Investigating potential immune mechanisms of trilaciclib administered prior to chemotherapy in patients with metastatic triple-negative breast cancer

Antoinette R Tan, Joyce O'Shaughnessy, Subing Cao, Sarah Ahn, John S Yi, Antoinette R Tan, Joyce O'Shaughnessy, Subing Cao, Sarah Ahn, John S Yi

Abstract

Purpose: In a phase II trial in patients with metastatic triple-negative breast cancer (mTNBC; NCT02978716), administering trilaciclib prior to gemcitabine plus carboplatin (GCb) enhanced T-cell activation and improved overall survival versus GCb alone. The survival benefit was more pronounced in patients with higher immune-related gene expression. We assessed immune cell subsets and used molecular profiling to further elucidate effects on antitumor immunity.

Methods: Patients with mTNBC and ≤ 2 prior chemotherapy regimens for locally recurrent TNBC or mTNBC were randomized 1:1:1 to GCb on days 1 and 8, trilaciclib prior to GCb on days 1 and 8, or trilaciclib alone on days 1 and 8, and prior to GCb on days 2 and 9. Gene expression, immune cell populations, and Tumor Inflammation Signature (TIS) scores were assessed in baseline tumor samples, with flow cytometric analysis and intracellular and surface cytokine staining used to assess immune cell populations and function.

Results: After two cycles, the trilaciclib plus GCb group (n = 68) had fewer total T cells and significantly fewer CD8+ T cells and myeloid-derived suppressor cells compared with baseline, with enhanced T-cell effector function versus GCb alone. No significant differences were observed in patients who received GCb alone (n = 34). Of 58 patients in the trilaciclib plus GCb group with antitumor response data, 27 had an objective response. RNA sequencing revealed a trend toward higher baseline TIS scores among responders versus non‑responders.

Conclusion: The results suggest that administering trilaciclib prior to GCb may modulate the composition and response of immune cell subsets to TNBC.

Keywords: CDK4/6; Chemotherapy; Immune profiling; Metastatic triple-negative breast cancer; Trilaciclib.

Conflict of interest statement

Antoinette R. Tan reports institutional clinical trial support and personal fees from G1 Therapeutics, Inc.; outside of the submitted work, institutional clinical trial support from Arvinas, Genentech/Roche, Merck, and Pfizer, and personal fees from AstraZeneca, Genentech/Roche, Jazz Pharmaceuticals, Novartis, Puma, Seagen, and Stemline Therapeutics. Joyce O’Shaughnessy reports institutional clinical trial support and personal fees from G1 Therapeutics, Inc.; outside of the submitted work, personal fees from AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, BMS, Celgene, Eisai, Genentech, Immunomedics, Ipsen, Jounce Therapeutics, Lilly, Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, Prime Oncology, Puma Biotechnology, Roche, Seattle Genetics, and Syndax Pharmaceuticals. Subing Cao and Sarah Ahn (at the time of the study), and John S. Yi are paid employees and shareowners of G1 Therapeutics, Inc.

© 2023. The Author(s).

Figures

Fig. 1
Fig. 1
Changes to a immune cell populations and b T-cell function in peripheral blood over two cycles (C1D1 vs. C3D1) in patients receiving trilaciclib prior to GCb or GCb alone. C1D1 cycle 1, day 1 C3D1 cycle 3, day 1 CD cluster of differentiation, GCb gemcitabine plus carboplatin, IFNγ interferon gamma, IL interleukin, MDSC myeloid-derived suppressor cell, Treg regulatory T cell
Fig. 2
Fig. 2
Changes to immune cell populations in peripheral blood over two cycles (C1D1 vs. C3D1) for trilaciclib responders and non-responders. C1D1 cycle 1, day 1, C3D1 cycle 3, day 1, CD cluster of differentiation, MDSC myeloid-derived suppressor cell, Treg regulatory T cell
Fig. 3
Fig. 3
Changes to a CD4+ and b CD8+ T-cell function in peripheral blood over two cycles (C1D1 vs. C3D1) for trilaciclib responders and non-responders. C1D1 cycle 1, day 1, C3D1 cycle 3, day 1, CD cluster of differentiation, HLA-DR human leukocyte antigen—DR isotype, IFNγ interferon gamma, IL interleukin
Fig. 4
Fig. 4
a Differential gene expression analysis (adjusted P value < 0.05; red dots, │log2FC│ > 1; blue dots, │log2FC│ ≤ 1) and b tumor inflammation signatures in tumor samples from trilaciclib responders and non-responders. False discovery rate < 0.25. FC fold change, IFNγ interferon gamma, NK natural killer, TIS tumor inflammation score

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