Background: CheckMate 227 (NCT02477826) is a large phase 3 study of 1L nivo + ipi, nivo, or nivo + chemo vs chemo in advanced NSCLC. The study met its co-primary endpoint demonstrating significantly prolonged progression-free survival with nivo + ipi vs chemo in patients (pts) with tumor mutational burden ≥10 mutations/Mb. The safety profile of 1L nivo + low-dose ipi was consistent with previous reports. Additional detailed analyses may inform the management of immune-related adverse events. Methods: Pts (N = 1739) with chemo-naive, stage IV/recurrent NSCLC without known sensitizing EGFR/ALK mutations were randomized 1:1:1 to nivo (3 mg/kg Q2W) + ipi (1 mg/kg Q6W), nivo monotherapy (240 mg Q2W), or chemo for pts with ≥1% tumor PD-L1 expression and to nivo + ipi, nivo (360 mg Q3W) + chemo, or chemo for pts with < 1% tumor PD-L1 expression. Tx continued until disease progression or unacceptable toxicity for up to 2 yr. Safety and PROs were exploratory endpoints. Safety analyses included time to onset and resolution of select treatment-related adverse events (select TRAEs; those with a potential immunologic cause) and corticosteroid use. PROs were assessed using the Lung Cancer Symptom Scale and EQ-5D instruments. Results: Minimum follow-up was 11.2 mo. Median duration of therapy was 4.2 mo with nivo + ipi and 2.6 mo with chemo. Rates of any grade and grade 3–4 TRAEs were 75% and 31% with nivo + ipi, and 81% and 36% with chemo, respectively. TRAEs led to discontinuation in 17% of pts receiving nivo + ipi and in 9% of pts receiving chemo. Most frequent grade 3–4 select TRAEs in pts receiving nivo + ipi were hepatic (8%), endocrine (4%), skin (4%), pulmonary (3%), and gastrointestinal (2%). Median time to onset of select TRAEs ranged from 2–15 wk, and the majority resolved with corticosteroid use (median time to resolution was ≤10 wk). PRO results will be reported in the final presentation. Conclusions: In CheckMate 227, nivo + low-dose ipi was well tolerated in NSCLC. Toxicities were manageable with previously established tx algorithms, including corticosteroids. Clinical trial information: NCT02477826