A retrospective study evaluating the order of treatments for patients with synchronous oligometastatic NSCLC without an actionable genetic alteration has found that while both upfront and delayed local radical treatment combined with an immune checkpoint inhibitor can result in a three-year overall survival of about 45%, the most optimal sequence of therapy has yet to be determined.

This large, real-world retrospective analysis addressed a common and unresolved clinical question in the immunotherapy era: how best to sequence immune checkpoint inhibitor (ICI)-based systemic therapy vs local radical treatment (LRT) in patients with synchronous oligometastatic NSCLC. Rather than offering a practice-changing conclusion, the study is best read as a clinical decision-support analysis that helps frame multidisciplinary discussions in a space in which prospective data remain limited and existing guidelines acknowledge uncertainty.

Study Methodology

The researchers evaluated outcomes in patients with de novo NSCLC and a single synchronous extrathoracic metastasis (M1b disease) without actionable genomic alterations. The patients were treated between 2018 and 2022, and all received ICI-based first-line therapy. Two distinct treatment strategies were examined. The first, drawn from the Netherlands Cancer Registry, included 225 patients who underwent upfront LRT to the metastatic site followed by ICI-based systemic therapy, with LRT to the primary tumor and regional nodes delivered selectively at the discretion of the treating team. The second cohort, drawn from a multicenter institutional series, included 33 patients treated initially with ICI or chemo-ICI, with the intent to deliver LRT to all known disease sites only if there was no progression on induction systemic therapy.

The primary endpoint was overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. Importantly, the researchers did not attempt a formal statistical comparison between cohorts given differences in patient selection, data granularity, and cohort size. Instead, the analysis is explicitly hypothesis-generating, reflecting real-world practice patterns rather than protocolized trial behavior.

Results

The researchers found that long-term outcomes were notable across both cohorts. Median OS was 26 months in the upfront LRT cohort and 25 months in the upfront ICI cohort, with nearly identical three-year OS rates of approximately 45%. Median PFS was also similar at approximately 11 months in both cohorts.

These findings reinforce a key clinical takeaway: when combined with immunotherapy, both upfront and delayed LRT strategies can be associated with meaningful long-term survival in carefully selected patients with synchronous oligometastatic NSCLC. No clear survival signal emerged to suggest superiority of one sequencing approach over the other.

Rather than sequence, patient and disease characteristics appeared to be the dominant drivers of outcome. In the larger registry cohort, favorable prognostic factors included good performance status (WHO PS 0), non-squamous histology, and high PD-L1 expression (particularly 50% or greater). Patients with brain metastases had better outcomes than those with bone or other metastatic sites, a finding consistent with prior observations that intracranial disease may be more amenable to durable local control. The five-year OS rate for all patients was 35%.

Squamous histology and poorer performance status were associated with worse survival. In the smaller upfront ICI cohort, younger age and non-squamous histology were associated with improved outcomes, though the limited sample size constrains interpretation.

Study Limitations

These data underscore the importance of thoughtful patient selection rather than rigid adherence to a specific treatment sequence, according to the researchers. They also highlight the reality that many patients never proceed to planned local therapy, either because of early progression, treatment toxicity, or evolving goals of care—an important consideration when counseling patients and designing treatment strategies. From a biological perspective, the study reflects the competing rationales clinicians weigh daily: initiating systemic therapy early to address occult micrometastatic disease vs reducing tumor burden with LRT to potentially enhance immunotherapy efficacy and achieve durable local control.

The researchers emphasized the limitations inherent in retrospective analyses, including selection bias, incomplete staging data, and cohort imbalance. As such, the findings should not be interpreted as supporting a guideline change or a preferred sequencing strategy. Instead, they provide reassurance that flexibility in sequencing—when guided by disease biology, performance status, PD-L1 expression, histology, and patient preferences—can still yield favorable long-term outcomes.

This study does not resolve the question of optimal sequencing of ICI and LRT in synchronous oligometastatic NSCLC. Rather, it helps clinicians navigate ongoing uncertainty in the immunotherapy era, reinforcing the central role of multidisciplinary decision-making and individualized care while awaiting more definitive prospective data.

“Both upfront and delayed LRT combined with an ICI-based treatment can result in long-term survival in this patient population. However, the most optimal sequence has yet to be determined,” concluded lead study author Lizza E.L. Hendriks, MD, of Maastricht University Medical Center, the Netherlands, and colleagues.

Key Points

• Both upfront and delayed LRT combined with ICI results in a 3-year overall survival of about 45%.

• Brain metastasis, good performance status, and high PD-L1 correlated with better overall survival.

• Squamous histology was associated with poor survival.

The authors declared having no competing interests.

Source: Lung Cancer