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.

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 .

• Authors: Margaret von Mehren, Michael C Heinrich, Hongliang Shi, Sergio Iannazzo, Raymond Mankoski, Saša Dimitrijević, Gerard Hoehn, Silvia Chiroli, Suzanne George
• Journal: BMC cancer (BMC Cancer) Vol. 21 Issue 1 Pg. 291 (Mar 19 2021) ISSN: 1471-2407 [Electronic] England
• PMID: 33740926 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Protein Kinase Inhibitors
• Pyrazoles
• Pyrroles
• Triazines
• avapritinib
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Clinical Trials, Phase I as Topic
• Female
• Gastrointestinal Stromal Tumors (drug therapy, genetics, mortality)
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Progression-Free Survival
• Protein Kinase Inhibitors (administration & dosage, adverse effects)
• Pyrazoles (administration & dosage, adverse effects)
• Pyrroles (administration & dosage, adverse effects)
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors, genetics)
• Retrospective Studies
• Triazines (administration & dosage, adverse effects)