Clinical efficacy comparison of avapritinib with other tyrosine kinase inhibitors in gastrointestinal stromal tumors with PDGFRA D842V mutation: a retrospective analysis of clinical trial and real-world data

BackgroundAvapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST).MethodsThis retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan-Meier survival curves were compared by Cox regression.ResultsFifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300mg (recommended phase 2 dose) or 400mg (maximum tolerated dose) avapritinib starting dose (n=38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan-Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6months for Study 1002 patients; OS rate at 6/48months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P= 0.0001). In the 300/400mg subgroup, adjusted OS rates at 6/36months were 100%/73 and 68%/20% in Study 1002 (P= 0.0016). Adjusted median PFS was 29.5months in NAVIGATOR and 3.4months in Study 1002.ConclusionsIn this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST.Trial registrationThe NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532.

Automated summary

Avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST, showing significant clinical activity and a favorable overall survival rate.