Abstract：
OBJECTIVE: Dysregulated signaling by mesenchymal epithelial transition factor (MET) and heightened AXL activation are implicated in the pathogenesis of non-small cell lung cancer (NSCLC). Glesatinib (MGCD265) is an investigational, oral inhibitor of MET and AXL.
METHODS: This open-label, Phase II study investigated glesatinib (free-base suspension [FBS] capsule 1050 mg BID or spray-dried dispersion [SDD] tablet 750 mg BID) in patients with advanced, previously treated NSCLC across four cohorts grouped according to presence of MET activating mutations or amplification in tumor or ctDNA. The primary endpoint was objective response rate (ORR).
RESULTS: Sixty-eight patients were enrolled: n = 28 and n = 8 with MET exon 14 skipping mutations in tumor tissue and ctDNA, respectively, and n = 20 and n = 12 with MET gene amplification in tumor tissue and ctDNA, respectively. Overall, ORR was 11.8 %, median progression-free survival was 4.0 months, and median overall survival was 7.0 months. Among patients with MET activating mutations, ORR was 10.7 % with tumor testing and 25.0 % with ctDNA testing. For MET amplification, responses were observed only in patients enrolled by tumor testing (ORR 15.0 %). Diarrhea (82.4 %), nausea (50.0 %), increased alanine aminotransferase (41.2 %), fatigue (38.2 %), and increased aspartate aminotransferase (36.8 %) were the most frequent adverse events assessed as related to study medication. Glesatinib exposure was similar with the SDD tablet and FBS capsule formulations. The study was terminated early by the sponsor due to modest clinical activity.
CONCLUSIONS: Glesatinib had an acceptable safety profile in patients with advanced, pre-treated NSCLC with MET activating alterations. Modest clinical activity was observed, which likely reflects suboptimal drug bioavailability suggested by previously reported Phase I data, and pharmacodynamic findings of lower than anticipated increases in circulating soluble shed MET ectodomain (s-MET).
METHODS: This open-label, Phase II study investigated glesatinib (free-base suspension [FBS] capsule 1050 mg BID or spray-dried dispersion [SDD] tablet 750 mg BID) in patients with advanced, previously treated NSCLC across four cohorts grouped according to presence of MET activating mutations or amplification in tumor or ctDNA. The primary endpoint was objective response rate (ORR).
RESULTS: Sixty-eight patients were enrolled: n = 28 and n = 8 with MET exon 14 skipping mutations in tumor tissue and ctDNA, respectively, and n = 20 and n = 12 with MET gene amplification in tumor tissue and ctDNA, respectively. Overall, ORR was 11.8 %, median progression-free survival was 4.0 months, and median overall survival was 7.0 months. Among patients with MET activating mutations, ORR was 10.7 % with tumor testing and 25.0 % with ctDNA testing. For MET amplification, responses were observed only in patients enrolled by tumor testing (ORR 15.0 %). Diarrhea (82.4 %), nausea (50.0 %), increased alanine aminotransferase (41.2 %), fatigue (38.2 %), and increased aspartate aminotransferase (36.8 %) were the most frequent adverse events assessed as related to study medication. Glesatinib exposure was similar with the SDD tablet and FBS capsule formulations. The study was terminated early by the sponsor due to modest clinical activity.
CONCLUSIONS: Glesatinib had an acceptable safety profile in patients with advanced, pre-treated NSCLC with MET activating alterations. Modest clinical activity was observed, which likely reflects suboptimal drug bioavailability suggested by previously reported Phase I data, and pharmacodynamic findings of lower than anticipated increases in circulating soluble shed MET ectodomain (s-MET).
摘要：
目的：间充质上皮转化因子（MET）的信号调节异常和AXL激活增强与非小细胞肺癌（NSCLC）的发病机制有关。格利沙替尼（MGCD265）是一种研究性的，MET和AXL的口服抑制剂。
方法：这个开放标签，II期研究调查了晚期患者的格利沙替尼（游离碱悬浮液[FBS]胶囊1050mgBID或喷雾干燥分散体[SDD]片剂750mgBID），根据肿瘤或ctDNA中是否存在MET激活突变或扩增,将之前治疗过的NSCLC分为4个队列.主要终点是客观缓解率（ORR）。
结果：68例患者入选：n=28和n=8，肿瘤组织和ctDNA中MET外显子14跳跃突变，分别,n=20和n=12，在肿瘤组织和ctDNA中进行MET基因扩增，分别。总的来说,ORR为11.8%，中位无进展生存期为4.0个月,中位总生存期为7.0个月.在MET激活突变的患者中，肿瘤检测的ORR为10.7%，ctDNA检测的ORR为25.0%。对于MET扩增，仅在通过肿瘤检测纳入的患者中观察到应答(ORR15.0%).腹泻（82.4%），恶心（50.0%），丙氨酸转氨酶增加（41.2%），疲劳(38.2%)，天冬氨酸转氨酶升高(36.8%)是与研究药物相关的最常见的不良事件.格列沙替尼暴露与SDD片剂和FBS胶囊制剂相似。由于适度的临床活动，赞助商提前终止了该研究。
结论：格来替尼在晚期患者中具有可接受的安全性，具有MET激活改变的预处理的NSCLC。观察到适度的临床活动，这可能反映了先前报道的I期数据所暗示的次优药物生物利用度，和药效学发现低于预期的循环可溶性脱落MET胞外域（s-MET）的增加。
方法：这个开放标签，II期研究调查了晚期患者的格利沙替尼（游离碱悬浮液[FBS]胶囊1050mgBID或喷雾干燥分散体[SDD]片剂750mgBID），根据肿瘤或ctDNA中是否存在MET激活突变或扩增,将之前治疗过的NSCLC分为4个队列.主要终点是客观缓解率（ORR）。
结果：68例患者入选：n=28和n=8，肿瘤组织和ctDNA中MET外显子14跳跃突变，分别,n=20和n=12，在肿瘤组织和ctDNA中进行MET基因扩增，分别。总的来说,ORR为11.8%，中位无进展生存期为4.0个月,中位总生存期为7.0个月.在MET激活突变的患者中，肿瘤检测的ORR为10.7%，ctDNA检测的ORR为25.0%。对于MET扩增，仅在通过肿瘤检测纳入的患者中观察到应答(ORR15.0%).腹泻（82.4%），恶心（50.0%），丙氨酸转氨酶增加（41.2%），疲劳(38.2%)，天冬氨酸转氨酶升高(36.8%)是与研究药物相关的最常见的不良事件.格列沙替尼暴露与SDD片剂和FBS胶囊制剂相似。由于适度的临床活动，赞助商提前终止了该研究。
结论：格来替尼在晚期患者中具有可接受的安全性，具有MET激活改变的预处理的NSCLC。观察到适度的临床活动，这可能反映了先前报道的I期数据所暗示的次优药物生物利用度，和药效学发现低于预期的循环可溶性脱落MET胞外域（s-MET）的增加。
