Background <p>Adavosertib is a highly selective, small molecule Wee1 inhibitor that sensitizes tumor cells to cytotoxic agents.</p> Objective <p>We report results from the lead-in cohorts of two phase II studies: carboplatin/pemetrexed plus adavosertib versus carboplatin/pemetrexed in first-line metastatic non-squamous non-small-cell lung cancer (NSCLC) (NCT02087241); and docetaxel plus adavosertib versus docetaxel in recurrent NSCLC (NCT02087176).</p> Patients and Methods <p>Both lead-in cohorts assessed early safety and efficacy (objective response rate [ORR]). First-line metastatic treatment was carboplatin (area under the curve to 6 h [AUC₆]) plus pemetrexed 500&#xa0;mg/m² intravenously on day 1, every 21 days; recurrent treatment was docetaxel 75&#xa0;mg/m² intravenously on day 1 plus prophylactic granulocyte-colony stimulating factor 6&#xa0;mg subcutaneously on day 4 every 21 days. All patients received adavosertib 225&#xa0;mg twice daily orally on days 1–3 (five doses). After a planned safety analysis of the first-line trial, dose and schedule were modified to reduce toxicity.</p> Results <p>First-line: 14 patients were enrolled in four treatment cohorts. Median time on trial was 17.3 weeks, with an ORR of 29%. The most common adverse events were diarrhea (50%), nausea (50%), vomiting (50%), anemia (43%), neutropenia (43%), decreased appetite (43%), and dehydration (43%). Recurrent: 32 patients were enrolled. The ORR was 9%. The most common adverse events were diarrhea (66%), anemia (50%), nausea (47%), fatigue (47%), vomiting (44%),&#xa0;and thrombocytopenia (41%).</p> Conclusions <p>Both studies terminated early; the recurrent study after an interim analysis showed increased toxicity and limited efficacy, and the first-line study after a change in first-line standard of care.</p> Trial Registrations <p>ClinicalTrials.gov, NCT02087241 and NCT02087176.</p>