Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.
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DOI：
10.1002/onco.13632
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Havnaer T
中科院分区：
文献类型：
--
作者：
Joseph CP;Abaricia SN;Angelis MA;Polson K;Jones RL;Kang YK;Riedel RF;Schöffski P;Serrano C;Trent J;Tetzlaff ED;Si TD;Zhou T;Doyle A;Bauer S;Roche M;Havnaer T
Avapritinib是一种新型KIT/PDGFRA抑制剂，在美国获批用于治疗患有PDGFRA外显子18突变型不可切除或转移性胃肠道间质瘤（U/M GIST）的成人。我们评估了avapritinib的安全性，并提供了关于avapritinib相关不良事件（AE）管理的循证指南，包括认知影响和颅内出血。我们对一项两部分、单组剂量递增/扩展I期研究（NAVIGATOR; NCT 02508532）的数据进行了事后分析，该研究在接受口服avapritinib 30-600 mg每日一次治疗的U/M GIST患者中进行。主要终点是安全性和耐受性;剂量调整（中断和/或减量）对无进展生存期（PFS）的影响是次要终点。疗效分析仅限于以300 mg（批准剂量）开始avapritinib治疗的患者。在入组研究的250例患者中，74.0%的患者出现KIT突变，24.8%的患者出现PDGFRA 18号外显子突变; 66.8%的患者开始接受300 mg avapritinib治疗。最常见的治疗相关AE（任何级别）为恶心（59.2%）、疲乏（50.0%）、眶周水肿（42.0%）、贫血（39.2%）、腹泻（36.0%）、呕吐（36.0%）和流泪增多（30.8%）。未发生治疗相关死亡。在167例开始接受300 mg Avapritinib治疗的患者中，所有患者的全因认知效应发生率（1-2级）为37.0%，≥65岁的患者为52.0%。剂量调整后（1.3-3.1周）的认知效应改善至较低级别的速度快于未调整剂量（4.9-7.6周）。调整剂量后的中位PFS为11.4个月，未调整剂量的中位PFS为7.2个月。耐受性指导的avapritinib剂量调整是管理GIST患者AE的有效策略。早期识别不良事件和量身定制的剂量调整似乎是管理治疗相关不良事件和维持患者接受avapritinib治疗的有效方法。剂量降低似乎不会导致疗效降低。应在基线时评估患者的认知功能，并在avapritinib治疗期间仔细监测认知不良事件的发生。建议在首次出现任何认知效应（包括1级事件）时中断给药。本报告全面评估了avapritinib每日一次给药方案的安全性和耐受性，并为发生不良事件（包括认知影响和颅内出血）的患者的管理提供了循证指南，以及剂量中断和/或减量对该药物疗效的任何潜在影响。
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. 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). 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. Tolerability‐guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs. 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. This report provides a comprehensive assessment of the safety and tolerability of an avapritinib once‐daily regimen and evidence‐based guidance on the management of patients with adverse events, including cognitive effects and intracranial bleeding, and any potential effects of dose interruption and/or reduction on efficacy of this agent.
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影响因子：
4.6
作者：
Giampieri R;Prete MD;Prochilo T;Puzzoni M;Pusceddu V;Pani F;Maccaroni E;Mascia R;Baleani MG;Meletani T;Berardi R;Lanzillo AM;Mariotti S;Zaniboni A;Cascinu S;Scartozzi M
通讯作者：
Scartozzi M
影响因子：
4.9
作者：
McShane TM;Wolfe TA;Ryan JC
通讯作者：
Ryan JC
DOI：
10.1097/coc.0000000000000659
发表时间：
2020-04-01
影响因子：
2.6
作者：
Florindez, Jorge;Trent, Jonathan
通讯作者：
Trent, Jonathan
影响因子：
11.5
作者：
Cassier, Philippe A.;Fumagalli, Elena;Hohenberger, Peter
通讯作者：
Hohenberger, Peter
影响因子：
51.1
作者：
Heinrich, Michael C.;Jones, Robin L.;George, Suzanne
通讯作者：
George, Suzanne