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Comparative Study
. 2021 Mar 19;21(1):291.
doi: 10.1186/s12885-021-08013-1.

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  1 , Michael C Heinrich  2 , Hongliang Shi  3 , Sergio Iannazzo  3 , Raymond Mankoski  3 , Saša Dimitrijević  3 , Gerard Hoehn  3 , Silvia Chiroli  3 , Suzanne George  4
Affiliations
Comparative Study

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 et al. BMC Cancer. .

Abstract

Background: 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).

Methods: This 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.

Results: Fifty-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.

Conclusions: In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST.

Trial registration: The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .

Keywords: Avapritinib; GIST; PDGFRA D842V mutation.

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Conflict of interest statement

Dr. von Mehren reported receiving other support from Arog Pharmaceuticals and Deciphera Pharmaceuticals outside the submitted work and other support from Blueprint Medicines Corporation during the conduct of the study. Dr. von Mehren and Dr. Heinrich both report funding from GIST Cancer Research Fund and the Jonathan David Foundation. Dr. Heinrich reports grants and personal fees from Blueprint Medicines Corporation, and a US Veterans Administration Merit Review Grant (I01 BX000338, MCH) during the conduct of the study, grants and personal fees from Deciphera Pharmaceuticals, outside the submitted work, other from MolecularMD, during the conduct of the study and personal fees and other from Novartis; in addition, Dr. Heinrich has a patent “Treatment of Gastrointestinal Stromal Tumors” licensed to Novartis, and having a patent “Activating Mutations of PDGFRA” issued. At the time of development of this study, Sergio Iannazzo was employed by Hetegy, a health economics consulting company which received consulting fees from Blueprint Medicines Corporation. Sergio Iannazzo is currently an employee and shareholder of Blueprint Medicines Corporation. Dr. George reports personal fees from Bayer, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly, Exelixis, MORE Health, Research to Practice and UpToDate, and grants from ARIAD, Bayer, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Novartis, Pfizer, outside the submitted work; stock in Abbott Laboratories and Allergan; expert testimony for Bayer; relationship with Research to Practice; and royalties from UpToDate. Hongliang Shi, Raymond Mankoski, Saša Dimitrijević, Gerard Hoehn and Silvia Chiroli are employees and shareholders of Blueprint Medicines Corporation.

Figures

Fig. 1
Fig. 1
Patient disposition. Abbreviations: GIST, gastrointestinal stromal tumor; PDGFRA, platelet-derived growth factor receptor A; TKI, tyrosine kinase inhibitor. aEnrollment at the data cutoff of November 16, 2018. bThe D842V population included all patients with PDGFRA D842V mutations from part 1 and part 2. cAll patients were treated with an approved treatment for GIST or investigational TKI, with initial treatment administered between January 1, 2000, and July 1, 2016
Fig. 2
Fig. 2
Adjusted Kaplan–Meier overall survival estimates. a Overall NAVIGATOR population vs Study 1002. b NAVIGATOR 300/400 mg subgroup vs Study 1002. c Adjusted OS landmark analyses for NAVIGATOR population and Study 1002. d Adjusted OS landmark analyses for NAVIGATOR 300/400 mg subgroup and Study 1002
Fig. 3
Fig. 3
Unadjusted Kaplan–Meier overall survival estimates. a Overall NAVIGATOR population vs Study 1002. b NAVIGATOR 300/400 mg subgroup vs Study 1002. c Undjusted OS landmark analyses for NAVIGATOR population and Study 1002. d Unadjusted OS landmark analyses for NAVIGATOR 300/400 mg subgroup and Study 1002
Fig. 4
Fig. 4
Adjusted Kaplan–Meier progression-free survival estimates. a Overall NAVIGATOR population vs Study 1002. b NAVIGATOR 300/400 mg subgroup vs Study 1002. c Adjusted PFS landmark analyses for NAVIGATOR population and Study 1002. d Adjusted PFS analyses for NAVIGATOR 300/400 mg subgroup and Study 1002
Fig. 5
Fig. 5
Unadjusted Kaplan–Meier progression-free survival estimates. a Overall NAVIGATOR population vs Study 1002. b NAVIGATOR 300/400 mg subgroup vs Study 1002. c Unadjusted PFS landmark analyses for NAVIGATOR population and Study 1002. d Unadjusted PFS analyses for NAVIGATOR 300/400 mg subgroup and Study 1002
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