Response to ‘Letter to the Editor: “Lymphocyte‐Monocyte Ratio Predicts Survival in Patients With Unresectable Hepatocellular Carcinoma Treated With Durvalumab Plus Tremelimumab: A Multicenter Analysis”’

Thank you for your interest [1] in our article “Lymphocyte-Monocyte Ratio Predicts Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Durvalumab Plus Tremelimumab: A Multicenter Analysis” [2]. In this study, we demonstrated that baseline lymphocyte-to-monocyte ratio (LMR) serves as a promising simple inflammatory biomarker associated with overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC) receiving durvalumab plus tremelimumab (Dur/Tre). We appreciate the insightful comments regarding sex imbalance, external validity, and LMR cutoff generalizability. Sex constitutes an established prognostic factor in HCC [3]. Our cohort exhibited male predominance, reflecting the real-world epidemiology of unresectable HCC in Japan. Given that our objective was to characterize outcomes of Dur/Tre in routine clinical practice rather than within a trial-balanced cohort, we enrolled consecutive patients. To address potential confounding, we employed inverse probability weighting (IPW) based on propensity scores incorporating age, sex, body mass index, ECOG performance status, etiology, tumor stage, liver function, tumor markers, and treatment line. Elevated LMR remained significantly associated with prolonged OS following adjustment. Furthermore, in a sensitivity analysis confined to male patients, high LMR—defined by this prespecified cutoff—remained significantly associated with prolonged OS (HR, 0.094; 95% CI, 0.014–0.648; p = 0.016) (Figure 1), suggesting that the prognostic value of LMR cannot be attributed solely to sex imbalance. Nevertheless, we acknowledge that residual confounding and IPW-related limitations may persist. Cumulative IPW-adjusted OS curves stratified by LMR in male patients. Regarding external validity, all participants received treatment at 12 institutions within the Kansai region. Regional variations in HCC etiology, patient demographics, and LMR distribution may limit generalizability. Our cutoff value (3.19) was derived through time-dependent ROC analysis, and restricted cubic spline analyses indicated a favorable OS range for LMR between approximately 2.5 and 4.0. Sensitivity analyses employing cutoffs of 3.0 and 3.5 yielded consistent trends. Consequently, we consider 3.19 a cohort-specific and context-dependent threshold rather than a universally applicable cutoff, and external validation in diverse populations remains imperative. We further recognize that our real-world cohort differs substantially from the HIMALAYA trial population, which comprised treatment-naive patients with Child–Pugh class A and ECOG performance status 0–1 [4]. Our cohort included patients receiving first-through later-line therapies and individuals with Child–Pugh class B or ECOG performance status 2–3. The study objective was to evaluate LMR's prognostic utility within a pragmatic clinical context rather than to establish direct comparisons with trial outcomes or define trial-ready thresholds. In summary, we concur that our findings warrant cautious interpretation. Limitations include the retrospective design, modest sample size, and limited female representation. Nonetheless, our results consistently support baseline LMR as a simple cost-effective blood biomarker associated with OS in patients with unresectable HCC treated with Dur/Tre. Future prospective multicenter studies encompassing larger more heterogeneous cohorts will be essential to elucidate the optimal LMR threshold and definitively establish whether LMR functions as an independent prognostic factor in this clinical setting. We wish to thank all those who contributed to the data collection for this study. The authors have nothing to report. Informed consent was obtained in the form of an opt-out via the institutional website. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of the Kobe University Graduate School of Medicine (approval no. B230107). Toshifumi Tada is an editorial board member of Hepatology Research. Toshifumi Tada received lecture fees from AstraZeneca K.K., AbbVie G.K., Eisai Co. Ltd., and Chugai Pharmaceutical Co. Ltd. All other authors declare no potential conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.