Current Controversies and Challenges in Non–Oncogene-Addicted Synchronous Oligometastatic Non–Small Cell Lung Cancer

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. 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. 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.