Retrospective and preclinical studies have provided evidence for a “limited metastatic” phenotype in non–small-cell lung cancer (NSCLC), and the role of aggressive local therapy in this subset of patients is controversial and has not been explored in randomized clinical studies. Gomez and colleagues performed a randomized study to assess the effect of aggressive local consolidative therapy (LCT) in patients with oligometastatic NSCLC who did not progress after induction systemic therapy (IST).1 In this study, patients with histologically confirmed stage IV NSCLC, ≤3 metastases, and no RECIST progression after IST (defined as either ≥4 cycles of platinum doublet therapy or ≥3 months of erlotinib/crizotinib for patients with EGFR mutations or ALK fusions, respectively) were randomized to either LCT ([chemo]radiation or surgical resection of all sites) with or without systemic therapy (ST) versus ST alone. The ST regimen was physician choice from predefined standard-of-care regimens. The primary end point was progression-free survival (PFS). Patient follow-up was every 6 to 10 weeks for the first year, then at the physician’s discretion. Randomization was balanced dynamically by number of metastases, IST response, central nervous system metastases, nodal status, and EGFR/ALK status. Based on the recommendation of the Data Safety Monitoring Committee, the study was closed early due to significant efficacy benefit observed in the study arm. A total of 49 patients were randomized (25 in the LCT arm), 7 of which had EGFR/ALK alterations. LCT consisted of hypofractionated radiation therapy (RT; 52%), combination chemo-radiation therapy plus hypofractionated RT (16%), combination surgery and RT (12%), chemo-RT alone (12%), or surgery alone (4%). At a median follow-up time of 16.2 months, the median PFS time in the LCT arm was 14.4 months (95% confidence interval [CI], 5.2 months-NR), compared with 3.9 months (95% CI, 2.2-6.6 months) in the no-LCT arm (hazard ratio, 0.36; P = 0.013). Seventeen patients in the no-LCT arm crossed over, 14 due to progression. Patterns of treatment failure differed among the 2 arms of the study, with a higher proportion of locoregional-only failures in the no-LCT arm and a higher proportion of metastatic-only failures in the LCT arm, but there was a higher proportion of both locoregional and metastatic failures in the no-LCT arm versus the LCT arm (29% vs 8%, respectively).
No grade 3-5 toxicity was observed in the LCT group. Of the 28 patients who progressed (12 in LCT, 16 in no-LCT), 7 had progression in the primary site, 3 in a known metastasis, 7 in a different metastasis, and 11 in a combination of sites. The median overall survival time has not yet been reached, and patients continue to be followed for this end point. The authors conclude that in oligometastatic NSCLC patients (≤3 metastases) without progression after IST, immediate LCT ± ST improved PFS compared with ST alone. LCT also increased the time to development of new lesions, suggesting a reduction in metastatic spread. The limitations of the study were acknowledged—it included a small number of patients with patient and treatment heterogeneity—but study feasibility was demonstrated, and future studies will further attempt to define which NSCLC patient subsets benefit most from LCT.
