Non-small cell lung cancer accounts for 85% of lung cancer and is the leading cause of cancer-related mortality (1). Non-small cell lung cancer is the primary cause of cancer-related death in the world mainly because patients with lung cancer often develop advanced metastases (2). Approximately 25–50% of patients with NSCLC exhibit an oligometastatic status (3). The concept of “oligometastasis” builds on two models of cancer progression: the Halsted model of continuous progression and a systemic model that hypothesizes that disease is a manifestation of extensive systemic clinical involvement (4). Patients with oligometastatic NSCLC may achieve long-term disease control and may even be cured. In retrospective studies, survival in patients with oligometastatic NSCLC had better overall survival (OS) than patients with a large number of metastases (3, 5). Therefore, it is important to investigate selection of treatment for these patients with limited metastatic NSCLC.

A number of previous studies (6–8) on oligometastatic NSCLC have shown that use of local treatment (LT) at all metastatic sites resulted in longer OS and progression-free survival (PFS) than those following palliative treatment. Immunotherapy has become the standard treatment for patients with metastatic NSCLC (9). The KEYNOTE-189 (10) and KEYNOTE-407 (11) studies have shown that pembrolizumab in combination with specific chemotherapy improved OS and PFS in patients with untreated metastatic NSCLC, regardless of PD-L1 expression. Therefore, use of LT combined with immunotherapy for treatment of oligometastatic NSCLC is an area of active investigation.

Joshua M et al (12) reported in a phase II clinical study that pembrolizumab improved PFS in patients with oligometastatic NSCLC after LT. Although this study showed that pembrolizumab could improve the prognosis of patients with oligometastatic NSCLC, this study did not consider the effect of factors such as the location and the number of organs affected by oligometastases on prognosis, and there are no phase III clinical prospective trials focused on oligometastatic NSCLC. Several previous studies have confirmed that the prognosis of patients with oligometastatic NSCLC was closely related to the site and number of metastatic organs (3, 13, 14). Ashworth AB et al (14) reported that prognosis in patients with oligometastatic NSCLC was associated with brain metastasis but did not address the relationship between prognosis and other metastatic sites.

No study has elucidated the effects of immunotherapy in patients with oligometastatic NSCLC at different metastatic sites. Therefore, our goal was to investigate the effect of different metastatic sites on immunotherapy for oligometastatic NSCLC following LT.

We analyzed the prognostic significance of immunotherapy at different sites in patients with oligometastatic NSCLC from the SEER and the single-center cohorts. To our knowledge, this was the largest sample size, and the first analysis to assess the role of immunotherapy in treating oligometastatic NSCLC according to different metastatic sites. Immunotherapy is US Food and Drug Administration approved for use alone or in combination with chemotherapy for patients with NSCLC, and has been evaluated after locally ablative therapy for oligometastatic disease (12). However, phase III clinical studies are still lacking in the field of immunotherapy treatment of oligometastatic NSCLC. Whether immunotherapy can confer a survival benefit in patients with oligometastatic NSCLC remains controversial, particular in those with different metastatic sites. Our study showed that immunotherapy improved OS and CSS in patients with oligometastatic NSCLC. These findings agreed with previous findings of improved survival following treatment of metastatic NSCLC with PD-1 inhibitors (15, 16). Recent clinical trials focused on use of immunotherapy to treat various solid tumors have shown a clear association between immunotherapy and increased OS and improved prognosis (17, 18). We also observed reduced OS in patients in the LIM and MOM subgroups. This was consistent with the findings of previous studies showing that patients with NSCLC that had metastasized to multiple organs or the liver had worse OS relative to those with other metastases (19–22). These results showed the value of immunotherapy for treatment of oligometastatic NSCLC patients with liver and multiple organ metastases.

We found that being male was significantly associated with poorer prognosis, which agreed with the results of a study by Radkiewicz C et al, who reported that men with NSCLC had consistently poorer lung cancer-specific survival across stages (23). Moreover, our results showed that patient prognosis was related to tumor location, and patients with tumors located in the main bronchus had worse outcomes than those who had tumors in other locations, which agreed with the results of a study by Li C et al (24). A recent study showed that chemotherapy combined with immunotherapy had superior efficacy for improving anticancer activity (25). Radiotherapy is not an independent prognostic factor for improvement of OS and CSS, due to the remarkable effects of recently developed targeted therapies.

The definition of oligometastatic NSCLC differed across many previous studies, with the maximum number of metastases ranging from 3 to 6 (26). Recently, a number of studies have shown that LT improved the prognosis of patients with oligometastatic NSCLC (27, 28). However, several studies have also shown that immunotherapy was effective for treatment of patients with oligometastatic NSCLC, especially for those at high risk of distant metastases (29, 30). In the most recent NCCN guidelines, immunotherapy is a recognized front-line treatment approach for metastatic NSCLC (31). Therefore, we studied the efficacy of immunotherapy for treatment of oligometastatic NSCLC based on different metastatic sites.

Previous studies focused on metastatic NSCLC have demonstrated that different sites of metastasis can predict clinical outcomes (20, 21, 32).Patients with NSCLC with bone metastasis have the best prognosis (32), which we further confirmed in the present study. We found that patients in the LOM and MOM subgroups had the worst OS and CSS compared to those in other subgroups, which was consistent with the results of a study by Yang J et al, which identified that the mortality risk was highest with MOM and liver metastases (20). We also found that immunotherapy improved OS and CSS in the BRM and MOM subgroups. A recent study found that local control and overall survival were both improved in patients with NSCLC who received concurrent immune checkpoint inhibitor treatment with radiosurgery (33), which was consistent with our results. Another study (34) that brain irradiation induces the strongest immune activation effects and patient outcome compared with those achieved through irradiation of other organs, which may be consistent with our results. However, patients in the LOM subgroup did not benefit from immunotherapy, which may have been associated with poorer response of liver metastasis to immunotherapy. A study reported that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models, resulting in a systemic immune desert through siphoning of activated CD8+ T cells from the systemic circulation (35). Our results showed that patients in the MOM subgroup benefited most from immunotherapy, which was consistent with the results of a study by Ma SC et al (36), who reported that increased number of metastatic sites (≥2) we associated with pronounced OS benefits from atezolizumab versus docetaxel. This may indicate that these patients represent a subgroup that may benefit from aggressive treatment.

Our study had several limitations. First, the SEER database does not provide a detailed description of the specific immunotherapy used. Second, limited information is provided by the SEER database, and there may be some degree of error in the coding of individual patients. Transfer of patients in a particular group (bone, brain, liver) were restricted to this organ, although patients may have had metastases at other sites not explicitly documented in the SEER database (the most common unrecorded site may be the adrenal). Finally, this study was a retrospective study, and the efficacy of immunotherapy in oligometastatic NSCLS with different metastatic sites should be evaluated in prospective clinical trials.

Our study showed that immunotherapy improved OS and CSS in patients in the SEER and the single-center cohorts. Furthermore, we found that immunotherapy improved the prognosis of patients in the BRM and MOM subgroups, but not those in the BOM, OTM, or LIM subgroups. The MOM subgroup experienced the greatest benefit from immunotherapy in both cohorts. Therefore, metastatic sites may affect the efficacy of immunotherapy. These subgroups may benefit from aggressive treatment, and our results may have implications for clinical guidance. However, our findings need to be validated in future large-sample prospective clinical trials.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was not obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

J-CM, J-XZ, FW, DC and JY contributed to the study. DC and JY designed the project and approved the final manuscript. J-XZ and FW are responsible for modifying and editing this article. J-CM collected the clinical patients information and drafted the article. All authors contributed to the article and approved the submitted version.

This work was supported by National Natural Science Foundation of China (82172676), Science Foundation of Shandong (ZR2021YQ52, ZR2020LZL016), Foundation of Bethune Charitable Foundation (2021434953), and the Young Elite Scientist Sponsorship Program by CAST (YESS20210137).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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