• NRG-LU002: Randomized phase II/III trial of maintenance systemic therapy versus local consolidative therapy (LCT) plus maintenance systemic therapy for limited metastatic non-small cell lung cancer (NSCLC)

Background: First line therapy options for advanced NSCLC without actionable molecular alterations include immunotherapy (IO) -/+ chemotherapy or chemotherapy alone. NRG-LU002 was a randomized phase II/III study assessing the benefits of local consolidative therapy (LCT) when added to systemic therapy as maintenance in management of oligometastatic NSCLC. Methods: Eligible patients had metastatic NSCLC with 3 or fewer extracranial metastatic sites (excluding primary) exhibiting at least stable disease after 4 cycles of 1st line systemic therapy. Patients were randomized 1:2 to maintenance systemic therapy or LCT (radiation and/or surgery) followed by maintenance systemic therapy until progression, death, or intolerable toxicity. Stratification factors included histology and IO use. In the randomized phase II (RPhII) portion of the study, the primary endpoint was progression-free survival (PFS) with a planned decision analysis after 216 patients were enrolled and 138 PFS events observed. Secondary endpoints included overall survival (OS), quality of life, and toxicity. The RPhII portion was designed to provide at least 95% power to detect a PFS hazard ratio (HR) of 0.60 at 1-sided significance level of 0.15, and the phase III portion warranted only if the estimated HR was less than 0.83. Results: NRG-LU002 accrual was initiated in 4/2017 and suspended in 11/2021 when the RPhII portion sample size was met. Following the planned interim analysis, the study was closed in 12/2023. Overall, 215 patients (81 -LCT arm, 134 +LCT arm) were enrolled from 68 sites with a median age of 65 years (40-86), 77% white, 95% PS 0/1, 78% non-squamous histology, and 90% having received IO-based systemic therapy. Median follow-up among all/surviving patients were 21.9/29.4 months, respectively. With 138 PFS events from both arms, estimated 1-yr and 2-yr PFS rates were 48% (95% CI: 35.9, 59.0) and 36% (95% CI: 24.8, 47.2) in the maintenance systemic therapy arm and 52% (95% CI: 42.5, 59.8) and 40% (95% CI: 31.5, 48.6) in the LCT + maintenance systemic therapy arm, respectively (2-sided log-rank test p-value = 0.66). Corresponding HR was 0.93 (95% CI: 0.66, 1.31). Of 185 patients treated with IO-containing regimens, the PFS HR was 0.90 (95% CI: 0.61, 1.32). OS HR between two arms was 1.05 (0.70, 1.56) among all patients and 1.05 (0.68, 1.63) among IO-treated patients. For adverse events reported as definitely, probably or possibly related to treatment, there were more LCT + maintenance systemic therapy patients with overall grade 2 or higher toxicities (73% vs 84%) and grade 3 or higher pneumonitis (1% vs 10%). Conclusions: LCT added to IO-based 1st line systemic therapy was associated with a PFS HR of 0.90. Reducing toxicity and increasing biologically-driven patient selection may optimize this therapeutic ratio. Clinical trial information: NCT03137771.