Multicenter phase I/II study of abemaciclib and ramucirumab in metastatic gastroesophageal adenocarcinoma (GEA): CDK4/6 and cyclin D1 alterations as a predictor of response and survival.

4063 Background: CDK4/6 and Cyclin D1 are highly expressed in GEA cancers, suggesting that CDK4/6 inhibition may be a promising strategy. In vitro and in vivo studies have shown that abemaciclib (A) demonstrates potent antitumor efficacy in GEA by directly inhibiting this pathway. Currently, ramucirumab (RAM) ± paclitaxel is an approved 2 nd line treatment for metastatic GEA cancers. Methods: This multicenter, open-label, phase I/II study investigated the safety and efficacy of A combined with RAM in pretreated advanced GEA (2 nd or 3 rd line). The primary objective was to describe the safety profile of A (150mg po bid) and RAM (8mg/kg iv every 2 weeks) using CTCAE version 4.03. Secondary objectives included assessing the objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS). Correlative studies to evaluate alterations in CDK4/6 and Cyclin D1 as determined by next generation sequencing as predictive biomarkers of efficacy were performed. Results: From July 2021 to December 2024, 20/30 patients were enrolled. The study was terminated prematurely due to slow accrual. The median age was 61.5 years (Range: 30.0, 80.0) and most patients were male (18/20). Seven patients (35%) were HER-2 positive, 11/18 patients (61.1%) were PDL1 CPS > 1 and 15 patients (75%) had cancer localized in the E. Baseline ECOG performance status was 0 in 8 patients (40%) and 55% of patients had received prior immunotherapy with 1 st line chemotherapy. A combined with RAM was generally well-tolerated without unexpected toxicities. The most common treatment-related adverse events (AEs) were anemia (10%), hypertension (10%), and dysphagia (10%). Treatment-related AEs ≥ grade 3 occurred in 50% of the patients. Median PFS and mOS were 2.7 months (95% CI: 1.5 - 14.5) and not reached (NR) (95% CI: 3.4 - NR), respectively. ORR was 10% (2/20) and DCR was 40% (8/20). In evaluable patients, 64.7% (11/17) patients with baseline tissue CDK4/6 pathway alterations trended towards longer mPFS (3.4 vs. 1.3 months; HR:1.1) and mOS (NR vs. 5.2 months; HR: 1.4) compared to patients without alterations (p > 0.05). Notably, one study patient with a CDK6 amplification had a partial response of 64% and has been on treatment for > 24 months. Conclusions: A plus RAM demonstrated promising antitumor activity in previously treated E/GEJ adenocarcinomas in the 2 nd and 3 rd line metastatic setting with manageable toxicities. Alterations in the CDK4/6 and Cyclin D1 pathways appear to enrich for efficacy and may be predictive but need future validation. In-depth molecular studies investigating changes in the expression of selected serum/tissue genomic markers of response for the cytostatic regimen will be presented at the meeting. Clinical trial information: NCT04921904 .