Neoadjuvant pembrolizumab with FLOT chemotherapy and short-course radiation for locally advanced gastroesophageal junction cancer

An Open Label Phase 2 Study of Total Neoadjuvant Therapy (TNT) Consisting of FLOT With Pembrolizumab and Short Radiation for Patients With Locally Advanced Gastroesophageal Junction Adenocarcinoma

This treatment plan will test whether pembrolizumab plus FLOT chemotherapy given before and after a short course of radiation can let some patients with locally advanced gastroesophageal junction adenocarcinoma avoid surgery or improve cancer control.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 26 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: National Cancer Center Hospital East (Academic / other)
• Drugs / interventions: pembrolizumab, radiation
• Locations: 1 site (Kashiwa, Chiba)
• Trial ID: NCT07018570 on ClinicalTrials.gov

What this trial studies

Patients with treatment‑naive, locally advanced gastroesophageal junction adenocarcinoma receive two doses of pembrolizumab every 21 days and two cycles of FLOT chemotherapy every 14 days before short‑course radiotherapy. Radiation is delivered as 5 Gy daily for five days (total 25 Gy), followed by additional pembrolizumab and FLOT in an immunochemotherapy phase. After two efficacy assessments, patients with complete or near‑complete response continue non‑operative management with further pembrolizumab and FLOT, while those without sufficient response proceed to surgery followed by postoperative adjuvant pembrolizumab and FLOT. The protocol tests whether this total neoadjuvant approach can increase organ preservation without compromising oncologic outcomes.

Who should consider this trial

Good fit: Adults (≥18) with treatment‑naive, histologically confirmed Siewert type I–III gastroesophageal junction adenocarcinoma staged T2–T4, N any, M0, with ECOG performance status 0–1 and adequate blood and organ function are ideal candidates.

Not a fit: Patients with metastatic disease (M1), prior systemic therapy, ECOG ≥2, recent blood transfusion, or significant organ dysfunction are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could allow some patients to avoid major surgery and preserve the esophagus while maintaining cancer control.

How similar studies have performed: Combining immune checkpoint inhibitors with perioperative chemotherapy and radiation has produced promising pathological responses in early trials, but organ‑preservation approaches for GEJ adenocarcinoma remain experimental.

Eligibility criteria

\<Inclusion Criteria\>

1. Patients with histologically confirmed esophagogastric junction adenocarcinoma.
2. Patients who are naive to systemic therapy and have esophagogastric junction carcinoma of Siewert Type I to III classified as T: 2-4, N: any, and M: 0 according to the 8th edition of the UICC-TNM classification.
3. Patients aged 18 years or older as of the day of informed consent.
4. Patients with ECOG Performance Status (PS) 0 or 1.
5. Patients whose most recent laboratory values within 14 days before registration meet all of the following criteria (testing on the same day of the week two weeks before the date of registration is acceptable).

\[1\] Neutrophil count ≥1,500/mm3 \[2\] Hemoglobin ≥9.0 g/dL \[3\] Platelet counts ≥100,000/mm3 \[4\] Total bilirubin ≤1.5 mg/dL \[5\] AST (GOT) ≤100 IU/L \[6\] ALT (GPT) ≤100 IU/L \[7\] Serum creatinine ≤1.5 mg/dL 6) Patients who did not receive blood transfusion within 7 days before registration (ineligible if transfusion was performed on the same day of the week one week before the date of registration).

7)Female patients of childbearing potential who tested negative for pregnancy within 14 days before registration. Male and female patients who have agreed to practice appropriate highly effective contraception with low user dependency during the study and for up to 120 days after discontinuation of the investigational drug.

8)Patients who have given consent to provide samples for biomarker analysis. 9)Patients who have given their own written consent to participate in the study

\<Exclusion Criteria\>

1. Patients with a history of using an anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody.
2. Patients with a history of acute coronary syndrome (including myocardial infarction and angina unstable), coronary angioplasty, or stent implantation within 6 months before registration.
3. Patients with a history or findings of congestive heart failure of Class II or higher according to the New York Heart Association (NYHA) classification of cardiac function.
4. Patient with active double cancers \[simultaneous double cancers and metachronous double cancers with a disease-free interval of ≤2 years. However, carcinoma in situ or lesions equivalent to intramucosal carcinoma judged to have been cured by local treatment shall not be included in active double cancers\].
5. Patients with serious (requiring hospitalization) complications (e.g., intestinal paralysis, intestinal obstruction, pulmonary fibrosis, difficult-to-control diabetes mellitus, cardiac failure, myocardial infarction, angina unstable, renal failure, hepatic failure, psychiatric disorder, cerebrovascular disorder).
6. Patients with active hepatitis B (HBs antigen positive) or hepatitis C.
7. Patients with a history of HIV.
8. Patients with complicated interstitial lung disease/pneumonitis or with a history of (non-infectious) interstitial lung disease/pneumonitis requiring steroid administration.
9. Patients who received a live vaccine within 30 days before the start of investigational drug administration.
10. Patients with concomitant autoimmune disease or a history of chronic or recurrent autoimmune disease.
11. Patients who require systemic corticosteroids (except for prophylactic administration for testing or allergic reactions, or temporary use to reduce edema associated with radiotherapy) or immunosuppressive medication, or those who have received any of these treatments within 14 days before registration in this study.
12. Patients with unhealed wounds (requiring sutures, antimicrobial administration, and cleaning procedures), ulcers, or fractures.
13. Pregnant or lactating patients.
14. Patients who are unwilling or unable to comply with the study protocol.
15. Patients deemed by the investigator to be ineligible for this study.

Where this trial is running

Kashiwa, Chiba

• National Cancer Center Hospital East — Kashiwa, Chiba, Japan (Recruiting)

Study contacts

• Study coordinator: Kohei Shitara, MD

Conditions Gastroesophageal Junction Adenocarcinoma; Esophagogastric junction carcinoma; Total neoadjuvant therapy; TNT; Radiation; Surgery; Pembrolizumab; FLOT