Neoadjuvant single-dose trilaciclib prior to combination chemotherapy in patients with early triple-negative breast cancer: Safety, efficacy, and immune correlate data from a phase 2 study.
Authors: Force Jeremy Meyer , O'Shaughnessy Joyce , Wang Lisa S. , Mosalpuria Kailash , Hurvitz Sara A. , Goel Shom , Ahn Sarah , Cao Subing , Russo Melissa , Yi John S. , Oyekunle Taofik , Jacobson Amanda , Beelen Andrew Paul , Danso Michael A. 
Published: June 2023

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Background: Trilaciclib, an intravenous CDK4/6 inhibitor, induces transient G1 cell cycle arrest. In preclinical studies, trilaciclib demonstrated immune-modulating effects by enhancing T-cell activation, favorably altering the tumor microenvironment (TME), and improving long-term immune surveillance. Preliminary data from this phase 2, single-arm, open-label study of neoadjuvant trilaciclib in triple-negative breast cancer (TNBC; NCT05112536) showed that single-dose trilaciclib increased CD8+ T-cell/Treg ratios within the TME. Here, we combine immune analysis with clinical outcomes to identify correlates of treatment response. Methods: Patients (pts) with early-stage TNBC received single-dose trilaciclib followed by trilaciclib + dose-dense anthracycline/cyclophosphamide and taxane (AC/T). Per investigator discretion, pts received pembrolizumab (pembro) 400 mg Q6W from cycle 1 and/or carboplatin (carbo) AUC 1.5 QW from cycle 5. Tumor biopsies and blood samples were collected prior to treatment, 7 days post single-dose trilaciclib, and during surgery, with an additional blood sample at cycle 2. PDL1 status was assessed per Ventana SP142 assay (positive immune cell score ≥ 1%). The primary objective is to evaluate the immune-based mechanism of action of single-dose trilaciclib. Results: As of January 3, 2023, 18/24 pts had completed treatment and/or had definitive surgery; 1 pt with neuroendocrine features discontinued due to disease progression. Median age was 57 years. At diagnosis, 79% of pts had stage II tumors (88% with ductal carcinoma; 38% with PDL1+ tumors). 18 pts received pembro + carbo, 3 pts pembro only, and 3 pts carbo only. Common treatment-related adverse events (TRAEs) were fatigue (79%), nausea, (67%), alopecia (67%), and neutropenia events (63%); 42% of pts had grade 3/4 neutropenia events. 4 serious TRAEs occurred in 2 (8%) pts: pembro-related colitis and hypertransaminasemia, trilaciclib/paclitaxel-related urosepsis, and AC-related febrile neutropenia. Response data were available for 15 pts; pathologic complete response (pCR) was observed in 7 (47%) pts, with pCR rates of 86% vs 13% for pts with PDL1+ vs PDL1– tumors, respectively. Immune analysis of the TME post trilaciclib monotherapy demonstrated several pCR-related features, such as increased stromal tumor-infiltrating lymphocytes and granzyme B+ cells. Correlative blood analysis revealed increased circulating baseline CD8+ T cells in pts achieving pCR. Conclusions: Safety and tolerability data are encouraging for trilaciclib in combination with AC/T ± pembrolizumab ± carboplatin in the neoadjuvant setting for early-stage TNBC. Preliminary efficacy data align with standard neoadjuvant chemotherapy regimens. Final pCR data from all pts and immune correlates from tumor and blood samples will be presented. Clinical trial information: NCT05112536 .