PMID- 33301227 OWN - NLM STAT- MEDLINE DCOM- 20210618 LR - 20240331 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 26 IP - 4 DP - 2021 Apr TI - Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors. PG - e622-e631 LID - 10.1002/onco.13632 [doi] AB - 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. CI - (c) 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. FAU - Joseph, Cissimol P AU - Joseph CP AD - The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. FAU - Abaricia, Sarah N AU - Abaricia SN AD - Washington University School of Medicine, St. Louis, Missouri, USA. FAU - Angelis, Michelle A AU - Angelis MA AD - James Cancer Hospital and Solove Research Institute and The Ohio State University Wexner Medical Center, Columbus, Ohio, USA. FAU - Polson, Kathleen AU - Polson K AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Jones, Robin L AU - Jones RL AD - Royal Marsden Hospital and Institute of Cancer Research, London, England. FAU - Kang, Yoon-Koo AU - Kang YK AD - Asan Medical Center, University of Ulsan, Seoul, South Korea. FAU - Riedel, Richard F AU - Riedel RF AD - Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA. FAU - Schoffski, Patrick AU - Schoffski P AD - University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium. FAU - Serrano, Cesar AU - Serrano C AD - Vall d'Hebron Institute of Oncology, Barcelona, Spain. FAU - Trent, Jonathan AU - Trent J AD - Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA. FAU - Tetzlaff, Eric D AU - Tetzlaff ED AD - Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. FAU - Si, Tuan Dong AU - Si TD AD - Blueprint Medicines Corporation, Cambridge, Massachusetts, USA. FAU - Zhou, Teresa AU - Zhou T AD - Blueprint Medicines Corporation, Cambridge, Massachusetts, USA. FAU - Doyle, Ashley AU - Doyle A AD - Blueprint Medicines Corporation, Cambridge, Massachusetts, USA. FAU - Bauer, Sebastian AU - Bauer S AD - University of Duisburg-Essen, Essen, Germany. FAU - Roche, Maria AU - Roche M AD - Blueprint Medicines Corporation, Cambridge, Massachusetts, USA. FAU - Havnaer, Tracy AU - Havnaer T AD - Oregon Health & Science University, Portland, Oregon, USA. LA - eng SI - ClinicalTrials.gov/NCT02508532 GR - Not applicable/Blueprint Medicines Corporation/ PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210105 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Pyrazoles) RN - 0 (Pyrroles) RN - 0 (Triazines) RN - 513P80B4YJ (avapritinib) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit) RN - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor alpha) SB - IM MH - Adult MH - *Gastrointestinal Stromal Tumors/drug therapy/genetics MH - Humans MH - Mutation MH - Proto-Oncogene Proteins c-kit/genetics MH - Pyrazoles MH - Pyrroles MH - Receptor, Platelet-Derived Growth Factor alpha/genetics MH - Triazines PMC - PMC8018323 OTO - NOTNLM OT - Avapritinib OT - Cognitive effects OT - Gastrointestinal stromal tumor OT - KIT OT - PDGFRA COIS- Disclosures of potential conflicts of interest may be found at the end of this article. EDAT- 2020/12/11 06:00 MHDA- 2021/06/22 06:00 PMCR- 2021/04/01 CRDT- 2020/12/10 12:19 PHST- 2020/08/07 00:00 [received] PHST- 2020/11/25 00:00 [accepted] PHST- 2020/12/11 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/12/10 12:19 [entrez] PHST- 2021/04/01 00:00 [pmc-release] AID - ONCO13632 [pii] AID - 10.1002/onco.13632 [doi] PST - ppublish SO - Oncologist. 2021 Apr;26(4):e622-e631. doi: 10.1002/onco.13632. Epub 2021 Jan 5.