METHODS: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients.
RESULTS: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %).
CONCLUSIONS: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable.
BACKGROUND: ClinicalTrials.gov NCT02335944.
方法:在阶段1b,第一代/第二代EGFR-TKIs出现进展的患者接受剂量递增的卡马替尼200~400mgbid加纳扎替尼50~150mgqd.一旦宣布了MTD/RP2D,第2阶段开始于患者根据突变状态和先前的治疗线进入组:第1组(禁食;EGFR-TKI耐药;1-3个先前的线;EGFRL858R/ex19del;任何T790M/MET);第2组(禁食;EGFR-TKI未治疗;0-2个先前线;从头T790M+;任何MET;第3组(19FexR990第2阶段的主要终点是研究者根据RECISTv1.1评估的总体缓解率(ORR)(第1-3组),安全,与食物组合的耐受性(第4组)。通过T790M和MET状态评估患者亚组的疗效。
结果:RP2D为卡马替尼400mgbid加纳扎替尼100mgqd。在第二阶段(n=144),ORR为28.8%,33.3%,61.7%,第一组为42.9%(n=52),2(n=3),3(n=47),和4(n=42),分别。在第1组+1b期RP2D中,ORR为45.8%,26.2%,37.9%,MET+(n=24)为32.4%,MED-(n=42),T790M+(n=29),和T790M-(n=34)患者。最常见的任何级别治疗相关的不良事件(≥25%;n=144)是周围水肿(54.9%),恶心(41.7%),腹泻(34.0%),和斑丘疹(25.0%)。
结论:卡马替尼联合纳扎替尼在EGFR-TKI耐药患者中显示出抗肿瘤活性,EGFR突变的非小细胞肺癌。总体安全性是可以接受的。
背景:ClinicalTrials.govNCT02335944。