Oncotarget | https://doi.org/10.18632/oncotarget.26998 Celina Ang, Samuel J. Klempner, Siraj M. Ali, Russell Madison, Jeffrey S. Ross, Eric A. Severson, David Fabrizio, Aaron Goodman, Razelle Kurzrock, James Suh,...

Systemic inflammation is a hallmark of cancer, and it has a pivotal role in hepatocellular carcinoma (HCC) development and progression. We conducted a retrospective study including 362 patients receiving immune check-point inhibitors (ICIs) across three continents, evaluating the influence of neutrophiles to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), and prognostic nutritional index (PNI) on overall (OS), progression free survival (PFS), and radiologic responses. In our 362 patients treated with immunotherapy, median OS and PFS were 9 and 3.5 months, respectively. Amongst tested inflammatory biomarkers, patients with NLR ≥ 5 had shorter OS (7.7 vs. 17.6 months, p < 0.0001), PFS (2.1 vs. 3.8 months, p = 0.025), and lower objective response rate (ORR) (12% vs. 22%, p = 0.034); similarly, patients with PLR ≥ 300 reported shorter OS (6.4 vs. 16.5 months, p < 0.0001) and PFS (1.8 vs. 3.7 months, p = 0.0006). NLR emerged as independent prognostic factors for OS in univariate and multivariate analysis (HR 1.95, 95%CI 1.45–2.64, p < 0.001; HR 1.73, 95%CI 1.23–2.42, p = 0.002) and PLR remained an independent prognostic factor for both OS and PFS in multivariate analysis (HR 1.60, 95%CI 1.6–2.40, p = 0.020; HR 1.99, 95%CI 1.11–3.49, p = 0.021). Systemic inflammation measured by NLR and PLR is an independent negative prognostic factor in HCC patients undergoing ICI therapy. Further studies are required to understand the biological mechanisms underlying this association and to investigate the predictive significance of circulating inflammatory biomarkers in HCC patients treated with ICIs.

Systemic inflammation is a key risk factor for hepatocellular carcinoma (HCC) progression and poor outcomes. Inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) may have prognostic value in HCC treated with standard of care atezolizumab plus bevacizumab (Atezo-Bev). We conducted a multicenter, international retrospective cohort study of patients with unresectable HCC treated with Atezo-Bev to assess the association of NLR and PLR with overall survival (OS), progression-free survival (PFS), and objective response rates. Patients with NLR ≥ 5 had a significantly shorter OS (9.38 vs. 16.79 months, p < 0.001) and PFS (4.90 vs. 7.58 months, p = 0.03) compared to patients with NLR < 5. NLR ≥ 5 was an independent prognosticator of worse OS (HR 2.01, 95% CI 1.22–3.56, p = 0.007) but not PFS. PLR ≥ 300 was also significantly associated with decreased OS (9.38 vs. 15.72 months, p = 0.007) and PFS (3.45 vs. 7.11 months, p = 0.04) compared to PLR < 300, but it was not an independent prognosticator of OS or PFS. NLR and PLR were not associated with objective response or disease control rates. NLR ≥ 5 independently prognosticated worse survival outcomes and is worthy of further study and validation.

Immune checkpoint inhibitors (ICI) have shown positive results in patients with hepatocellular carcinoma (HCC). As liver function contributes to prognosis, its precise assessment is necessary for the safe prescribing and clinical development of ICI in HCC. We tested the accuracy of the albumin-bilirubin (ALBI) grade as an alternative prognostic biomarker to the Child-Turcotte-Pugh (CTP). In a prospectively maintained multi-centre dataset of HCC patients, we assessed safety and efficacy of ICI across varying levels of liver dysfunction described by CTP (A to C) and ALBI grade and evaluated uni- and multi-variable predictors of overall (OS) and post-immunotherapy survival (PIOS). We studied 341 patients treated with programmed-death pathway inhibitors (n = 290, 85%). Pre-treatment ALBI independently predicted for OS, with median OS of 22.5, 9.6, and 4.6 months across grades (p < 0.001). ALBI was superior to CTP in predicting 90-days mortality with area under the curve values of 0.65 (95% CI 0.57–0.74) versus 0.63 (95% CI 0.54–0.72). ALBI grade at ICI cessation independently predicted for PIOS (p < 0.001). Following adjustment for ICI regimen, neither ALBI nor CTP predicted for overall response rates or treatment-emerging adverse events (p > 0.05). ALBI grade identifies a subset of patients with prolonged survival prior to and after ICI therapy, lending itself as an optimal stratifying biomarker to optimise sequencing of systemic therapies in advanced HCC.

Atezolizumab/bevacizumab (A/B) is now a standard first-line treatment for advanced hepatocellular carcinoma (HCC), but the optimal second-line regimen is not known. We evaluated real-world treatment patterns and outcomes to investigate factors associated with post-progression survival (PPS). In this multicenter, international, retrospective study, we examined clinical characteristics and outcomes of patients with advanced HCC who progressed on first-line A/B. The primary outcome of PPS was defined as time from first radiographic progression on A/B to death. A total of 406 patients alive after progression on first-line A/B were included in the final analysis, of whom 45.3% (n = 184) received best supportive treatment (BST) and 54.7% (n = 222) continued active systemic treatment. In the second line, 155 patients were treated with tyrosine kinase inhibitors (TKIs), 45 with immune checkpoint inhibitor (IO)-based regimens, and 3 had missing data. Median PPS of the whole cohort (mPPS) was 6.0 months (95% CI 5.2-7.2). On multivariate Cox regression analysis, absence of portal vein tumor thrombus, ECOG <2, and continued active treatment were predictors of better PPS. mPPS was significantly longer for patients who continued active treatment vs. BST (9.7 vs. 2.6 months; HR 0.41, p <0.001). In the second-line setting, patients treated with TKIs had a numerically shorter mPPS compared to those treated with IO (8.4 vs. 14.9 months; HR 1.37, p = 0.256). Continuation of active therapy after A/B progression was independently associated with better survival even after adjusting for baseline disease characteristics. mPPS with IO-based therapy exceeded a year, suggesting that IO continuation post-progression may retain benefit. The precise sequencing of TKI and IO regimens warrants further investigation. There is currently a lack of level 1 data on second-line treatment options for patients with advanced hepatocellular carcinoma who progress after frontline atezolizumab plus bevacizumab, as all second-line approvals were established during the frontline sorafenib era. Our study aims to fill in some of the knowledge gap by investigating real-world patient outcomes in the second-line treatment setting. Findings from this study show that patients who continued active treatment had improved post-progression survival compared to those who received best supportive care, and medication regimens incorporating tyrosine kinase inhibitors as well as immunotherapy agents were active. These results can help inform clinicians of possible treatment options for patients who progress after frontline atezolizumab plus bevacizumab while we await maturing data from randomized-controlled trials.