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（atezolizumab）联合贝伐珠单抗（bevacizumab）治疗方案对不可切除肝细胞癌（hepatocellular carcinoma, HCC）患者具有显著临床疗效。然而，约20%接受阿替利珠单抗联合贝伐珠单抗治疗的HCC患者会出现疾病进展（progressive disease, PD），进而导致不良预后。因此，对HCC的早期预测与精准检测至关重要。
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留存基线血清样本的不可切除HCC患者，并根据治疗启动后6周的疾病进展情况将其分为早期疾病进展组（early PD, n=13）与非早期疾病进展组。其中，分别选取早期疾病进展组与非早期疾病进展组各4例患者进行细胞因子芯片（cytokine array）与基因分析。本研究鉴定出的潜在预测因子在验证队列（n=60）中得到验证，并在接受仑伐替尼（lenvatinib）治疗的患者群体中进行了疗效评估。
结果：循环肿瘤DNA（circulating tumor DNA）的基因变异未观察到显著组间差异。细胞因子芯片分析数据显示，基线状态下的MIG（CXCL9）、ENA-78及RANTES在早期疾病进展组与非早期疾病进展组患者间存在显著表达差异。验证队列的后续分析表明，早期疾病进展组患者的基线CXCL9水平显著低于非早期疾病进展组；预测早期疾病进展的血清CXCL9最佳截断值为333 pg/mL（灵敏度：0.600，特异度：0.923，曲线下面积AUC=0.75）。在血清CXCL9水平低于333 pg/mL的患者中，35.3%（12/34）的患者在接受阿替利珠单抗联合贝伐珠单抗治疗后出现早期疾病进展，且其无进展生存期（progression-free survival, PFS）显著短于CXCL9水平≥333 pg/mL的患者（中位PFS：126天 vs 227天；风险比HR=2.41，95%置信区间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水平显著低于无客观应答的患者。
结论：基线血清CXCL9水平低于333 pg/mL可有效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。