Supplementary Material for: Low baseline CXCL9 predicts early progressive disease in unresectable HCC with atezolizumab plus bevacizumab treatment

Introduction: Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial.
Methods: Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (n = 68) were screened and classified according to their PD, six weeks after treatment initiation (early PD; n = 13). Of these, four patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (n = 60) and evaluated in patients treated with lenvatinib.
Results: No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (< 333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs 227 days; HR: 2.41, 95% CI: 1.22–4.80, p = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without.
Conclusion: Baseline low serum CXCL9 (< 333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.

引言：阿替利珠单抗联合贝伐珠单抗治疗方案在不可切除肝细胞癌（hepatocellular carcinoma, HCC）患者中疗效显著。然而，约20%接受该方案治疗的HCC患者会出现疾病进展（progressive disease, PD），预后不佳。因此，对HCC的早期预测与检测至关重要。
方法：本研究筛选了68例接受阿替利珠单抗联合贝伐珠单抗治疗且基线血清样本留存完好的不可切除HCC患者，根据治疗启动后6周的疾病进展情况分为早期PD组（n=13）与非早期PD组。从中各选取4例患者开展细胞因子阵列检测与遗传分析。本研究鉴定出的潜在标志物在验证队列（n=60）中进行验证，并在接受仑伐替尼（lenvatinib）治疗的患者中进行评估。
结果：循环肿瘤DNA的遗传变异未观察到显著组间差异。细胞因子阵列检测结果显示，早期PD组与非早期PD组患者的基线MIG（CXCL9）、ENA-78及RANTES水平存在显著差异。验证队列的后续分析表明，早期PD组患者的基线CXCL9水平显著低于非早期PD组；血清CXCL9预测早期PD的最佳截断值为333 pg/mL（灵敏度：0.600，特异度：0.923，AUC=0.75）。在血清CXCL9水平低于333 pg/mL的患者中，35.3%（12/34）接受阿替利珠单抗联合贝伐珠单抗治疗后出现早期PD，且其无进展生存期（progression-free survival, PFS）显著短于CXCL9水平达标患者（中位PFS：126天 vs 227天；HR=2.41，95%CI：1.22–4.80，p=0.0084）。此外，对仑伐替尼治疗存在客观应答的患者，其CXCL9水平显著低于无应答者。
结论：基线血清CXCL9水平低于333 pg/mL，可用于预测接受阿替利珠单抗联合贝伐珠单抗治疗的不可切除HCC患者的早期疾病进展。