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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.