Abstract PO1-18-07: Phase I trial of combination pembrolizumab and ruxolitinib in metastatic triple negative breast cancer
Authors: Kassi Anelia , Carmona Jacqueline , Green Sarah M. , Kosiorek Heidi , Barrett Michael T. , Pockaj Barbara A. , Northfelt Donald , Anderson Karen S. 
Published: May 2024

Abstract
BACKGROUND: The amplification of genes PDL-1, PDL-2, and JAK2 on chromosome 9p24, known as the PDJ amplicon, has been identified in 15% of triple negative breast cancer (TNBC) and is associated with tumor infiltrating lymphocytes and elevated JAK2 mRNA, suggesting a coordinated inflammatory response in TNBC. Adding pembrolizumab to chemotherapy in KEYNOTE trials 355 and 522 has validated the use of PD-1 blockade in TNBC and redefined the standard of care. Despite preclinical data suggesting a role for targeting the IL- 6/JAK2/STAT3 pathway, the JAK1/JAK2 inhibitor ruxolitinib has not shown efficacy as a single Agent in breast cancer. This is the first phase I clinical trial evaluating the combination of pembrolizumab and ruxolitinib in the treatment of metastatic TNBC. METHODS: We conducted a phase I clinical trial with accrual from 2018 to 2023 at Mayo Clinic Arizona. Patients (n=12) received 200 mg of IV pembrolizumab per cycle (every 3 weeks) with 3+3 dose escalation of oral ruxolitinib twice a day (dose level 0: 10 mg PO BID, level 1: 15 mg PO BID, level 2: 20 mg PO BID). The primary endpoint was to determine the maximum tolerated dose (MTD) of ruxolitinib and secondary endpoints were treatment safety and efficacy. Clinical response was assessed by computed tomography of the chest, abdomen, and pelvis every 3 cycles. PD-L1 expression in tumor was measured by immunohistochemistry (IHC). The effect of the combined therapies on T and B cell populations were assessed by flow cytometry and antibody profiling of 695 tumor antigens and 8 viral antigens by nucleic acid protein programmable array. RESULTS: Twelve female patients with chemotherapy refractory metastatic TNBC were treated on study. All received 200 mg IV pembrolizumab every cycle. Due to rapid disease progression of three patients early after treatment initiation, eligibility was restricted to prohibit patients with extensive pulmonary disease or elevated LDH. Those patients were excluded from efficacy or correlative analysis. The most common toxicities were transaminitis (n=12), anemia/leukopenia (n=12), and fatigue (n=9). The majority of adverse events were grade 1 and occurred at dose level 2. There were 5 adverse events grade 3 or higher: respiratory or thoracic complications (n=3), hypertension (n=1), and abdominal pain (n=1), but MTD was not established. The median number of cycles was 4 for each dose level (range n=2.0-9.0) and the median time to progression was 3 months (range n=1.4-6.3). No patient had tumor response by RECIST v1.1 criteria and there was no association of disease stability with PD-L1 tumor expression by IHC. Circulating antibodies to tumor antigens remained stable, and viral-specific antibodies mildly decreased by month 2 in all patients at dose levels 0 and 1. Of the 7 patients reactive to TRIM21 autoantibodies, 2 patients had a transient increase at 2 months. CONCLUSIONS: The combination of pembrolizumab with ruxolitinib was well tolerated at all dose levels, and the number but not the severity of adverse events increased with higher ruxolitinib dose. Two of six patients in dose level 0 and 1 had stable disease for six months on treatment, suggesting that the lower dose levels of ruxolitinib (i.e. 10 mg PO BID) may have more activity in combination with pembrolizumab.
Citation Format: Anelia Kassi, Jacqueline Carmona, Sarah M. Green, Heidi Kosiorek, Michael T. Barrett, Barbara A. Pockaj, Donald Northfelt, Karen S. Anderson. Phase I trial of combination pembrolizumab and ruxolitinib in metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-07.