This study is an open-label, biomarker-integrated umbrella trial designed to evaluate the clinical efficacy of molecular subtype- and genomic biomarker-guided precision therapies in patients with advanced esophageal cancer refractory to prior immunotherapy. Conducted in a two-step process, the study first enrolls patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) who have progressed on prior immunotherapy, performing circulating tumor DNA (ctDNA) sequencing to stratify them into three distinct treatment cohorts, after which patients receive tailored combination regimens matched to their specific molecular profiling in the second step. Specifically, Cohort 1 includes patients with high EGFR expression or activation of EGFR-related signaling pathways, who will receive Afatinib (40 mg, p.o., Q.D.) combined with Toripalimab (240 mg, i.v., Q21D) in a 21-day treatment cycle, continuing until radiographic disease progression (PD), unacceptable toxicity, loss to follow-up, death, or other investigator-determined criteria for discontinuation, with a maximum toripalimab treatment duration of 24 months. Cohort 2 comprises patients harboring genomic alterations directly associated with cell cycle regulation or activation of cell cycle signaling pathways, who will be treated with Dalpiciclib (125 mg, p.o., Q.D. for 21 consecutive days followed by a 7-day off period in a 28-day cycle \[Q4W\]) combined with Pyrotinib maleate (320 mg, p.o., Q.D., administered within 30 minutes post-meal, Q4W) until disease progression, unacceptable toxicity, initiation of a new anti-tumor therapy, withdrawal of consent, or investigator's decision for treatment discontinuation. Cohort 3 includes patients with other molecular profiles who do not fit Cohorts 1 or 2, who will receive Camrelizumab (200 mg, i.v., Q3W) and Apatinib (250 mg, p.o., Q.D.), with clinical efficacy evaluations performed every 6 weeks, continuing until radiographic PD, unacceptable toxicity, death, or treatment discontinuation, whichever occurs first. The study aims to recruit an estimated maximum of 90 subjects, enrolling up to 30 subjects per cohort, with the final sample size dependent on the observed toxicities and the prevalence of each molecular cohort within the screened population.
Signed written informed consent from previous studies and age ≥18 years.
Histologically or cytologically confirmed esophageal squamous cell carcinoma (ESCC).
Locally advanced, unresectable, or metastatic ESCC that progressed on or after standard second-line or later therapy containing immunotherapy (including but not limited to PD-1, PD-L1, CTLA-4 antibodies, or bispecific antibodies).
At least one measurable lesion per RECIST 1.1.
Currently receiving concurrent antitumor therapies (including chemotherapy, systemic therapy, immunotherapy, radiotherapy, or surgery) at the time of enrollment.
History of other malignancies within the past 3 years (except for cured thyroid cancer, cervical carcinoma in situ, basal/squamous cell skin cancer, or other cured localized tumors with disease-free survival >3 years).
Adverse events (AEs) from prior antitumor therapies that have not resolved to baseline or Grade ≤1 (excluding alopecia, Grade 2 anemia, or irreversible, clinically insignificant, asymptomatic laboratory abnormalities).
Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose, or not fully recovered from surgical procedures; or plans for surgery during the study period.
Peking University Cancer Hospital & Institute
Lead sponsor