Background: Osimertinib is a standard treatment for patients with NSCLC positive for activating and T790M mutations of EGFR after failure of prior EGFR-TKI treatment. The efficacy and safety of osimertinib combined with platinum-based chemotherapy has been unknown. Methods: This open label, randomized phase 2 study enrolls adults with clinical stage IIIB or IV or postoperative recurrent NSCLC harboring activating and T790M mutations of EGFR after prior EGFR-TKI treatment failure. Patients are randomly assigned to receive osimertinib (80 mg/day) alone or in combination with carboplatin-pemetrexed (area under the curve of 5 and 500 mg/m², respectively, on day 1 every 3 weeks). The primary end point is progression-free survival. A safety review of the first treatment course by an independent data monitoring committee was planned after enrollment of 12 patients in each arm. Results: As of 27 November 2017, 24 patients (median age, 67 years [range, 46–80]; 58.3% male; 83.3% stage IV; 100% adenocarcinoma; 58.3% exon-19 deletion and 41.7% L858R mutations of EGFR; 54.2% never-smokers) had been assigned equally to the two arms and received the protocol treatment at least once. Treatment-emergent adverse events were reported in all patients. One such event of grade (G) ≥3 (decreased neutrophil count of G3) occurred in the osimertinib arm, whereas four episodes each of decreased white blood cell count, decreased neutrophil count, decreased platelet count, and anemia of G3 or G4; two episodes of skin rash of G3; and one episode each of bronchial infection, oral mucositis, hypertension, and hypokalemia of G3 occurred in the combination arm. The event frequency in the combination arm was similar to that in previous studies of carboplatin-pemetrexed. Exaggeration of adverse events by osimertinib or previously unobserved events were not apparent in the combination arm. Conclusions: The combination treatment was safe in the selected patient population. Clinical trial information: 000024438.