Non-small cell lung cancer (NSCLC), as the leading cause of cancer-related deaths, poses a serious health issue worldwide¹, according to the Global Cancer Statistics 2022. Approximately 30% of NSCLC patients are diagnosed at an advanced or metastatic stage with a 5-year overall survival (OS) rate ranging from 7%–18%². Unlike localized NSCLC, which can be treated with curative intent, patients with metastatic NSCLC typically undergo systemic treatment to delay progression and prolong survival.

The concept of oligometastasis, first described in 1995, refers to an intermediate stage between localized disease and widespread metastasis³. Oligometastasis is traditionally defined as a limited number of radiographically identifiable metastases. The International Association for the Study of Lung Cancer (IASLC) consensus statement has proposed the definition of oligometastatic NSCLC as a maximum of 5 distant metastases in up to 3 organs⁴. For patients with a limited metastatic burden, local treatment, such as surgery or radiotherapy, might provide the possibility for a cure. Local therapy can be offered upfront before systemic therapy or following induced systemic therapy as local consolidative therapy (LCT) for residual disease in patients with oligometastatic NSCLC. Residual disease at the time of maximal response to systemic therapy indicates that prior systemic therapy did not completely eradicate the tumor, which often harbors drug-resistant clones. LCT for oligometastatic NSCLC after induced systemic therapy has been reported to improve survival in patients with advanced NSCLC and oligo-residual disease following effective systemic treatment in several clinical trials. However, the recent NRG-LU002 trial demonstrated no survival benefit from LCT, highlighting the need to identify which patients truly benefit from this approach.

Current evidence regarding the application of LCT in oligometastatic NSCLC is introduced herein from several randomized clinical trials. Additionally, unresolved issues in clinical practice focusing on the beneficial patient population are discussed. Furthermore, a novel treatment paradigm is proposed based on biomarkers in oligometastatic NSCLC.

Several randomized prospective studies have suggested that LCT for residual lesions in oligometastatic NSCLC after effective systemic chemotherapy prolongs progression-free survival (PFS) and OS and may even be curative for some patients with acceptable toxicity. Forty-nine patients with limited metastases who did not develop disease progression after first-line drug therapy were randomly assigned to either maintenance systemic therapy or LCT (radiotherapy or surgery) for all active residual disease in a multicenter phase II study, as reported by Gomez et al. (NCT01725165). The LCT arm demonstrated significant benefits in PFS and OS (median PFS, 14.2 months vs. 4.4 months; P = 0.022 and median OS, 41.2 months vs. 17.0 months; P = 0.017). The incidence of grade ≥ 3 toxicity was 20% in the LCT arm compared to 8% in the non-LCT arm^5,6. Another randomized phase II trial by Iyengar et al. (NCT02045446) included 29 patients with oligometastatic NSCLC using radiotherapy as the sole LCT method. LCT administered after induction chemotherapy prolonged the median PFS (9.7 months vs. 3.5 months; P = 0.01). The incidence of grade ≥ 3 toxicity was 29% in the LCT arm compared to 20% in the non-LCT arm⁷. The majority of participants in these two trials received induction chemotherapy. Both trials were recommended for premature cessation by the Ethics Committee based on the efficacy results of the interim analysis.

A randomized phase II trial (NCT03595644) assessed the efficacy and safety of radiotherapy as LCT after induced first-line EGFR-tyrosine kinase inhibitors (TKIs), as reported by Peng et al. Sixty-one patients with oligometastatic NSCLC harboring EGFR-sensitive mutations who had received first-generation EGFR-TKIs were included and randomly assigned to receive radiotherapy for primary and/or metastatic sites. The results showed that patients receiving radiotherapy had a significantly prolonged median PFS (17.6 months vs. 9.0 months; P = 0.016) and OS (33.6 months vs. 23.2 months; P = 0.026). No grade ≥ 3 toxicity was observed in either group⁸. Recent data from the unicentric phase II NORTHSTAR trial (NCT03410043), which added LCT (radiotherapy or surgery) for patients with EGFR-mutant advanced NSCLC who did not progress within 6–12 weeks of osimertinib (a third-generation EGFR-TKI), reported that osimertinib plus LCT was well tolerated without a significant increase in grade ≥ 3 adverse events compared to osimertinib alone (29% vs. 16%; P = 0.09), with 2.3% of patients experiencing grade 3 pneumonitis⁹. Survival data is anticipated.

In contrast, findings for immunotherapy appeared different. The phase II/III NRG-LU002 trial (NCT03137771) reported negative results, including 215 patients with oligometastatic NSCLC receiving first-line chemotherapy or immunotherapy with or without subsequent LCT (radiotherapy and/or surgery), with 90.7% of patients receiving immunotherapy. The 1- and 2-year PFS and OS rates were not statistically different between the LCT and non-LCT arms (PFS: HR = 0.93; P = 0.664; OS: HR = 1.05, P = 0.821). Patients receiving LCT with maintenance systemic therapy experienced a higher incidence of grade ≥ 3 pneumonitis (10% vs. 1%). Results from the NRG-LU002 trial do not support the routine use of LCT in oligometastatic NSCLC after immunotherapy¹⁰. Reasons for the negative outcome of the NRG-LU002 trial remain unclear because further details have not yet been disclosed. The NRG-LU002 trial mainly included patients without disease progression after 4 cycles of immunotherapy, of whom the proportion with stable disease (SD) was 57.8%. It appears that this population did not truly identify patients who benefit from aggressive LCT. Specifically, it remains unclear if patients with the best overall SD response will benefit less from local treatment compared to patients with a partial response to immunotherapy.

A summary of the randomized clinical trials evaluating the application of LCT in patients with oligometastatic NSCLC is shown in Table 1.

The results from different randomized clinical trials appear controversial, leading to unresolved issues in clinical practice (i.e., how are patients selected who might benefit from LCT after effective systemic treatment?).

In these trials, the same imaging criteria are often used to select NSCLC patients with oligometastasis along with a uniform time frame for systemic treatment. However, it is crucial to recognize the heterogeneity of tumors, which presents a challenge: the enrollment population may not be sufficiently precise if based solely on the same clinical characteristics. One key to treatment selection in patients with oligometastatic NSCLC is identifying patients likely to benefit from aggressive LCT. Precision biomarkers are needed to aid in selecting these beneficiary populations.

In theory, patients typically exhibit the lowest tumor burden at the time of maximum response to systemic therapy when LCT targeting residual sites is most likely to yield substantial efficacy with minimal side effects. However, defining the time of maximum response poses a challenge. There is a lack of research on the optimal duration of induced systemic therapy before local treatment. However, most studies have mandated that induced systemic therapy last at least 3 months. Some phase III clinical trials reported that > 80% of responders experienced the first response to EGFR-TKIs or chemotherapy within 12 weeks, which may partly explain the cut-off duration. It was also noted that the most significant tumor shrinkage usually occurs within 40 days after the initiation of EGFR-TKI treatment and further shrinkage becomes difficult after 90 days¹¹. Greater than 80% of first responses to immunotherapy occur within 12 weeks after 4 cycles of administration¹². However, exploratory analysis data indicate that in 75% of responders receiving chemoimmunotherapy tumors continue to regress to maximum tumor remission after achieving initial remission with a median time from the first response to maximum tumor response reported to be 109 days (ranging from 26–438 days)¹³. Persistent tumor regression represents one of the differences in response characteristics between immunotherapy and other anti-tumor therapies, such as conventional chemotherapy and targeted therapy. Unlike conventional chemotherapy and targeted therapy, which directly target tumor cells, immunotherapy induces indirect antitumor effects by restoring systemic antitumor immunity. The immune cells activated by immunotherapy provide a more comprehensive and lasting attack on tumor cells. Consequently, an exposure duration of 4 cycles before LCT may not be sufficient to achieve optimal efficacy during the immunotherapy period, which might also be a protentional reason for negative outcomes in the NRG-LU002 trial.

The inclusion criteria for oligometastasis varied among different trials, although all utilized the number of metastases for patient enrollment. The trial by Gomez et al. included patients with < 3 metastases (excluding the primary tumor) after frontline systemic therapy. Each lesion was counted separately but regional lymph node metastases were counted collectively as one lesion. Central nervous system lesions were counted towards the total number of metastases even if local treatment had been administered before randomization. The majority of patients in this trial had 0–1 metastases (65.3%), followed by 2–3 metastases (34.7%)⁵. The trial by Iyengar et al. allowed patients with up to 6 sites of extracranial disease (including the primary tumor, with ≤ 3 sites in the liver or lung) prior to the initiation of LCT. Up to 2 contiguous vertebral metastases were considered a single site of disease. The median number of disease sites prior to induction chemotherapy was 2–3, with a range of 2–6⁷. The trial by Peng et al. admitted patients with ≤ 5 discrete distant metastases with most exhibiting 1 metastatic organ (51.5%)⁸. The NRG-LU002 trial enrolled patients with ≤ 3 extracranial metastases after induction systemic therapy, with the majority of patients presenting with 1 lesion (59%), followed by 2 lesions (26%), 3 lesions (14%), and 4–5 lesions (1%)¹⁰.

The absence of biomarkers renders imaging the most relevant diagnostic method for defining oligometastatic disease. Despite some consensus on an image-based definition of oligometastatic disease, clinical outcomes after LCT for this condition vary widely¹⁴. There is still a lack of biological or pathologic evidence suggesting that a clinical condition exists which separates oligometastatic NSCLC with a defined number of detectable metastases from those with widespread metastases. Furthermore, it remains unclear whether patients with synchronous oligometastasis exhibit different biological characteristics compared to patients with metachronous oligometastasis or whether induced oligometastasis differs from repeated oligometastasis. From the perspective of precision medicine, incorporating biomarkers that reflect the underlying biological characteristics of the tumor and immune contexture could enhance these definitions.

The definition, assessment, and overall management of treatment strategies in oligometastatic NSCLC remain controversial and challenging. We conclude that three aspects should be considered when evaluating the benefits of LCT for oligometastatic NSCLC: 1) systemic treatment strategies and durations before LCT; 2) radiologic criteria for oligometastatic disease; and 3) pre-treatment ctDNA status before LCT. Future research is warranted to further clarify the criteria for defining oligometastatic disease and to determine optimal treatment strategies to improve patient survival and quality of life. Additionally, the rational use of biomarkers for personalized treatment and the collaboration of multidisciplinary teams will become central to future research efforts.