A Phase 2 Study of Capmatinib in Patients With MET-Altered Lung Cancer Previously Treated With a MET Inhibitor.
A Phase 2 Study of Capmatinib in Patients With MET-Altered Lung Cancer Previously Treated With a MET Inhibitor.
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DOI：
10.1016/j.jtho.2021.01.1605
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Heist RS
中科院分区：
文献类型：
--
作者：
Dagogo-Jack I;Moonsamy P;Gainor JF;Lennerz JK;Piotrowska Z;Lin JJ;Lennes IT;Sequist LV;Shaw AT;Goodwin K;Stevens SE;Do A;Digumarthy SR;Price K;Muzikansky A;Hata AN;Heist RS
基于在未接受过靶向治疗的患者中的活性，卡马替尼被批准用于治疗 MET 外显子 14 改变的 NSCLC。我们进行了一项 II 期研究，以评估卡马替尼对既往接受 MET 抑制剂治疗的患者的疗效。患有 MET 扩增或 MET 外显子 14 跳跃的晚期 NSCLC 患者接受卡马替尼 400 mg，每日两次。主要终点是客观缓解率。次要终点包括无进展生存期（PFS）、疾病控制率（DCR）、颅内缓解率和总生存期（OS）。分析循环肿瘤 DNA 以确定卡马替尼耐药机制。 2016年5月至2019年11月期间入组了20名患者，其中15名患有MET跳跃改变的患者和5名患有MET扩增的患者。所有患者均接受克唑替尼治疗；三人还接受了其他 MET 定向治疗。克唑替尼和卡马替尼之间的中位间隔为 22 天（范围 4-374）。两名 (10%) 患者对卡马替尼取得客观缓解，14 名患者病情稳定，DCR 为 80%。在 5 名因不耐受而停用克唑替尼的患者中，DCR 为 83%，其中两名患者的最佳肿瘤缩小率为 -25% 和 -28%。 4 名可测量脑转移患者的颅内 DCR 率为 100%，未观察到颅内客观反应。总体而言，中位 PFS 和 OS 分别为 5.5（95% CI 1.3-11.0）和 11.3（95% CI 5.5-未达到）个月。在克唑替尼治疗后、卡马替尼治疗前血浆中反复检测到 MET D1228 和 Y1230 突变以及 MAPK 改变。在卡马替尼治疗进展时，血浆中检测到新的和持续的 MET 突变和 MAPK 通路改变。卡马替尼在克唑替尼预处理的 MET 改变的 NSCLC 中具有适度的活性，可能是由于重叠的耐药机制。
Capmatinib is approved for MET exon 14-altered NSCLC based on activity in targeted therapy-naïve patients. We conducted a phase II study to assess efficacy of capmatinib in patients previously treated with a MET inhibitor. Patients with advanced NSCLC harboring MET amplification or MET exon 14 skipping received capmatinib 400 mg twice daily. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), intracranial response rate, and overall survival (OS). Circulating tumor DNA was analyzed to identify capmatinib resistance mechanisms. Twenty patients were enrolled between 5/2016 and 11/2019, including 15 patients with MET skipping alterations and 5 patients with MET amplification. All patients had received crizotinib; three had also received other MET-directed therapies. The median interval between crizotinib and capmatinib was 22 days (range 4–374). Two (10%) patients achieved an objective response to capmatinib and 14 had stable disease, yielding a DCR of 80%. Among 5 patients who discontinued crizotinib for intolerance, DCR was 83%, including two patients with best tumor shrinkage of −25% and −28%. Intracranial DCR among 4 patients with measurable brain metastases was 100%, with no observed intracranial objective responses. Overall, the median PFS and OS were 5.5 (95% CI 1.3–11.0) and 11.3 (95% CI 5.5-not reached) months, respectively. MET D1228 and Y1230 mutations and MAPK alterations were recurrently detected in post-crizotinib, pre-capmatinib plasma. New and persistent MET mutations and MAPK pathway alterations were detected in plasma at progression on capmatinib. Capmatinib has modest activity in crizotinib-pretreated MET-altered NSCLC, potentially due to overlapping resistance mechanisms.
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DOI：
10.1056/nejmoa2004407
发表时间：
2020-09-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Paik PK;Felip E;Veillon R;Sakai H;Cortot AB;Garassino MC;Mazieres J;Viteri S;Senellart H;Van Meerbeeck J;Raskin J;Reinmuth N;Conte P;Kowalski D;Cho BC;Patel JD;Horn L;Griesinger F;Han JY;Kim YC;Chang GC;Tsai CL;Yang JC;Chen YM;Smit EF;van der Wekken AJ;Kato T;Juraeva D;Stroh C;Bruns R;Straub J;Johne A;Scheele J;Heymach JV;Le X
通讯作者：
Le X
影响因子：
82.9
作者：
Drilon A;Clark JW;Weiss J;Ou SI;Camidge DR;Solomon BJ;Otterson GA;Villaruz LC;Riely GJ;Heist RS;Awad MM;Shapiro GI;Satouchi M;Hida T;Hayashi H;Murphy DA;Wang SC;Li S;Usari T;Wilner KD;Paik PK
通讯作者：
Paik PK
影响因子：
11.5
作者：
Engstrom, Lars D.;Aranda, Ruth;Christensen, James G.
通讯作者：
Christensen, James G.
影响因子：
46.9
作者：
Frampton GM;Fichtenholtz A;Otto GA;Wang K;Downing SR;He J;Schnall-Levin M;White J;Sanford EM;An P;Sun J;Juhn F;Brennan K;Iwanik K;Maillet A;Buell J;White E;Zhao M;Balasubramanian S;Terzic S;Richards T;Banning V;Garcia L;Mahoney K;Zwirko Z;Donahue A;Beltran H;Mosquera JM;Rubin MA;Dogan S;Hedvat CV;Berger MF;Pusztai L;Lechner M;Boshoff C;Jarosz M;Vietz C;Parker A;Miller VA;Ross JS;Curran J;Cronin MT;Stephens PJ;Lipson D;Yelensky R
通讯作者：
Yelensky R
影响因子：
11.5
作者：
Rotow, Julia K.;Gui, Philippe;Blakely, Collin M.
通讯作者：
Blakely, Collin M.