Background: CheckMate 227 (NCT02477826), a phase 3 study of 1L nivo + ipilimumab (ipi), nivo, or nivo + chemo vs chemo in advanced NSCLC, met its co-primary endpoint of prolonged progression-free survival (PFS) with nivo + ipi vs chemo in patients (pts) with tumor mutational burden ≥10 mutations/Mb. Identifying effective tx for pts without known predictive biomarkers remains an unmet need. Prior studies suggest addition of chemo to anti–PD-(L)1 tx can improve outcomes in an unselected pt population, although benefit is most pronounced in pts with higher tumor PD-L1 expression. We report results for nivo + chemo vs chemo in pts with < 1% tumor PD-L1 expression. Methods: Pts (n = 550) with chemo-naive, stage IV/recurrent NSCLC, no known sensitizing EGFR/ALK mutations, and < 1% tumor PD-L1 expression were stratified by tumor histology and randomized 1:1:1 to nivo 3 mg/kg Q2W + ipi 1 mg/kg Q6W, nivo 360 mg Q3W + chemo, or chemo (optional pemetrexed maintenance after chemo for nonsquamous [non-SQ] NSCLC). Pts were treated up to 2 yr. A descriptive analysis was performed for the secondary endpoint of PFS for nivo + chemo vs chemo in pts with < 1% tumor PD-L1 expression. No alpha was allocated for this analysis. Results: Baseline characteristics were balanced between nivo + chemo (n = 177) and chemo (n = 186) arms. PFS was improved with nivo + chemo vs chemo (HR = 0.74 [95% CI: 0.58, 0.94]; minimum follow-up 11.2 mo; descriptive comparison). PFS benefit with nivo + chemo was observed across most subgroups. Among histologic subgroups, benefit was more pronounced in non-SQ (HR = 0.68) relative to SQ NSCLC (HR = 0.92). Rates of any grade tx-related adverse events leading to discontinuation were 13% with nivo + chemo and 14% with chemo. Conclusions: 1L nivo + chemo improved PFS vs chemo in pts with advanced NSCLC and < 1% tumor PD-L1 expression, and was well tolerated. Results are encouraging in this analysis, which includes only pts with < 1% PD-L1. CheckMate 227 Part 2 (ongoing) is evaluating nivo + chemo vs chemo irrespective of PD-L1 expression and will further inform benefit from this combination across different subgroups of NSCLC. Clinical trial information: NCT02477826