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

[PURPOSE] The CDK4/6 inhibitor palbociclib delays progression in patients with advanced dedifferentiated liposarcoma (DDLPS). 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.

[PATIENTS AND 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 (scRNA-seq), and peripheral blood by high-parameter flow cytometry. Analyses focused on cell cycle, senescence, and immune-related changes.

[RESULTS] Twelve patients were treated before the study was halted because of a 42% immune-related toxicity rate. The overall response rate was 8.3%, and the disease control rate was 75%. Median progression-free and overall survival rates were 7.1 and 26.8 months, respectively. Nine patients had at least one tumor biopsy analyzed; three 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, whereas expression of LAG-3, ICOS, and CD38 increased in select subsets.

[CONCLUSIONS] 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.

[SIGNIFICANCE] In this phase 2 study of palbociclib and retifanlimab, treatment led to immune-related adverse events, halting enrollment. scRNA-seq and flow cytometry revealed cell-cycle suppression, senescence, and T-cell changes. These findings highlight the rationale for this combination and the need for safer dosing strategies in larger cohorts.