Abstract CT223: AACR Adaptive Biomarker-Driven Organ Preservation Trial in GE Adenocarcinomas (AACR-ADOPT-GEA)

Abstract Background: Localized gastroesophageal adenocarcinomas (GEA) are molecularly heterogeneous and often exhibit limited sensitivity to current systemic therapies. The 5-year survival rate with standard perioperative chemotherapy is ∼40%, and only ∼15% of patients achieve a pathologic complete response (pCR). AACR-ADOPT-GEA was designed to overcome these barriers and assess, for the first time in GEA, if organ preservation is achievable by delivering biomarker-matched targeted therapies to patients. Notably, several targetable biomarkers - HER2, MSI, EBV, and CLDN18.2 - have demonstrated therapeutic relevance in metastatic GEA. In AACR-ADOPT-GEA, we hypothesize that in biomarker-selected cohorts, addition of a targeted agent for treatment of locally advanced GEA can increase pCR rates and enable 5-year organ preservation in approximately 20% of patients. Methods: AACR-ADOPT-GEA (NCT07290985) is a prospective, multi-center, two-stage adaptive platform trial. Eligible participants include patients diagnosed with resectable (stage II or higher [≥T2 N0-3 M0 or T0-4a N1-3 M0] as per NCCN guidelines) adenocarcinoma of the stomach, esophagus, or gastroesophageal junction, have an ECOG performance score of 0-1, adequate organ function, to be a candidate for curative surgery, and test positive for one of the targetable tumor biomarkers. Participants may receive one cycle of FLOT/mFOLFOX during the screening period. Following screening and biomarker confirmation, participants will be enrolled into a corresponding sub-study and treated with a biomarker-specific targeted agent in addition to mFOLFOX plus an immune checkpoint inhibitor (ICI) for 4 months. Pre-operative treatment will be followed by surgery and an 8-month post-operative treatment consisting of the targeted agent and an ICI. This two-stage study is designed to assess pCR rates for each targeted regimen with an initial cohort of up to 24 patients in Stage I. An interim analysis will be conducted after enrollment of 12 evaluable patients in each sub-study to drop futile regimens. Those regimens achieving a pCR rate ≥25% (6 out of 24 patients) will graduate and proceed to Stage II where a machine learning predictive model, utilizing clinical data, tumor biology, and serial ctDNA dynamics will be developed to establish a signature predictive of pCR. In stage II, 97 patients will be enrolled to achieve 80% power to test the area under the ROC curve of 0.80 against 0.65 to predict pCR at a two-sided significance level of 0.05. During this stage, patients with a complete clinical/radiological response and predicted pCR after 4 months of treatment may omit surgery and continue on 8 months of maintenance therapy with protocol-specified surveillance. Those with residual disease will undergo surgical resection followed by postoperative therapy. Importantly, access to pre- and post-treatment tissue samples in Stage II will enable multiomic analyses for response/resistance biomarkers to catalyze future work in this area. Citation Format: Elena Elimova, Jaffer Ajani, Samuel J. Klempner, Kurt Schalper, Zev Wainberg, Yuan Ying, Jan D. Baranski, Scott Boerner, Sienna M. Durbin, Denise Gallagher, Huh Won Jae, Ronan A. McLaughlin, Matthew R. Strickland, Eric H. Rubin, Lillian L. Siu, Timothy A. Yap, Patricia LoRusso. AACR Adaptive Biomarker-Driven Organ Preservation Trial in GE Adenocarcinomas (AACR-ADOPT-GEA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT223.