Abstract：
OBJECTIVE: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC).
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.
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.
摘要：
目的：本1b/2期试验评估了卡马替尼联合纳扎替尼治疗晚期EGFR突变非小细胞肺癌（NSCLC）的疗效和安全性。
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。
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。
