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.

Inclusion Criteria:

1. Signed written informed consent from previous studies and age ≥18 years.

2. Histologically or cytologically confirmed esophageal squamous cell carcinoma (ESCC).

3. 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).

4. At least one measurable lesion per RECIST 1.1.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Anticipated life expectancy ≥12 weeks.

7. Adequate organ and bone marrow function within 14 days prior to the first dose (without blood transfusion, EPO, G-CSF, or other hematologic supports), as defined by:

   • Absolute neutrophil count (ANC) ≥1.5×109/L
   • Platelet count ≥100×109/L
   • Hemoglobin ≥9 g/dL (or ≥5.6 mmol/L)
   • Serum albumin >30 g/L
   • Serum creatinine ≤1.5×ULN (Upper Limit of Normal) or calculated creatinine clearance ≥60 mL/min (using the Cockcroft-Gault formula)
   • Total bilirubin ≤1.5×ULN
   • AST and ALT ≤2.5×ULN (≤5.0×ULN for patients with documented liver metastases, provided total bilirubin is within normal limits)
   • International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5×ULN, and activated Partial Thromboplastin Time (aPTT) ≤1.5×ULN

8. Female patients of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days prior to the first dose. WOCBP and male patients with WOCBP partners must agree to use highly effective contraception from signing the informed consent throughout the treatment period and for at least 6 months after the last dose. (Highly effective methods include oral/implanted hormonal contraceptives, intrauterine devices [IUDs], or barrier methods combined with spermicide. Postmenopausal women aged >50 years must have been amenorrheic for ≥12 months to be considered postmenopausal).

9. Required washout periods prior to the first dose of study treatment are as follows:

   • Systemic anticancer therapies (chemotherapy, targeted therapy, immunotherapy, biological therapy, or hormonal therapy) or participation in clinical trials: >4 weeks.
   • Systemic small-molecule targeted therapies: >2 weeks or 5 half-lives (whichever is longer).
   • Prior Chinese herbal medicine with anti-tumor activity: >2 weeks.
   • Prior major surgery or radiotherapy: >4 weeks (palliative radiotherapy for bone metastases: >2 weeks).

Exclusion Criteria:

Exclusion Criteria

1. Currently receiving concurrent antitumor therapies (including chemotherapy, systemic therapy, immunotherapy, radiotherapy, or surgery) at the time of enrollment.

2. 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).

3. 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).

4. 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.

5. Active peripheral neuropathy (PN) or neurotoxicity ≥ Grade 2, history of Grade 3 neurotoxicity/PN, or prior permanent discontinuation of treatment due to neurotoxicity/PN.

6. Active pneumonitis/interstitial lung disease (ILD), history of pulmonary radiation within 12 months prior to the first dose, or clinically significant underlying pulmonary disease (e.g., chronic obstructive pulmonary disease).

7. Symptomatic or active central nervous system (CNS) metastases requiring intervention (including steroid therapy with prednisone >10 mg/day or equivalents, or anticonvulsants) within 4 weeks prior to the first dose.

8. Any other severe underlying medical condition, including but not limited to: uncontrolled diabetes, active infections, vaccination within 4 weeks, active peptic ulcer, uncontrolled epilepsy, cerebrovascular accident within 6 months, gastrointestinal bleeding within 3 months, or clinical signs of coagulopathy.

9. Clinically significant cardiovascular disease, including:

   • Left ventricular ejection fraction (LVEF) ≤50% or below the institutional lower limit of normal (LLN) determined by echocardiography (ECHO) or MUGA scan (if ECHO is unavailable).
   • Heart failure classified as NYHA Class ≥III.
   • Uncontrolled hypertension (systolic BP ≥150 mmHg and/or diastolic BP ≥95 mmHg despite optimal medical therapy).
   • Prior or current cardiomyopathy.
   • Unstable angina, or myocardial infarction within 6 months.
   • Serious arrhythmia requiring medical intervention (excluding controlled atrial fibrillation or paroxysmal supraventricular tachycardia).

10. QTc interval ≥450 ms for males, or ≥470 ms for females (using Fridericia's formula), or history of congenital long QT syndrome.

11. Dyspnea due to advanced malignancy complications or other diseases, requiring continuous supplemental oxygen therapy at rest.

12. Any other severe psychiatric, psychological, familial, or geographical conditions that, in the investigator's opinion, could interfere with study compliance, protocol execution, follow-up, or place the patient at high risk of treatment-related complications.

13. History of HIV infection or positive HIV serology.

14. Active viral hepatitis B or C (Note: Patients with HBV are eligible if HBV DNA is within the normal range/suppressed on antivirals; patients with positive HCV antibody are eligible if HCV RNA is undetectable via PCR). Frequent viral load monitoring is mandatory.

15. History of life-threatening allergies, known hypersensitivity to any study drug components, recombinant proteins, or excipients, or intolerance to EGFR antibodies or eribulin.

16. Pregnant or lactating women.

17. Any concurrent medical condition that, in the investigator's clinical judgment, could compromise protocol compliance.