Background: Primary resistance to immune checkpoint inhibitor (ICI) therapy remains a major challenge in clinical oncology. Here, we describe the clinical outcome of patients who experienced radiologic progression within 12 weeks of therapy with nivolumab and ipilimumab (I+N) for metastatic non-small cell lung cancer (mNSCLC). Methods: The LONESTAR study is an ongoing phase III study (NCT03391869). Study enrolls patients with immunotherapy naïve mNSCLC (prior chemotherapy is allowed). All patients receive I+N for 12 weeks and are randomized to experimental therapy vs. control arm if they did not have disease progression. Patients who experience radiologic progression per RECIST v1.1 are not randomized and removed from the study. Treatment beyond progression is allowed if they clinically benefit from the systemic therapy. We prospectively collected clinicopathologic and radiologic outcome data from patients who experienced radiologic progression within 12 weeks of I+N therapy and have not randomized to investigational therapy. We described the primary progression pattern. We collected subsequent treatment, radiologic, and toxicity data and calculated clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Results: Of the 194 patients who received at least one dose of I+N therapy, 72 patients had clinical and/or radiologic progression at ≤ 12 weeks. Thirty-five (35; 48%) patients did not receive subsequent treatment, 21 (29%) patients received subsequent 2^nd line systemic therapy, and 16 (22%) patients were continued on I+N beyond radiologic progression due to ongoing clinical benefit. Among patients treated with 2nd line therapy, 13 patients were treated with platinum doublet +/- anti-PD-(L)1, seven (7) patients were treated with single-agent chemotherapy +/- VEGF inhibitor, and one (1) patient was treated with targeted therapy. The PFS for the 2^nd line therapy was 6.5 months (95%CI: 4.8, 8.9), and OS was 10.4 months (95%Cl: 6.6, 16.1). Among the 16 patients treated with I+N beyond progression, 13 had a mixed response to induction therapy, where primary progression was most frequently observed in mediastinal lymph nodes. LCT with radiotherapy was utilized with I+N in 10 patients. The median duration of post-progression treatment with I+N plus LCT was 8.7 months (95%Cl: 5.9, 22.3) and 5.6 months (95%Cl 4.4, 11.5) with I+N alone. The OS was 19.5 months (95% CI: 6.2,18.7). Conclusions: In this study cohort, primary resistance to I+N was observed in 37% of the patients, and in a subset of these patients treated with post-progression I+N, either alone or in combination with LCT, durable clinical benefit was observed. Further studies are warranted to identify which patients are most likely to benefit from post-progression I+N. Clinical trial information: NCT03391869.