Background: Nivolumab combined with ipilimumab is currently one of many first line treatment options for patients with advanced non-small cell lung cancer (NSCLC). The benefit of this regimen in patients with NSCLC previously treated with a programmed death 1 (PD1) axis inhibitor is unclear. Methods: We conducted a phase II study (NCT03262779) of nivolumab and ipilimumab in patients with PDL1 unselected advanced NSCLC with either primary resistance (cohort 1) or acquired resistance (cohort 2) to prior PD1 axis inhibitor therapy. Nivolumab 3 mg/kg was administered intravenously every 2 weeks, and ipilimumab 1 mg/kg every 6 weeks, and continued until disease progression or treatment limiting toxicity. If > 1 response or prolonged stability (> 24 weeks) using immune related response criteria were observed in the first 10 patients treated on cohort 1, an additional 30 patients would be accrued (simon 2-stage). A total of 10 patients would be accrued to cohort 2 (exploratory cohort). The primary endpoint was objective response rate (ORR) by RECIST v1.1 in cohort 1. Secondary endpoints included, ORR in cohort 2, progression free survival (PFS) and overall survival (OS) in both cohorts. Results: Among 10 patients with primary resistance to PD1 axis inhibitor therapy, no objective responses were observed (8 patients had progressive disease (PD) and 2 patients had unconfirmed stable disease (SD) as best response). Among 10 patients with acquired resistance to PD-1 axis inhibitor therapy, ORR was 10% (1 patient with confirmed complete response, 5 patients with confirmed SD including 4 patients with SD lasting more than 9 months, 3 patients with unconfirmed SD, and 1 patient with PD). Durable clinical benefit (DCB, response or SD for at least 6 months) rate was 50%. Median duration of benefit in the 5 patients with DCB was 11.9 months. Nine of the 10 patients in cohort 2 developed initial resistance to PD-1 axis inhibitor monotherapy (rather than combination chemo-immunotherapy), all received immunotherapy as part of their last line of therapy. The remaining patient developed resistance while on maintenance chemoimmunotherapy after initial response to chemoimmunotherapy; best response to trial therapy in this patient was unconfirmed SD. Median PFS/ OS in cohort 1 were 1.8 months/ 6.8 months, and in cohort 2, 6.7 months/ 31.8 months. Grade 3 treatment-related adverse events (TRAEs) occurred in 4 patients across both cohorts, including colitis (2 pts), diabetes (1 pt), pneumonia (1 pt) and elevated lipase (1 pt). There were no grade 4/5 TRAEs. Two patients discontinued trial therapy due to toxicity (colitis), both in cohort 2. Conclusions: Combination immunotherapy with nivolumab and ipilimumab does not overcome primary resistance to PD1 axis inhibitor therapy; however, can overcome acquired resistance to PD1 axis inhibitor therapy. Translational studies from tumor and serial peripheral blood collections are ongoing. Clinical trial information: NCT03262779.