent with the previously reported safety profiles for avapritinib. Cognitive effects related to avapritinib (memory impairment, cognitive disorder, confusional state, and encephalopathy) seem to be reversible and can be managed with dose reductions or brief interruptions. Recognition and awareness of these AEs are important for patient management.In the NAVIGATOR study, avapritinib demonstrated unprecedented, durable anti-tumor activity in heavily pretreated patients with advanced GIST harboring PDGFRA D842V mutations, providing an ORR of 91% (51/56 patients).The NAVIGATOR study assessed efficacy and safety in patients without PDGFRA D842V mutation in the fourth- or later-line cohort and reported an ORR of 17% and median PFS of 3.7 months.In this China-specific study, we conducted an exploratory efficacy analysis per IRRC assessment according to Choi criteria. ORRs were 89% and 52% in the PDGFRA D842V and fourth- or later-line populations, respectively, indicating visible differences between the results evaluated per Choi and mRECIST criteria and a numerically higher ORR per Choi criteria. The common metastatic sites of GIST are the peritoneum and liver,This study had limitations, including the open-label design, lack of a control/comparator group, and the small sample size, because of the low rate of incidence and mutation. The key strength of this study was that it targeted Chinese patients with PDGFRA D842V-mutant GIST, and those who had received at least 3 prior lines of therapy, which represents a currently important unmet need.In conclusion, avapritinib provided pronounced anti-tumor activity in patients with PDGFRA D842V mutations and those who had received at least 3 prior lines of therapy. The demonstrated therapeutic activity and favorable safety profile of avapritinib in the PDGFRA D842V study population indicate that avapritinib may be an effective treatment for GIST patients with PDGFRA D842V mutations. The National Medical Products Administration has approved avapritinib as SOC for patients with PDGFRA D842V-mutant GIST in China based on this study, in combination with the global NAVIGATOR study.