Final overall survival analysis and exploratory biomarker study from JUPITER-06: a randomized phase III trial of...

The interim analysis of the JUPITER-06 study reveals significantly longer progression-free survival (PFS) and overall survival (OS) in advanced esophageal squamous-cell carcinoma (ESCC) patients treated with toripalimab in combination with paclitaxel (Taxol) plus cisplatin (TP). 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. Here, we present the final analysis of the JUPITER-06 study and further explore potential biomarkers associated with OS.

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. The coprimary endpoints were OS and PFS assessed by blinded independent central review. Whole exome sequencing of 486 tumors enabled biomarker analyses.

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). The 3-year OS rates were 29.7% and 19.9% in the two groups, respectively. Neither programmed death-ligand 1 (PD-L1) expression nor TMB significantly correlated with OS benefit. In contrast, prespecified biomarkers, ccTMB, and EGIC scheme robustly stratified patients with different long-term OS benefits from immunochemotherapy. 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. Importantly, CDK4/6 and PORCN inhibitors were identified as potential partners to overcome resistance and enhance the efficacy of immunochemotherapy.

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.