Efficacy and safety of XELOX combined with anlotinib and penpulimab vs XELOX as an adjuvant therapy for ctDNA-positive gastric and gastroesophageal junction adenocarcinoma: a protocol for a randomized, controlled, multicenter phase II clinical trial (EXPLORING study)

Front Immunol. 2023 Oct 31:14:1232858. doi: 10.3389/fimmu.2023.1232858. eCollection 2023.

Abstract

Background: The efficacy of current adjuvant chemotherapy for gastric adenocarcinoma/gastroesophageal junction adenocarcinoma (GA/GEJA) leaves much to be desired. ctDNA could serve as a potential marker to identify patients who are at higher risk of recurrence. Reinforcing standard adjuvant chemotherapy with immunotherapy has already been indicated to significantly improve clinical outcome, albeit such evidence is rare in GA/GEJA. Here, we intend to explore the clinical benefit of the reinforcement of adjuvant immunotherapy and antiangiogenics alongside with chemotherapy in patients who are deemed in high risk of recurrence by ctDNA analysis, which might shed light on further improvements in adjuvant therapy for GA/GEJA.

Methods/design: This study is designed as a prospective, multicenter, randomized, controlled phase II study in patients histologically or cytologically diagnosed with GA/GEJA who underwent D2 gastrectomy and achieved R0 or R1 resection. From February 2022, a total of 300 stage III patients will be enrolled and subjected according to ctDNA sequencing results, and those with positive results will subsequently be randomized 1:1 to arm A or B. Patients in arm A will receive anlotinib, penpulimab and XELOX for 6-8 cycles, maintained with anlotinib and penpulimab for up to 1 year, while patients in arm B will receive XELOX alone for 6-8 cycles. ctDNA-negative patients will be assigned to arm C, and patients who are ctDNA positive but failed in randomization will be assigned to arm D. Patients in arms C and D will receive the investigator's choice of therapy. The primary endpoint is the median disease-free survival (DFS) of arm A versus arm B determined via CT/MRI imaging. Secondary endpoints include the DFS of ctDNA positive patients versus ctDNA negative patients, the 2- and 3-year DFS rates, overall survival (OS), the impact of hallmark molecules on the treatment response, adverse events (AEs), and the impact of nutrition status or exercise on recurrence.

Discussion: We expect that ctDNA would be a strong prognostic factor and ctDNA-positive patients are at higher risk of relapse than ctDNA-negative patients. The addition of anlotinib and penpulimab to XELOX, may contribute to delaying relapse in ctDNA-positive patients.

Trial registration: https://www.clinicaltrials.gov, identifier NCT05494060.

Keywords: CtDNA; GA/GEJA; XELOX adjuvant chemotherapy; anlotinib; clinical trial; penpulimab; protocol; vascular normalization.

Publication types

  • Clinical Trial Protocol
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma* / drug therapy
  • Adenocarcinoma* / genetics
  • Clinical Trials, Phase II as Topic
  • Esophagogastric Junction
  • Fluorouracil* / therapeutic use
  • Humans
  • Multicenter Studies as Topic
  • Neoplasm Recurrence, Local / drug therapy
  • Oxaliplatin / therapeutic use
  • Prospective Studies
  • Randomized Controlled Trials as Topic
  • Recurrence

Substances

  • penpulimab
  • Fluorouracil
  • anlotinib
  • Oxaliplatin

Supplementary concepts

  • XELOX
  • Adenocarcinoma Of Esophagus

Associated data

  • ClinicalTrials.gov/NCT05494060

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82102981), the Key Program of Taizhou School of Clinical Medicine and Nanjing Medical University (TZKY20220306) Jiangsu Province Hospital (the First Affiliated Hospital with Nanjing Medical University) Clinical Capacity Enhancement Project (JSPH-MB-2022-1). This funding source did not have a role in the study design and preparation of the manuscript and will not have a role in execution, analysis, interpretation of data, or decision to publish results.