• 15例患者(14例ECOG评分1分)参与卡铂+紫杉醇+ AZD1775(WEE1抑制剂)治疗Ⅳ期sqNSCLC(二期临床试验);
  • 常见AE:53%腹泻、40%恶心、33%呕吐,3-4级AE:13%中性粒细胞减少症、20%疲劳,无患者因药物毒性停止治疗;
  • 10例可评价,3例PR,1例未证实PR,5例SD,1例PD,90% DCR;
  • 初次扫描,发现SD患者肿瘤分别减少15%、22%、23%、26%和28%;
  • AZD1775联合卡铂和紫杉醇耐受性良好,对治疗晚期sqNSCLC 有潜力。

Phase II trial of AZD1775 in combination with carboplatin and paclitaxel in stage IV squamous cell lung cancer (sqNSCLC): Preliminary results

二期临床试验初步结果:卡铂+紫杉醇+ AZD1775(WEE1抑制剂)治疗Ⅳ期sqNSCLC


Abstract & Authors:展开

Background: WEE1, a dual serine/threonine and tyrosine kinase involved in regulation of the G2/M cell cycle checkpoint, is an essential component for proper DNA damage response. In combination with platinum agents, the inhibition of WEE1 is expected to lead to unstable DNA replication structures, inability to repair DNA damage, loss of G2/M arrest and ultimately mitotic catastrophe. In NSCLC cell lines, we previously demonstrated that cisplatin exhibited enhanced effects in combination with AZD1775 (a WEE1 inhibitor). This trial tests AZD1775 combined with a platinum doublet in patients with sqNSCLC.
Methods: In this single-arm phase II trial, patients with stage IV sqNSCLC receive intravenous (IV) carboplatin AUC 5, IV paclitaxel 175 mg/m2, and oral AZD1775 225 mg twice/day for 2.5 days every 21 days for 4-6 cycles followed by maintenance AZD1775 at the same doses. Antiemetics prior to each dose of AZD1775 are mandatory. The primary endpoint is response rate per RECIST v1.1, with overall and progression-free survival as secondary endpoints. Archival tissue specimens are collected for correlative analyses of p53, PAXIP1, and WEE1.
Results: Interim analysis of the 15 patients [3/15 (20%) female] enrolled through 11/2016 show 14/15 (93%) were ECOG 1, and 1/9/5 (7%/60%/33%) were never/former/current smokers. The most frequent adverse events of any grade were diarrhea (53%), nausea (40%), and vomiting (33%). The 2 most common grade 3-4 adverse events were neutropenia (13%) and fatigue (20%). No patients required treatment discontinuation due to toxicity. Of the 10 patients evaluable for response, 3 (30%) had confirmed partial responses (PR), 1 (10%) had unconfirmed PR, 5 (50%) had stable disease (SD), and 1 (10%) had progressive disease for a disease control rate of 90%. In those with SD, tumors regressed by -15%, -22%, -23%, -26% and -28% at first scan.
Conclusions: AZD1775 combined with carboplatin and paclitaxel is tolerable and demonstrates promising activity in advanced sqNSCLC patients. Nausea and vomiting are manageable with antiemetics. The study continues to enroll. Correlative biomarker analyses of the tissue are planned. More mature data will be presented.

All Authors:
Jhanelle Elaine