Efficacy and Safety of Ultra-Low-Dose Immunotherapy in Relapsed Refractory Solid Tumors: Phase III Superiority Randomized Trial (DELII).

[PURPOSE] Immune checkpoint inhibitors (ICIs) achieve sufficient receptor occupancy at much lower than standard approved doses. We hypothesized that ultra-low-dose nivolumab would retain clinical efficacy.

[PATIENTS AND METHODS] In this phase III randomized superiority trial, patients with advanced solid tumors (Eastern Cooperative Oncology Group 0-1) and progression on ≥1 prior line of systemic therapy were randomly assigned 1:1 to ultra-low-dose nivolumab (20 mg intravenously once every 2 weeks) or standard chemotherapy (docetaxel or paclitaxel, as per tumor type). Treatment continued until progression or intolerable toxicity. The primary end point was overall survival (OS).

[RESULTS] From June 2020 to February 2024, we enrolled 500 patients: 250 per arm; 52% had head and neck and 36% lung cancers. The median number of prior lines of therapy was 1 (range, 1-8); 29% had received ≥2 prior lines. Median OS was significantly longer with ultra-low-dose nivolumab: 5.88 months (95% CI, 4.99 to 7.13) versus 4.70 months (95% CI, 3.91 to 5.65; hazard ratio [HR], 0.80 [95% CI, 0.66 to 0.97]; = .022). One-year OS was 27.3% versus 16.9%. Median progression-free survival was similar: 2.04 months (95% CI, 2.00 to 2.10) with ultra-low-dose nivolumab and 2.09 months (95% CI, 2.04 to 2.17) with chemotherapy (HR, 1.03 [95% CI, 0.86 to 1.23]; = .77). Grade ≥3 treatment-related adverse events were less frequent with ultra-low-dose nivolumab (42.5% 60.8%; < .001). Quality of life (QoL) was significantly better with ultra-low-dose nivolumab.

[CONCLUSION] Ultra-low-dose nivolumab significantly improves OS versus chemotherapy in pretreated solid tumors, with fewer severe toxicities and better QoL. These findings support re-evaluation of ICI dosing strategies and may enhance global access.