Background: In pre-clinical studies, WEE1 inhibitors have displayed synergy with cisplatin in lung cancer cell lines. Adavosertib (AZD1775) is an orally available inhibitor of the WEE1 kinase with platinum-doublet combination RP2D of 225 mg twice daily (BID) on days 1-3 (5 doses) of a 21-day cycle with the most common adverse events being bone marrow toxicity, diarrhea, vomiting, and fatigue. This phase II, single-arm, single-institution trial of carboplatin, paclitaxel, and AZD1775 was conducted at Moffitt Cancer Center (NCT02513563). Methods: Patients with advanced/metastatic SqCLC who had not previously received platinum or paclitaxel for metastatic disease were enrolled. Previous use of immune checkpoint inhibitors or vaccines was allowed. Patients were treated with carboplatin AUC5 and paclitaxel 175 mg/m2 plus AZD1775 PO 225 mg once daily for one day and BID for two days for a total of 5 doses over days 1-3 of a 21-day cycle for up to 6 cycles, followed by AZD1775 maintenance until disease progression, intolerance or withdrawal. The primary endpoint was PFS. Secondary endpoints included overall survival (OS), duration of response (DoR), duration of stable disease (DSD), and disease control rate (DCR). Outcomes were measure using 80% CI obtained from Kaplan-Meier estimator, with the lower bound corresponding to a one-sided 90% CI, to test whether the median PFS exceeds 4.0 months at α = 0.10. Results: Between 10/2015 and 09/2021, 42 patients were enrolled, and 41 received at least one of the planned treatments. Baseline characteristics included : median age 66 (range, 38-82), 66% male, 93% White, 90.2% Non-Hispanic, 90% ever smoker, 85% ECOG PS 1, and 44% with negative tumoral PD-L1 expression. Among the 41 patients, 32 were evaluable for response assessment. The median PFS was 4.8 months (80%CI, 4.1 to 5.7), and the median OS was 7.3 months (80%CI, 6.4 to 8.5). The DCR was 60.9 % (14 partial responses, 11 with stable disease), with a median DoR of 4.44 months (80%CI, 3.25 to 6.94), and a median DSD of 3.5 months (80%CI, 3.0 to 4.9). Adverse events (AEs) occurred in 36 of 41 patients (88%), including grade 3 AEs in 39% patients. The three most common AEs with the combination therapy were fatigue (61%), diarrhea (51%), and nausea (49%). Drug interruptions or delays occurred in 17 patients (41%). Conclusions: The study met its primary endpoint with a median PFS of 4.8 months with the combination of Adavosertib with carboplatin and paclitaxel. However, the study regimen achieved similar response rates and median PFS of platinum-doublet combination when comparing to historical data from phase II/III trials. Although the combination was safe, over a third of patients experienced grade 3 AEs, and 10% required dose reductions or delays due to AEs. Clinical trial information: NCT02513563.