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•Effective therapy for NSCLC patients who progress on immunotherapy remains limited.•The neddylation pathway plays crucial role in tumorigenesis in NSCLC.•Pevonedistat is a small molecular inhibitor of neddylation.•Docetaxel and pevonedistat show promise in relapsed/refractory NSCLC.
Postimmunotherapy (IO) treatment options for stage IV non–small-cell lung cancer (NSCLC) remain limited. Docetaxel alone or in combination with ramucirumab remains a standard of care, but response rates and survival benefit are suboptimal. Cullin-RING ligases (CRL) catalyze degradation of tumor suppressor proteins and are overactivated in NSCLC. Neddylation, which is catalyzed by the NEDD8 activating enzyme (NAE), is required for the activation of CRLs. Pevonedistat, a first-in-class small molecule NAE inhibitor, exerted antitumor activity when combined with docetaxel in preclinical studies.
We conducted a phase II, single-arm, investigator-initiated study evaluating the efficacy of pevonedistat plus docetaxel in patients with relapsed/refractory stage IV NSCLC. Patients received docetaxel 75 mg/m2 on day 1 and pevonedistat 25 mg/m2 on days 1, 3 and 5 of a 21-day cycle. The primary endpoint was objective response rate (ORR).
From March 5, 2018 to January 26, 2021, we enrolled 31 patients. The ORR was 22% (1 CR, 5 PR), median PFS was 4.1 months, and median OS was 13.2 months. The incidence of Grade ≥3 adverse events (AE) was 53% in patients (n = 30) who received at least 1 dose of both drugs, with the most frequent being neutropenia and AST/ALT elevation. One patient was taken off study for a Grade 4 transaminase elevation. There were no Grade 5 toxicities.
Our data suggest that the combination of docetaxel and pevonedistat is safe and exerts activity in patients with relapsed NSCLC. These encouraging results suggest that the neddylation pathway is an antitumor pathway that should be further studied.
Effective therapy options remain limited for patients with metastatic NSCLC who progress on checkpoint inhibitors. We conducted a phase II study of pevonedistat and docetaxel in 31 patients. Pevonedistat is an inhibitor of the NEDD8-activating enzyme and acts to inhibit neddylation. The combination demonstrated a meaningful ORR of 22%, PFS 4.1 months, OS 13.2 months.