Immune checkpoint inhibitors have transformed the management of non-small cell lung cancer, but how long should treatment be continued for optimal survival? Rod Tucker takes a closer look at the evidence.
It has long been recognised that a hallmark of cancer is immune evasion and that the immune system is held back by inhibitory immune checkpoint receptors and ligands. The discovery that immune checkpoint inhibitors (ICIs) could interrupt these immune checkpoints and thereby provide an anti-tumour effect, leading to cancer regression, was a major therapeutic advance in oncology.
The first ICI to receive FDA approval was ipilimumab in 2011 and, since then, there have been several other agents approved by regulatory authorities across the world.
Lung cancer is the leading cause of global cancer incidence and mortality and it accounts for an estimated two million diagnoses and 1.8 million deaths worldwide, with non-small cell lung cancer (NSCLC) responsible for more than 80% of cases.
ICIs have been deployed in the management of NSCLC and drugs such as nivolumab have proved to be very effective treatments. Nevertheless, an important and practical consideration is how long to continue with the therapy. Guidance on the use of ICIs, such as the advice in the UK from NICE for pembrolizumab in NSCLC, recommends that treatment is halted after two years. However, in its guidance, the clinical experts at NICE accept that the optimal treatment duration is unknown and they acknowledge that extended duration treatment courses are likely to be burdensome for patients, hence the restriction.
But is this somewhat arbitrary limit of two years sufficient to derive an optimal survival response, or should it be longer? In the absence of objective evidence, clinicians are left to ponder whether adhering to this duration best serves the interests of their patients. Although some evidence indicates a prolonged survival with ICIs after treatment has ceased, there is clearly a need for more definitive data.
Immune checkpoint inhibitors and survival
CheckMate 153 was the first randomised trial to examine the optimal duration of ICI therapy in patients with NSCLC. The trial compared a fixed one-year treatment regimen with nivolumab to a continuous one with exploratory analyses examining the incidence of adverse events, progression-free survival and overall survival. The results suggested a significant progression-free survival advantage favouring continuous treatment (hazard ratio, HR = 0.56, 95% CI 0.37 to 0.84).
The longest safety and efficacy data for patients with advanced NSCLC comes from the phase Ib KEYNOTE-001 study using pembrolizumab and included both previously treated and treatment naive patients. The findings, published in 2019, offered an insight of the five-year survival in those with advanced disease and the results were impressive. After 60.6 months, among previously treated patients, the median overall survival was 10.5 months in previously treated patients compared to 22.3 months in treatment-naive cohort.
Nivolumab also appears to provide impressive five-year survival data. In a study of previously treated patients with advanced NSCLC given nivolumab, the estimated five-year overall survival rate (after 96 weeks of therapy) was 16%.
Although these findings make clear that ICIs do improve survival in the longer term following cessation of treatment, there still remains the unanswered question as to how long is enough to derive these survival benefits.
The findings of a recent retrospective analysis could furnish clinicians with the answer they have been looking for.
Is two years enough?
Cognisant that most ICI trials continued for up to two years, researchers from the University of Pennsylvania evaluated the association between duration of therapy with overall survival. Publishing their findings in the journal JAMA Oncology, the team compared overall survival in those who had received ICI treatment for two years and those whose therapy continued for longer.
Survival outcomes were dichotomised as either between 700 and 760 days (i.e. two years, fixed duration) or greater than 760 days (i.e. an indefinite duration). After various adjustments for potential confounders, survival was found to be 79% in the two-year fixed-duration group and 81% for the indefinite-duration group. The hazard ratio for death associated with fixed-duration ICI therapy compared with the indefinite-duration group was non-significant (HR = 1.33, 95% CI 0.78 – 2.25, p = 0.29).
While there are recognised limitations from retrospective analyses, these findings do suggest that up to two years of ICI therapy is sufficient and that a longer duration – which is more costly and burdensome for patients – offers no survival benefit.
While guidance restricting the use of ICI therapy in NSCLC to no longer than two years might appear somewhat random, the latest evidence, although prefaced by important caveats, does appear to support that premise. Furthermore, the latest data should also offer reassurance to clinicians that these current restrictions are unlikely to affect their ability to deliver optimal care for patients with NSCLC.
