AACR Launches First-of-Its-Kind Phase II Trial Testing Organ Preservation in Gastroesophageal Cancer
核心洞察
The AACR Center for Cancer Clinical Trials has enrolled the first patient in AACR-ADOPT-GEA, a phase II adaptive platform trial for localized or locally advanced gastroesophageal adenocarcinoma (搜索).
The trial evaluates biomarker-matched targeted therapies—zanidatamab for HER2 (搜索)-positive and zolbetuximab for CLDN18.2 (搜索)-positive tumors—combined with tislelizumab and chemotherapy to potentially spare patients from gastrectomy or esophagectomy.
A two-stage design will first assess pathologic complete response rates and develop a predictive signature, then allow patients predicted to achieve pCR to skip surgery; regimens enabling at least 20% of patients to avoid surgery will advance.
The American Association for Cancer Research (搜索) (AACR) announced that its newly formed AACR Center for Cancer Clinical Trials has enrolled the first patient in AACR-ADOPT-GEA, a first-of-its-kind phase II adaptive platform trial testing whether biomarker-matched targeted therapies can allow patients with localized or locally advanced gastroesophageal adenocarcinoma (搜索) (GEA) to avoid life-altering surgery.
The prospective, multicenter trial targets patients with resectable stage 2-3 stomach or esophageal cancer. Currently, the standard of care for these patients involves neoadjuvant chemotherapy followed by surgical removal of the stomach (gastrectomy) or esophagus (esophagectomy)—procedures that carry severe, lifelong consequences for quality of life, including the need to sleep in an inclined position and avoid full-sized meals permanently.
"GEA is a devastating disease with fewer than 40% of patients alive five years after diagnosis," said Patricia M. LoRusso, DO, PhD (hc), FAACR, chair of the AACR Clinical Trials Advisory Council and chief of experimental therapeutics at Yale School of Medicine. "The current standard of care for nonmetastatic disease has debilitating consequences for the patient's quality of life, underscoring the high unmet need for novel therapeutic approaches to this cancer—a need that AACR-ADOPT-GEA aims to address."
Biomarker-Driven Treatment Strategy
The trial assigns patients to treatment arms based on their tumor's molecular profile. Patients with HER2 (搜索)-positive tumors receive zanidatamab (Ziihera), tislelizumab (Tevimbra), and chemotherapy. Those with claudin 18.2 (CLDN18.2 (搜索))-positive tumors receive zolbetuximab (Vyloy), tislelizumab, and chemotherapy. The adaptive platform design allows for additional treatment arms to be incorporated as new therapies emerge, with plans to enroll patients harboring other molecular alterations in the future.
"To date, perioperative studies in patients with GEA have applied a one-size-fits-all approach, with all patients being treated in the same way regardless of the molecular markers their tumors express and all these patients ultimately needing a large surgical procedure to achieve cure," said Elena Elimova, MD, co-principal investigator of the trial and a gastrointestinal medical oncologist at the Princess Margaret Cancer Centre in Toronto. "The AACR-ADOPT-GEA study is a departure from this paradigm. Additionally, the adaptive design allows for rapid assessment of novel or targeted therapies in the curative setting, where they can potentially have the most impact."
Two-Stage Adaptive Design
The trial employs a two-stage design. In the first stage, investigators will assess each regimen's ability to shrink or eliminate the tumor as measured by pathologic complete response (pCR) and develop a predictive signature to identify which patients are likely to achieve pCR. In the second stage, a new cohort of patients will receive biomarker-matched treatment, and those predicted to have a pCR based on the developed signature will forgo surgery.
Treatments that enable at least 20% of patients to avoid surgery will advance from the platform for future study. Patients in both stages will be followed for several years to evaluate short-term and long-term outcomes.
A New Chapter for AACR
AACR-ADOPT-GEA is the first clinical trial sponsored by the AACR Center for Cancer Clinical Trials, established in 2023 to leverage the scientific expertise of AACR's more than 65,000 members across academia, the pharmaceutical industry, and patient advocacy organizations.
"As the world's first and largest cancer research organization, AACR is uniquely positioned to take this bold new step toward advancing patient care," said AACR Chief Executive Officer Margaret Foti, PhD, MD (hc). "Through the AACR Center for Cancer Clinical Trials, AACR will draw from its more than 65,000 members to ensure its clinical trials are scientifically rigorous, clinically impactful, and patient centered."
The trial incorporates comprehensive collection and analysis of patient tissue and blood samples before, during, and after treatment to identify biomarkers of response and resistance, laying groundwork for future therapeutic advances.
"The AACR-ADOPT-GEA trial has the potential to establish an entirely novel clinical strategy for GEA patients that will strive to preserve the stomach or esophagus in some patients through a sophisticated molecularly customized clinical approach," said Jaffer A. Ajani, MD, co-principal investigator of the trial and a gastrointestinal medical oncologist and professor at The University of Texas MD Anderson Cancer Center. "In the future, this innovative organ preservation strategy could be applied to patients with other tumor types, such as rectal, bladder, breast, or lung."