Tumor and Immune Dynamics Following Sequential CDK4/6 and PD-1 Inhibition: Results from a Phase 2 Study in Dedifferentiated Liposarcoma

Abstract Background: The CDK4/6 inhibitor palbociclib delays progression in advanced dedifferentiated liposarcoma (DDLPS) patients. In carcinoma models, CDK4/6 and PD-1 inhibition induce intratumoral inflammation and synergistic activity. Comprehensive assessment of tumor and host dynamics is needed to understand response and resistance to this combination. Methods: We performed a phase 2 study of palbociclib and the PD-1 inhibitor retifanlimab in advanced DDLPS. Palbociclib was administered 2 weeks prior to retifanlimab. Tumor biopsies were analyzed by single-cell RNA sequencing and peripheral blood by high-parameter flow cytometry. Results: Twelve patients were treated before the study was halted due to a 42% immune-related toxicity rate. Overall response rate was 8.3% and disease control rate was 75%. Median progression-free and overall survival were 7.1 and 26.8 months, respectively. Nine patients had at least 1 tumor biopsy analyzed; 3 had paired. Ten patients had paired blood samples analyzed. Following treatment, tumor cells demonstrated decreased cycling and increased cell cycle checkpoint activity. Transcriptional scores for senescence increased in cancer cells, as did the proportion of intratumoral T and B cells. A cluster of cells emerged with upregulated cell cycle genes and downregulated HLA class I, suggesting innate or acquired resistance to treatment. In blood, a subset of CD4+ T cells decreased, while expression of LAG-3, ICOS, and CD38 increased in select subsets. Conclusion: A palbociclib lead-in prior to retifanlimab had a high rate of immune-related toxicities. Correlative analyses identified changes in tumor and immune cells attributable to treatment. A study of concurrent dosing of the combination is ongoing.