Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors

The oncologist

article

Cissimol P. Joseph¹  Jonathan Trent²  Eric D. Tetzlaff³  Tuan Dong Si⁴  Teresa Zhou⁴  Ashley Doyle⁴  Sebastian Bauer⁵  Maria Roche⁴  Tracy Havnaer⁶  Sarah N. Abaricia⁷  Michelle A. Angelis⁸  Kathleen Polson⁹  Robin L. Jones^1,10  Yoon-Koo Kang^1,11  Richard F. Riedel^1,12  Patrick Schöffski^1,13  César Serrano^1,14 

[1] The University of Texas MD Anderson Cancer Center;Sylvester Comprehensive Cancer Center, University of Miami;Fox Chase Cancer Center;Blueprint Medicines Corporation;University of Duisburg-Essen;Oregon Health & Science University;Washington University School of Medicine;James Cancer Hospital and Solove Research Institute and The Ohio State University Wexner Medical Center;Dana-Farber Cancer Institute;Royal Marsden Hospital and Institute of Cancer Research;Asan Medical Center, University of Ulsan;Duke Cancer Institute, Duke University Medical Center;University Hospitals Leuven, Leuven Cancer Institute;Vall d'Hebron Institute of Oncology

关键词: Avapritinib;    Gastrointestinal stromal tumor;    Cognitive effects;    PDGFRA;    KIT;   

DOI  :  10.1002/onco.13632

学科分类：地质学

来源: AlphaMed Press Incorporated

【 摘 要 】

Background Avapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence-based guidance on management of avapritinib-associated adverse events (AEs), including cognitive effects and intracranial bleeding. Materials and Methods We performed a post hoc analysis of data from a two-part, single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30–600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression-free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose). Results Of 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started avapritinib at 300 mg. The most common treatment-related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment-related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all-cause cognitive effects rate (grade 1–2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3–3.1 weeks) than without (4.9–7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without. Conclusion Tolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs. Implications for Practice Early recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment-related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events.

【 授权许可】

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