Overview

The purpose of this trial is to evaluate efficacy and safety of pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin and paclitaxel as neoadjuvant treatment in participants with locally advanced esophageal squamous cell carcinoma (ESCC), and to explore treatment resistance mechanisms.

Eligibility

Inclusion Criteria:

        [Participants are eligible to be included in the study only if all of the following
        criteria apply]
          1. Male/female participants who are at least 18 years of age on the day of providing
             documented informed consent with histologically or cytologically confirmed diagnosis
             of locally advanced and surgically resectable cT2-T4a NX M0 esophageal squamous cell
             carcinoma (ESCC) (per AJCC 8th edition) and who are previously untreated will be
             enrolled in this study.
          2. Male participants:
             A male participant must agree to use a contraception during the treatment period and
             for at least 95 days after the last dose of study treatment and refrain from donating
             sperm during this period.
          3. Female participants:
             A female participant is eligible to participate if she is not pregnant, not
             breastfeeding, and at least one of the following conditions applies:
               1. Not a woman of childbearing potential (WOCBP) OR
               2. A WOCBP who agrees to follow the contraceptive guidance during the treatment
                  period and for at least 120 days after the last dose of study treatment.
          4. The participant (or legally acceptable representative if applicable) provides written
             informed consent for the trial.
          5. Have measurable disease based on RECIST 1.1. Lesions situated in a previously
             irradiated area are considered measurable if progression has been demonstrated in such
             lesions.
          6. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy
             of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE)
             tissue blocks are preferred to slides. Newly obtained biopsies are preferred to
             archived tissue.
          7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
             Evaluation of ECOG is to be performed within 7 days prior to the first dose of study
             intervention.
          8. Have adequate organ function. Specimens must be collected within 10 days prior to the
             start of study intervention.
        Exclusion Criteria:
        [Participants are excluded from the study if any of the following criteria apply]
          1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation.
             If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
             test will be required.
          2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
             OX 40, CD137).
          3. Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to allocation.
          4. Has received prior radiotherapy within 2 weeks of start of study intervention.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
          5. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the
             first dose of study drug. Administration of killed vaccines is allowed.
          6. Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study intervention.
          7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug.
          8. Has a known additional malignancy that is progressing or has required active treatment
             within the past 2 years. Participants with basal cell carcinoma of the skin, squamous
             cell carcinoma of the skin, or carcinoma in situ (e.g, breast carcinoma, cervical
             cancer in situ) that have undergone potentially curative therapy are not excluded.
          9. Has known active CNS metastases and/or carcinomatous meningitis. Participants with
             previously treated brain metastases may participate provided they are radiologically
             stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
             (note that the repeat imaging should be performed during study screening), clinically
             stable and without requirement of steroid treatment for at least 14 days prior to
             first dose of study intervention.
         10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
         11. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment and is allowed.
         12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required
             steroids or has current pneumonitis/interstitial lung disease.
         13. Has an active infection requiring systemic therapy.
         14. Has a known history of Human Immunodeficiency Virus (HIV) infection.
         15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or known active Hepatitis C virus (defined as HCV RNA is detected)
             infection. Note: no testing for Hepatitis B and Hepatitis C is required unless
             mandated by local health authority.
         16. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the participant's
             participation for the full duration of the study, or is not in the best interest of
             the participant to participate, in the opinion of the treating investigator.
         17. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.
         18. Is pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of trial treatment.
         19. Has had an allogenic tissue/solid organ transplant.