Current Controversies and Challenges in Non-Oncogene-Addicted Synchronous Oligometastatic Non-Small Cell Lung Cancer: A Review

Importance: It has been stated that especially with the advancements in imaging, systemic therapy, and local radical treatment (LRT) that patients with synchronous oligometastatic disease (sOMD) can potentially benefit from curative-intent treatment. This statement is challenged by the results of the NRG-LU002 randomized phase 2/3 trial, showing no significant progression-free survival and overall survival improvements with the addition of LRT to maintenance systemic therapy in patients with oligometastatic non-small cell lung cancer (NSCLC) who achieved at least stable disease after induction systemic therapy (approximately 90% received an immunotherapy-based regimen). This Review discusses the current challenges and controversies in the treatment of non-oncogene-addicted sOMD. Observations: Whether LRT indeed can improve survival in a contemporary immunotherapy-based systemic treatment regimen is discussed as well as the optimal treatment sequence. Moreover, the NRG-LU002 trial also sparks debate of whether a true sOMD state exists. Genomic alterations, the tumor microenvironment of the primary tumor and metastasis, organotropism, and tumor heterogeneity can all influence metastatic potential, giving a biological explanation that there could be existence of a true sOMD state. However, as true sOMD cannot be distinguished from early-detected widespread metastatic disease with the current imaging modalities, it becomes difficult to select patients for a radical strategy and protect patients from futile treatment. Conclusions and relevance: It remains under debate whether synchronous oligometastatic NSCLC represents a distinct biological entity or merely a probabilistic imaging finding. Biomarkers such as circulating tumor DNA, microRNA, and radiomics may improve patient selection but require further validation. Clinical trials should prioritize translational research to address these challenges.