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

Margaret von Mehren,Saša Dimitrijević,Sergio Iannazzo,Silvia Chiroli,Gerard Hoehn,Suzanne George,Hongliang Shi,Michael C. Heinrich,Raymond Mankoski

doi:10.1186/s12885-021-08013-1

Abstract

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 300 mg (recommended phase 2 dose) or 400 mg (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 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P = 0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 (P = 0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months 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.

Highlights

Avapritinib, 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)
Patients A total of 56 patients in NAVIGATOR and 19 patients in Study 1002 were included in the analysis; of the 56 patients in NAVIGATOR, a subgroup of 38 patients who started avapritinib treatment at 300 mg or 400 mg was analyzed separately (Fig. 1)
22 patients were included in Study 1002 in total, three were excluded from the current analysis as the first tyrosine kinase inhibitor (TKI) treatment for unresectable/metastatic GIST could not be identified

Summary

Introduction

Avapritinib, 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). Over 85% of gastrointestinal stromal tumors (GIST) are driven by oncogenic mutations of the genes encoding KIT and/or platelet-derived growth factor receptor A (PDGFRA) receptor tyrosine kinases [1, 2]. Tyrosine kinase inhibitors (TKIs), developed to target pathogenic mutant kinases, have revolutionized the treatment landscape for patients with unresectable or metastatic GIST over the past two decades [7]. Patients with unresectable/metastatic PDGFRA D842Vmutant GIST have a poor prognosis because imatinib and other approved TKIs lack activity against PDGFRA D842V-mutant kinases [3, 11, 12]. Median progression-free survival (PFS) is between 2 and 10 months and median overall survival (OS) is approximately 9–25 months [13, 14, 17], thereby highlighting the urgent unmet medical need for patients with unresectable/metastatic GIST harboring the PDGFRA D842V mutation

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Results

Discussion

Conclusion