Characterization of on-target adverse events caused by TRK inhibitor therapy.
Characterization of on-target adverse events caused by TRK inhibitor therapy.
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DOI：
10.1016/j.annonc.2020.05.006
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Drilon A
中科院分区：
文献类型：
--
作者：
Liu D;Flory J;Lin A;Offin M;Falcon CJ;Murciano-Goroff YR;Rosen E;Guo R;Basu E;Li BT;Harding JJ;Iyer G;Jhaveri K;Gounder MM;Shukla NN;Roberts SS;Glade-Bender J;Kaplanis L;Schram A;Hyman DM;Drilon A
TRK通路控制食欲、平衡和疼痛敏感性。虽然这些功能反映在TRK抑制剂观察到的靶向不良反应（AE）中，但这些AE仍未得到充分认识，并且先前未报告停药后的疼痛。由于TRK抑制剂已被多个监管机构批准用于TRK或ROS 1融合阳性癌症，因此表征这些AE和相应的管理策略至关重要。在临床数据库检索中回顾性确定了接受TRK抑制剂治疗的晚期或不可切除实体瘤患者。在这些患者中，描述了AE（包括体重增加、头晕或共济失调和戒断痛）的频率、严重程度、持续时间和管理结局。确定了96名具有15种独特癌症组织学的患者接受TRK抑制剂治疗。在53%（95% CI，43%-62%）的患者中观察到体重增加，并且随着TRK抑制的时间而增加。药物干预，最常见的是GLP-1类似物或二甲双胍，似乎导致体重稳定或减轻。在41%（95% CI，31%-51%）的患者中观察到头晕（伴或不伴共济失调），至发作的中位时间为2周（范围：3天至16个月）。TRK抑制剂剂量减少是头晕最有效的干预措施。在35%（95% CI，24%-46%）的患者中观察到暂时或永久停用TRK抑制剂后的疼痛;这在TRK抑制剂使用时间较长的患者中更常见。TRK抑制剂的重新启动是最有效的干预戒断疼痛。TRK抑制剂相关AE（包括体重增加、头晕和戒断痛）发生在接受TRK抑制剂治疗的大部分患者中。这种安全性特征相对于其他抗癌疗法是独特的，需要仔细监测。这些靶向毒性可通过药物干预和剂量调整进行管理。
The TRK pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse effects (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial. Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized. Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% (95% CI, 43%-62%) of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with GLP-1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%-51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%-46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor re-initiation was the most effective intervention for withdrawal pain. TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.
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影响因子：
3.9
作者：
Indo, Y
通讯作者：
Indo, Y
DOI：
10.1002/neu.480251107
发表时间：
1994-11-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
BARBACID, M
通讯作者：
BARBACID, M
影响因子：
64.8
作者：
KLEIN, R;SILOSSANTIAGO, I;BARBACID, M
通讯作者：
BARBACID, M
DOI：
10.1038/s41571-018-0113-0
发表时间：
2018-12
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Cocco E;Scaltriti M;Drilon A
通讯作者：
Drilon A
影响因子：
28.2
作者：
Drilon A;Siena S;Ou SI;Patel M;Ahn MJ;Lee J;Bauer TM;Farago AF;Wheler JJ;Liu SV;Doebele R;Giannetta L;Cerea G;Marrapese G;Schirru M;Amatu A;Bencardino K;Palmeri L;Sartore-Bianchi A;Vanzulli A;Cresta S;Damian S;Duca M;Ardini E;Li G;Christiansen J;Kowalski K;Johnson AD;Patel R;Luo D;Chow-Maneval E;Hornby Z;Multani PS;Shaw AT;De Braud FG
通讯作者：
De Braud FG