Discontinuation of ICIs Produced Similar Results Compared With Continuous Use in NSCLC

Discontinuing the use of immune checkpoint inhibitors (ICIs) after 2 years produced similar results to that of continuing to use the treatment in advanced metastatic non-small cell lung cancer (amNSCLC), as immune-related adverse events would accumulate over time, according to a new review.¹

The length of time to use ICIs has varied, with no consensus on the optimal length of time that the ICIs must be used. The FDA has recommended that ICIs be used until either disease progression or toxicity, though certain ICIs are recommended for 2 years.² The optimal duration for use of ICIs has been studied rarely overall. Because of ongoing responses after premature discontinuation of ICI therapy, this systematic review aimed to assess the risks and benefits of discontinuing ICIs after 2 years for those living with amNSCLC.

The researchers used PubMed, Embase, Web of Science, and CENTRAL to collect studies from each of their inception points through to August 25, 2024. Studies were included if they had adult participants with metastatic or advanced NSCLC, took ICI either by itself or in combination, took the therapy for at least 2 years, and had a minimum follow-up of 3 years after starting ICI. Any repeated studies took the study with the most follow-up data.

Studies that did not report survival data of those who had at least 2 years of ICI therapy; were phase 1 trials; were case reports, case series, systematic reviews, or meta-analyses; had use of experimental agents; evaluated more than progression; or had included ICI therapy in an adjuvant or neo-adjuvant setting were not included.

There were 20 studies included in the review, of which all were written in English. There were 11 randomized controlled trials (RCTs) and 9 with a real-world evidence (RWE) design. A total of 5027 participants made up the 20 studies, split into 2 groups where patients either used ICI therapy for 2 years or used it for a continuous amount of time. ICI was used as a first line of treatment in 13 of the studies, with most participants receiving either pembrolizumab, nivolumab, or atezolizumab.

The RCTs found a range of overall survival (OS) outcomes in those who took ICI for 2 years, ranging from 61.8% in a 6-year OS and between 69.5% and 83% in a 5-year OS. A study found a lower OS of 56.6% after 3 years. Those in the RWEs had similar results, with 1 study finding a 6-year OS of 77.2%, a separate study finding a 4-year OS of 89.2%, and a last study reporting a 3-year OS of 98.2%.

The continuous treatment group had a 6-year OS of 77% in a study with 2156 patients. Other studies found a 4-year OS of 81%, and another found a 4-year OS of 93.1% in 61 patients. Neither group reached the median OS.

Studies that compared the survival between the groups were all RWE. The study with 2156 patients in the continuous group and 919 patients in the limited time group found an HR of 0.97 (95% CI, 0.75-1.26), which was not statistically significant. A separate study found an adjusted HR of 1.33 (95% CI, 0.78-2.25) when comparing the 2 groups, which was not significant. Progression-free survival outcomes were also not statistically significant between the 2 groups. Time to treatment failure was found to be a little shorter in those who were in the continuous group.

Several studies found that the rates of immune-related adverse events were higher in those who took ICIs for 2 years when compared with the original cohort, but the severity was the same or lower. Other studies found that immune-related adverse events and grade 3 or higher adverse events were more common in the continuous treatment group.

There were some limitations to this study. Some of the included RCTs were not blinded, and most of the RWEs had serious biases. The treatment regimens had heterogeneity across the studies. The effect of PD-L1s was not assessed in this review. All of the studies that compared the 2 groups were RWE studies and need to be taken with caution. There was a lack of data surrounding other ICI therapies.

“Two years are a reasonable time point for discontinuation of therapy for those without progressive disease,” the authors concluded. “Immune-related adverse events tend to accumulate over time, while rates of severe events are stable or lower… Continuous ICI therapy increases the overall health care costs and financial toxicity.”

References

1. Pandey T, Bhatti SA. Efficacy and safety of two-year fixed versus continuous immune checkpoint inhibitor therapy in advanced or metastatic non-small cell lung cancer: a systematic review. Cancer Immunol Immunother. 2025;74:317. doi:10.1007/s00262-025-04143-8

2. Libtayo. FDA. Updated April 2024. Accessed September 30, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761097s023lbl.pdf