Phase III randomized study comparing ultra-low dose immunotherapy to standard cytotoxic chemotherapy for solid tumors in second line and beyond setting (DELII: Development of Low dose Immunotherapy in India).

Abstract

2509 Background: Although immunotherapy (IO) is approved in the second line and beyond setting for most solid tumors, cost limits its accessibility. Lower doses of IO have been shown to achieve adequate target occupancy, persisting for 3 months post administration. We hypothesized that nivolumab would retain efficacy at one-twelfth the approved dose. Methods: Open-label, phase III randomized superiority study in 500 patients with solid tumors, whose disease had progressed on at least one line of systemic treatment, with performance status 0-1. Patients were randomized 1:1 to ultra-low-dose nivolumab (20 mg intravenously every 2 weeks) or standard chemotherapy. Standard chemotherapy options for lung and head-and-neck cancers were docetaxel 75 mg/m 2 every 3 weeks or paclitaxel 175 mg/m 2 every 3 weeks or paclitaxel 80 mg/m 2 once-a-week; esophageal and urothelial cancers: paclitaxel 175 mg/m 2 every 3 weeks or 80 mg/m 2 once-a-week. Therapy continued until progression or intolerable toxicity. Primary endpoint was overall survival (OS). Results: Between Jun 2020 and Feb 2024, we enrolled 500 patients: 250 to each arm. Median age was 49.5 years (IQR, 42-58), 408 (81.6%) patients were male. Primary cancers included head and neck (259, 51.8%), lung (182, 36.4%), esophagogastric (31, 6.2%), urothelial (14, 2.8%), and microsatellite instability-high colorectal cancers (14, 2.8%). Patients had received a median of one prior line of systemic therapy (range: 1-8); 144 (28.8%) patients had received at least two prior lines of systemic therapy. PD-L1 positivity (TPS or CPS > 0) was noted in 66.2% patients. Radiologic response was 7.7% and 8.1% in IO and chemotherapy arms, respectively; P = 0.882. Disease stabilization rate was 37.7% and 39.3% in IO and chemotherapy arms, respectively; P = 0.761. Median PFS was similar between the two arms: 2.04 months (95% CI, 2.0-2.1) in IO arm, and 2.09 months (95% CI, 2.04-2.17) in chemotherapy arm (HR, 1.03; 95% CI, 0.86-1.23; P = 0.77). Median OS was 5.88 months (95% CI, 4.99-7.13) in IO arm, versus 4.70 months (95% CI, 3.91-5.65) in chemotherapy arm; P = 0.022; HR, 0.80 (95% CI, 0.66-0.97). One-yr OS in IO and chemotherapy arms was 27.28% (22.19-33.54) and 16.88% (12.75-22.34), respectively; 2-yr OS was 11.19% (7.59-16.50) and 6.55% (3.95-10.89), respectively. Grade 3 and higher treatment-related adverse events were significantly lower in IO arm (42%) than chemotherapy arm (60.3%); P < 0.001. Conclusions: Ultra-low dose immunotherapy dosed at one-twelfth the standard approved dose is efficacious and significantly prolongs survival in patients with solid tumors in the second line and beyond setting, as compared to standard cytotoxic chemotherapy. Low dose IO should be tested in various settings and multiple malignancies. This will substantially increase global accessibility to IO. Clinical trial information: CTRI/2020/02/023441 .