Final overall survival analysis and exploratory biomarker study from JUPITER-06: a randomized phase III trial of toripalimab plus chemotherapy in advanced esophageal squamous-cell carcinoma.

Prior work proposed copy number alteration-corrected tumor mutational burden (ccTMB) and an esophageal cancer genome-based immuno-oncology classification (EGIC) scheme as prespecified biomarkers to predict treatment efficacy.

先前的工作提出了拷贝数变异校正的肿瘤突变负荷（ccTMB）和基于食管癌基因组的免疫肿瘤学分类（EGIC）方案作为预先设定的生物标志物，用于预测治疗效果。

Here, we present the final analysis of the JUPITER-06 study and further explore potential biomarkers associated with OS.

在这里，我们展示了JUPITER-06研究的最终分析，并进一步探讨了与总生存期（OS）相关的潜在生物标志物。

patients_and_methods

A total of 514 patients with treatment-naïve advanced ESCC were randomly assigned 1: 1 to receive toripalimab or placebo in combination with paclitaxel plus cisplatin every 3 weeks for up to six cycles, followed by toripalimab or placebo maintenance.

共有514名未经治疗的晚期食管鳞癌（ESCC）患者按1:1的比例随机分配，接受toripalimab或安慰剂联合紫杉醇加顺铂每3周一次，最多六个周期，随后进行toripalimab或安慰剂维持治疗。

The coprimary endpoints were OS and PFS assessed by blinded independent central review.

主要终点是通过盲法独立中央审查评估的总生存期(OS)和无进展生存期(PFS)。

Whole exome sequencing of 486 tumors enabled biomarker analyses.

对486个肿瘤进行全外显子组测序，使生物标志物分析成为可能。

result

As of 23 February 2023, toripalimab plus TP significantly improved OS versus placebo plus TP [17.7 months, 95% confidence interval(CI) 14.6-20.8 months versus 12.9 months, 95% CI 11.6-14.1 months; hazard ratio(HR) 0.72, 95% CI 0.58-0.88, P = 0.002).

截至2023年2月23日，托瑞利珠单抗联合TP方案显著改善了总生存期，与安慰剂联合TP方案相比[17.7个月，95%置信区间（CI）14.6-20.8个月，对比12.9个月，95% CI 11.6-14.1个月；风险比（HR）0.72，95% CI 0.58-0.88，P = 0.002）。

The 3-year OS rates were 29.7% and 19.9% in the two groups, respectively.

两组的3年总生存率分别为29.7%和19.9%。

Neither programmed death-ligand 1 (PD-L1) expression nor TMB significantly correlated with OS benefit.

程序性死亡配体1（PD-L1）表达和TMB均与总生存（OS）获益无显著相关性。

In contrast, prespecified biomarkers, ccTMB, and EGIC scheme robustly stratified patients with different long-term OS benefits from immunochemotherapy.

相比之下，预先设定的生物标志物、ccTMB和EGIC方案能够强有力地区分出接受免疫化疗后具有不同长期总生存获益的患者。

Further exploratory analysis discovered that loss-of-function alterations in the SWI/SNF chromatin remodeling complex were associated with improved OS, whereas gain-of-function alterations in cell cycle and WNT signaling pathways correlated with reduced survival benefits.

进一步的探索性分析发现，SWI/SNF染色质重塑复合体的功能丧失突变与总生存期的改善相关，而细胞周期和WNT信号通路的功能获得性突变与生存益处的减少相关。

Importantly, CDK4/6 and PORCN inhibitors were identified as potential partners to overcome resistance and enhance the efficacy of immunochemotherapy.

重要的是，CDK4/6和PORCN抑制剂被确定为潜在的伙伴，以克服耐药性并增强免疫化疗的疗效。

Conclusions

This final OS analysis of JUPITER-06 confirms the sustained survival benefit of toripalimab plus chemotherapy in advanced ESCC. ccTMB and EGIC enable consistently precise patient stratification, while pathway-specific vulnerabilities highlight actionable targets for exploratory combination strategies.

JUPITER-06研究的最终总生存分析证实了托瑞利珠单抗联合化疗在晚期食管鳞癌中的持续生存益处。