The lymphocyte stability index (LSI) forms a pan-cancer peripheral biomarker for overall survival post initiation of immune checkpoint blockade (ICB)

Robust, pan-cancer peripheral blood biomarkers for response to immune checkpoint blockade (ICB) are lacking. We have previously shown that a single nucleotide polymorphism at rs16906115 (intronic to IL7) associates with increased risk of ICB toxicity, but promotes increased lymphocyte count stability post-initiation of treatment. Individuals with a stable lymphocyte count had improved progression-free (PFS) and overall survival (OS) in metastatic melanoma (MM). We hypothesise that the Lymphocyte Stability Index (LSI) can predict outcome to ICB across a range of cancers. We retrospectively collected treatment, blood count and survival data on all individuals treated with ICB since 2014 at Oxford University Hospitals NHS Foundation Trust (n=706). We performed survival analysis based on lymphocyte stability. The LSI was calculated by dividing the post-treatment lymphocyte count by the pre-treatment count. Using a replication cohort, we validated our previous finding that patients with stable LSI (>0.8) had significantly improved overall survival in MM. This was also the case for those with stable LSI and a diagnosis of non-small cell lung cancer (NSCLC) or metastatic renal cell carcinoma (mRCC) with previous pre-treatment. Using a Cox proportional hazards model to control for a range of covariates including age and number of prior treatments, a stable LSI was associated with a hazard ratio for death of 0.38 (95% CI: 0.26-0.56, p<0.0001) for MM (combined cohorts), 0.49 (95% CI: 0.33-0.77, p<0.001) for NSCLC and 0.33 (95% CI: 0.14-0.89, p=0.013) for pre-treated mRCC. Patients with MM and stable LSI treated with single-agent PD-1 blockade had equivalent survival to those treated with combination ICB. The LSI is an extremely simple dynamic peripheral biomarker for survival following ICB treatment across multiple cancers with an underlying molecular and genetic association. Application of LSI in MM permits effective patient stratification, delineating those who single-agent ICB provides equivalent benefit to combination anti-PD1 and anti-CTLA-4 treatment, potentially sparing them of the associated toxicity burden.