Phase I trial of capecitabine with cemiplimab in patients with hormone receptor–positive metastatic breast cancer.

e13082 Background: Immunotherapy has been used in hormone receptor positive (HR+) HER2 negative metastatic breast cancer (MBC) and has shown modest clinical response and improved clinical benefit rate (CBR). Capecitabine has shown immunomodulatory activity by increasing interferon-gamma from activated tumor infiltrating immune cells, thus inducing PD-L1 expression. Therefore, patients may derive clinical benefit from the combination of capecitabine with cemiplimab. In our published preclinical studies, immunotherapy with activated lymphocytes administered a few days before chemotherapy to pre-sensitize the tumor and its microenvironment demonstrated substantial tumor cell death and response compared with a single agent alone. We hypothesize that timing and sequencing are important for a successful combination strategy. Methods: This is a phase I, single-arm, prospective trial for patients with HR+/HER2- MBC without prior chemotherapy or immunotherapy. The study was conducted at Moffitt Cancer Center between October 2021 and October 2023. Patients received a fixed dose of cemipilimab IV 350 mg on day 1 in combination with Capecitabine orally twice daily for 14 days on and 7 days off starting on day 3 of a 21-day cycle. Patients were started at capecitabine 800 mg/m2 and if well tolerated then increased to 1000 mg/m2. The primary endpoint was an analysis of adverse events and dose-limiting toxicity (DLT). Secondary endpoints included objective response rate (ORR), CBR, and progression free survival (PFS). Results: Thirteen eligible patients with HR+/HER2- MBC were enrolled. The median age was 57 years (46-70 years), 11 were Caucasian, 1 was Black/African American and 1 was Asian/Pacific Islander. All patients had progression on prior endocrine treatment (1 to 6 lines of treatment, mean 2.6) and 92.3% had received prior treatment with CDK4/6 inhibitor. The most common adverse events were hand and foot syndrome (30.8%, n = 4) followed by cough, decreased absolute neutrophil count, thromboembolic event, and dyspnea which occurred each in 15.4% (n = 2) patients. Only 1 immune related event of dry mouth (sicca) was seen (7.7%). A partial response (PR) was seen in 2 patients (15.4%), stable disease (SD) in 6 patients (46.2%) and progressive disease (PD) in 5 patients (38.5%). Median PFS is 4.1 months (95% CI 2.8 – NR). The ORR was 15.4% (95% CI: 4.3% - 42.3%), and the CBR was 61.5% (95% CI: 35.5% - 82.3%). 2 patients (15.4%) derived long term responses who continued treatment beyond 2 years. Conclusions: Our study found that the sequence of cemiplimab in combination with capecitabine had an acceptable safety profile. No unexpected adverse events or DLT were seen. Patients derived a reasonable clinical benefit from the combination treatment. 2 patients derived long term responses beyond 2 years. Further studies and biomarker analysis are warranted to explore this combination and improve patient selection. Clinical trial information: NCT05064085 .