Background: Combination of anti-PD1 and CTLA4 have showed superiority to chemotherapy (CT) in advanced non–small cell lung cancer (NSCLC), but data for fit elderly or PS2 patients are scarce. Methods: eNErgy compared the combination of nivolumab ipilimumab (N-I) to a platinum doublet in elderly or PS2 patients with advanced NSCLC. Primary endpoint was overall survival (OS), secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Main inclusion criteria were: stage IV histologically proven NSCLC, age ≥ 70 y, and PS 0/1/2 or age < 70 and PS2, EGFR ALK/ROS1 negative, judged fit enough to receive a platinum doublet. The main exclusion criteria were active cerebral metastasis or contraindication to N-I. Patients were randomly selected 1/1, stratified by age (≥ 70 vs. < 70 y), PS (0/1 vs. 2), and histology (squamous vs. no-squamous). Nivolumab (240 mg, 2w), ipilimumab, 1 mg/kg, 6w, was administrated until progression or unacceptable toxicity. CT was planned for 4 cycles, with carboplatin (AUC5) and pemetrexed (500 mg/m2, 3w) or paclitaxel (90 mg/m2, d1,d8, d15); 242 patients had to be randomized to detect a treatment effect hazard ratio (HR) on OS of 0.65, with a 85% power at a 2-sided alpha level of 5%. Results: A preplanned interim analysis carried out after observation of 33% of deaths, out of 174 randomized patients, showed a risk of futility especially for PS 2 patients, HR: 1.8 (95% CI, 0.99-3.3). This led to a halt in randomization but continued follow-up of the 204 patients randomized at the time of the decision. The current final analysis is carried out 18 months after the inclusion of the last patient: men, 71%, median age 74 (51-89, PS 0/1/2 in 30%, 37.5%, and 36.6% respectively), smokers or former smokers in 25.5 and 64.4%, with 62% adenocarcinoma. The median OS of N-I and chemo arms were 14.7 (95% CI, 8.0-19.7) and 9.9 (95% CI, 7.7-12.3) months, HR 0.85, 95% CI, 0.62-1.16. The subgroup analyses showed a significant benefit of the association N-I compared to CT for elderly PS 0/1 patients, with median OS of 22.6 (95% CI, 18.1-36) vs. 11.8 (95% CI, 8.9-20.5) months, p = 0.02. In PS2 patients, median OS of N-I and CT arms was 2.9 (1.4-4.8) vs. 6.1 (3.5-10.4) months (p = 0.22). Median PFS was significantly in favor of N-I arm in the entire population: 5.5 (2.8-8.7) vs. 4.6 (3.5-5.6); p = 0.015. Safety was similar with 31.4% of patients with grade ≥ 3 related SAES in N-I arm vs. 49.5% for CT. Treatment was discontinued for toxicity in 28.6% in N-I arm vs. 22.3% of patients in CT arm. Conclusions: Despite no statistically significant benefit in OS observed in the entire population, there was a clinical signal of efficacy of N-I combination over platinum doublet in elderly NSCLC patients PS 0-1 with a significant benefit of OS of 22.6 months vs. 11.8 for CT arm. Clinical trial information: NCT03351361.