Phase 1B Study of Momelotinib Combined With Trametinib in Metastatic, Kirsten Rat Sarcoma Viral Oncogene Homolog-Mutated Non-Small-Cell Lung Cancer After Platinum-Based Chemotherapy Treatment Failure.
Phase 1B Study of Momelotinib Combined With Trametinib in Metastatic, Kirsten Rat Sarcoma Viral Oncogene Homolog-Mutated Non-Small-Cell Lung Cancer After Platinum-Based Chemotherapy Treatment Failure.
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DOI：
10.1016/j.cllc.2018.07.004
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发表时间：
2018-11
影响因子：
3.6
通讯作者：
Koczywas M
中科院分区：
文献类型：
--
作者：
Barbie DA;Spira A;Kelly K;Humeniuk R;Kawashima J;Kong S;Koczywas M
我们对21例柯尔斯滕大鼠肉瘤病毒癌基因同源突变的非小细胞肺癌患者进行了多靶点Janus激酶/TRAF家族成员相关的核因子-κβ激活物(TANK)结合激酶1抑制剂莫洛替尼联合曲美替尼治疗的研究。莫美洛替尼的最大耐受量是150毫克，每天两次(不足以达到显著的TBK1抑制作用)。根据历史数据，没有患者获得客观反应，联合用药没有改善单药曲美替尼的活性。柯尔斯滕大鼠肉瘤病毒癌基因同源(KRAS)突变的非小细胞肺癌(NSCLC)缺乏特定的治疗选择，尽管其他突变驱动亚组的治疗取得了进展。在这项研究中，我们评估了多靶点Janus激酶/坦克结合激酶1(TBK1)抑制剂莫美洛替尼联合丝裂原/细胞外信号相关激酶(MEK)1/MEK2抑制剂曲美替尼治疗铂类药物治疗难治性、转移性、KRAS突变的NSCLC的疗效。剂量递增(3+3设计)：莫洛替尼联合曲美替尼1.0 mg每日1次，然后曲美替尼联合最大耐受量(MTD)。在患者的第一个28天周期中，根据剂量限制毒性(DLT)确定MTD。安全性是主要终点，疗效参数，包括8周时的疾病控制率(DCR)，是次要终点。21例患者入选(中位年龄：68岁；14例(66.7%)女性)。MTD为莫洛替尼150 mg，每日2次，联合曲美替尼1.0 mg，每日1次。测定MTD的DLT为谷丙转氨酶升高和疲劳。最常见的不良反应是恶心(n=14[66.7%])、腹泻(n=11[52.4%])和疲劳(n=11[52.4%])。最常见的≥3级事件是缺氧(n=3(14.3%))，无一例患者达到客观反应。8周DCR12例(57.1%)(90%可信区间[CI]，37.2%−75.5%)。中位无进展生存期为3.6个月(90%CI，2.2~5.6个月)，总生存期为7.4个月(90%CI，4.0~15.3个月)。莫美洛替尼的最大血药浓度在给药后1至2小时达到，但不足以达到显著的TBK1抑制作用。根据历史数据，在KRAS突变的非小细胞肺癌中，额外使用莫洛替尼和曲美替尼并不能改善单药曲美替尼的活性。
We evaluated the multitargeted Janus kinase/TRAF family member associated NF-κβ activator (TANK)-binding kinase 1 (TBK1) inhibitor momelotinib combined with trametinib in 21 patients with Kirsten rat sarcoma viral oncogene homolog-mutated non—small-cell lung cancer. The maximum tolerated dose of momelotinib was 150 mg twice daily (insufficient to achieve significant TBK1 inhibition). No patients achieved objective response and the combination did not improve on the activity of single-agent trametinib on the basis of historic data. Specific treatment options are lacking for Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated non—small-cell lung cancer (NSCLC) despite treatment advances in other mutation-drivensubgroups. In this study we evaluated the multitargeted Janus kinase/TANK-binding kinase 1 (TBK1) inhibitor momelotinib combined with the mitogen/extracellular signal-related kinase (MEK)1/MEK2 inhibitor trametinib in patients with platinum-treated, refractory, metastatic, KRAS-mutated NSCLC. Dose escalations (3 + 3 design) were conducted with momelotinib in combination with trametinib 1.0 mg once daily, then with trametinib inþcombination with the maximum tolerated dose (MTD) of momelotinib. MTD was determined from dose-limiting toxicity (DLT) during patients’ first 28-day cycle. Safety was the primary end point, and efficacy parameters, including disease control rate (DCR) at 8 weeks, were secondary end points. Twenty-one patients were enrolled (median age: 68 years; 14 [66.7%] female). The MTD was momelotinib 150 mg twice daily in combination with trametinib 1.0 mg once daily. DLTs that determined the MTD were increased alanine aminotransferase and fatigue. The most common adverse events of any grade were nausea (n = 14 [66.7%]), diarrhea (n = 11 [52.4%]), and fatigue (n = 11 [52.4%]). The most common Grade ≥3 event was hypoxia (n = 3[14.3%]) No patients achieved objective response. DCR at 8 weeks was 12 patients (57.1%) (90% confidence interval [CI], 37.2%−75.5%). Median progression-free and overall survival were 3.6 months (90% CI, 2.2–5.6 months) and 7.4 months (90% CI, 4.0–15.3 months), respectively. Maximum momelotinib plasma concentrations were reached 1 to 2 hours after dosing, but were insufficient to achieve significant TBK1 inhibition. The additional use of momelotinib with trametinib does not improve on the activity of single-agent trametinib in KRAS-mutated NSCLC on the basis of historic data.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
51.1
作者：
Infante, Jeffrey R.;Fecher, Leslie A.;Messersmith, Wells A.
通讯作者：
Messersmith, Wells A.
影响因子：
45.3
作者：
Mesa, Ruben A.;Kiladjian, Jean-Jacques;Gotlib, Jason
通讯作者：
Gotlib, Jason
影响因子：
28.2
作者：
Jenkins RW;Aref AR;Lizotte PH;Ivanova E;Stinson S;Zhou CW;Bowden M;Deng J;Liu H;Miao D;He MX;Walker W;Zhang G;Tian T;Cheng C;Wei Z;Palakurthi S;Bittinger M;Vitzthum H;Kim JW;Merlino A;Quinn M;Venkataramani C;Kaplan JA;Portell A;Gokhale PC;Phillips B;Smart A;Rotem A;Jones RE;Keogh L;Anguiano M;Stapleton L;Jia Z;Barzily-Rokni M;Cañadas I;Thai TC;Hammond MR;Vlahos R;Wang ES;Zhang H;Li S;Hanna GJ;Huang W;Hoang MP;Piris A;Eliane JP;Stemmer-Rachamimov AO;Cameron L;Su MJ;Shah P;Izar B;Thakuria M;LeBoeuf NR;Rabinowits G;Gunda V;Parangi S;Cleary JM;Miller BC;Kitajima S;Thummalapalli R;Miao B;Barbie TU;Sivathanu V;Wong J;Richards WG;Bueno R;Yoon CH;Miret J;Herlyn M;Garraway LA;Van Allen EM;Freeman GJ;Kirschmeier PT;Lorch JH;Ott PA;Hodi FS;Flaherty KT;Kamm RD;Boland GM;Wong KK;Dornan D;Paweletz CP;Barbie DA
通讯作者：
Barbie DA
影响因子：
50.5
作者：
Blumenschein, G. R., Jr.;Smit, E. F.;Jaenne, P. A.
通讯作者：
Jaenne, P. A.