This is one of the largest retrospective studies evaluating the changes in LMR and association with OS in patients with different malignancies treated with ICI. Patients with high baseline LMR had 9.6 months longer median OS than patients with low baseline LMR (p < 0.001). Furthermore, patients with on-treatment change to high LMR, even with low baseline LMR, had 14.7 months longer OS than patients with persistent low LMR after the first dose of ICIs (p < 0.001). Patients with on-treatment change to low LMR, even with high baseline LMR, had 9 months shorter OS than patients with persistent high LMR after the first dose of ICIs (p < 0.001). Patients with low baseline LMR but high on-treatment LMR had 34% lower risk of death than those with low baseline LMR and low on-treatment LMR (p < 0.001). Patients with high baseline LMR and high on-treatment LMR had 48% lower risk of death than those with low baseline LMR and low on-treatment LMR, after controlling for age, ECOG, smoking, BMI, type of cancer, type of ICI, and IrAEs. Patients with a high baseline LMR and low on-treatment LMR had 8 % lower risk of death those with low baseline LMR and low on treatment LMR. The changes in LMR after the first dose of ICI treatment can predict longer OS in cancer patients. Hence, LMR is a potential potent predictive biomarker for ICI effectiveness.
ICI therapy has led to a new era of cancer therapy with sustained response and significant survival advantages observed in multiple tumors, particularly in metastatic and advanced stage cancers. A subset of patients receive long term benefits, but many patients will recur. A comprehensive understanding and identification of predictive ICI-related biomarkers is important for predictive purpose. PD-L1 expression, MSI and TMB biomarkers have limitations to routine use during treatment. PD-L1 protein expression on tumor or immune cells has emerged as an accepted predictive biomarker for sensitivity to ICIs. It has shown great promise as a predictive marker, but variability of PD L1 expression observed during testing - type of tissue tested (fresh vs. archival), type of PD-L1 assay, PD-L1 expression cutoffs: 1, 5, and 50%, and type of cells (tumor vs. immune vs. both) tested for PD-L1 expression limit the predictability of response to ICI (18). In 2017, the FDA granted accelerated approval to pembrolizumab for pediatric and adult patients with MSI-high (MSI-H) or mismatch repair–deficient solid tumors, which is the first FDA approval for a cancer treatment based on a common biomarker rather than an organ-based approach (19). However, MSI-H is found only in limited types of cancer (20). Similar to PD-L1 analysis MSI status can only be determined from tissue samples. In 2020, the FDA granted accelerated approval of pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic TMB-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] solid tumors (21). TMB has been shown to be a promising predictive biomarker for the stratification of ICI response. However, the requirement of significant amount of tumor material and absence of standardization between the different tests to define low and high TMB currently limits its use in routine practice (22). PD-L1 expression, MSI-H and TMB analyses require invasive biopsies to obtain tissue samples, which are not practical to use for frequent biomarker monitoring, and they are expensive tests (23).
Peripheral blood is a noninvasive source to explore potential biomarkers for ICIs. The immune system plays a key role in cancer as it can destroy cancer cells but also interacts with the TME that facilitates cancer cell proliferation. Monocytes are direct precursors of hematopoietic stem cell-derived macrophages. After their recruitment into the tumor tissue, they can differentiate into tumor-associated macrophages (TAM). TAMs play a role in multiple stages of tumor metastasis, from promoting tumor cell escape from the primary site to facilitating tumor cell arrival and establishment at distant sites (24). A low lymphocyte count has been found to be associated with poor OS in patients with various types of cancer (25). A high monocyte count has been reported to be a poor prognostic factor in patients with solid tumors (26–28). LMR, as a simple biomarker of host immune system, has been able to predict improved long-term prognosis of patients with various malignancies,(29, 30) but its role has not been well defined in the era of ICIs and is not routinely clinically implemented.
Strengths of this study are a large cancer patient population as well as the inclusion of clinically relevant variables that impact survival, such as age, performance status, smoking, BMI, type of cancer, type of ICIs, and IrAEs. While this is one of the largest studies to date evaluating baseline LMR and changes in LMR after the first dose of ICI in diverse cancer patient population, the limitations of this study include most notably its retrospective nature. We were not able to evaluate variables with known predictive power in this context, including line of therapy, mutation status, and predictive biomarkers (PD-L1, TMB and MSI-H). We were also not able to evaluate the relationship with LMR with single agent ICI vs combination therapies which could be subject for further study. Routine complete blood count tests to calculate LMR are inexpensive, non-invasive and readily available compared to PD-L1, MSI and TMB biomarker testing, especially in developing countries. We suggest using LMR in prospective clinical trials to confirm its validity.