Background: For patients with stage IV NSCLC, treatment options are limited after progression on immunotherapy (IO) +/- platinum-based chemotherapy. Docetaxel alone or in combination with ramucirumab remains a standard of care, but response rates and survival benefit are suboptimal. Cullin-RING ligases (CRLs) catalyze the ubiquitylation and degradation of tumor suppressor proteins and are overactivated in NSCLC. Therefore, inhibition of CRLs has potential therapeutic value. Neddylation is required to activate CRLs; NAE (NEDD8 activating enzyme) catalyzes neddylation. In pre-clinical studies, pevonedistat, a first-in-class small molecule NAE inhibitor, exerts anti-tumor effects when combined with docetaxel. Methods: We conducted a phase II, single-arm, investigator-initiated study evaluating the efficacy of pevonedistat plus docetaxel in patients with stage IV NSCLC with progression on or after platinum-based chemotherapy +/- IO. Patients with tumors that had driver mutations in EGFR, ALK, ROS1, and BRAF must have also had progression on targeted inhibitors. A Simon Optimal two-stage design was utilized with 90% power and 15% type I error to detect the drug as promising when the true response rate is 25% and the historical control rate is 10%. A maximum of 37 response-evaluable (R-E) patients could be enrolled. Patients received docetaxel 75 mg/m² on day 1 and pevonedistat 25 mg/m² on days 1, 3 & 5 of a 21-day cycle. Response was assessed every 2 cycles based on RECIST v1.1 criteria. The primary objective was overall response rate (ORR). Those who received 2 cycles or had progression prior to the end of cycle 2 were considered R-E. Patients who received any treatment on protocol were evaluable for safety (S-E). Results: From 3/5/2018 to 1/26/2021, we enrolled 31 patients and 27 were R-E with a median follow-up of 38.7 months. The trial was terminated early due to the sponsor’s decision to discontinue the development of pevonedistat. In the R-E population, 52% were female with a median age of 63 and 85% had adenocarcinoma. The median number of prior regimens was 2, and 92% of patients had previously received IO. The ORR was 22% (95%CI 8.6-42.3%) and the disease control rate (SD+CR+PR) was 66.7% (95%IC 46.0- 83.5%). The median PFS was 4.1 (2.8-5.8) months and median OS was 13.1 (6.7-24.8) months. The median duration of response was 14.5 months. The incidence of Grade 3-4 adverse events (AE) was 53% in the 30 S-E patients. The most common grade 3-4 AEs were decrease in blood counts (anemia and neutropenia) and elevation in liver transaminases. There were no Grade 5 toxicities. Conclusions: Our data suggest that the combination of docetaxel and pevonedistat is safe and may have improved anti-tumor activity compared to historical data with docetaxel alone. These results suggest that the neddylation pathway is a targetable anti-tumor pathway that should be further studied in patients with NSCLC. Clinical trial information: NCT03228186.