Abstract PS2-05: PRESERVE 2: A randomized, phase 3, double-blind trial of trilaciclib or placebo in patients (pts) receiving first-line gemcitabine/carboplatin (GCb) for locally advanced or metastatic triple-negative breast cancer (mTNBC)

Abstract Background: TNBC is an aggressive malignancy for which chemotherapy is a backbone of treatment. Trilaciclib is an intravenous (IV), selective, and reversible cyclin-dependent kinase 4/6 inhibitor. In a randomized phase 2 trial in pts with previously treated mTNBC, trilaciclib administered prior to GCb resulted in a clinically meaningful improvement in overall survival (OS) versus GCb alone, regardless of programed death-ligand 1 (PD-L1) status, potentially via protection and direct activation of immune function. The multinational, randomized, double-blind, placebo-controlled, phase 3 PRESERVE 2 trial (NCT04799249) was designed to further evaluate efficacy and safety of trilaciclib prior to GCb in previously untreated pts with mTNBC. Here, we report final data from pts receiving first-line therapy, regardless of tumor PD-L1 status (cohort 1). Methods: Eligible pts had locally advanced, unresectable, or metastatic TNBC, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1, received no prior systemic therapy in the advanced/metastatic setting, and were ineligible/unable to receive treatment with a programmed cell death protein-1 (PD-1)/PD-L1 inhibitor. Pts were stratified according to tumor PD-L1 status (positive vs negative), disease-free interval (DFI; ≥ 6 months and < 12 months vs ≥ 12 months or de novo mTNBC), and country, and randomized 1:1 to receive IV placebo or trilaciclib 240 mg/m2 prior to gemcitabine (1000 mg/m2) and carboplatin (AUC 2) on days 1 and 8 of 21-day cycles. Primary endpoint: OS; secondary endpoints: OS according to PD-L1 status, progression-free survival (PFS), antitumor response (including overall response rate [ORR]), quality of life measures, myeloprotection, and safety/tolerability. Results: Overall, 187 pts from 11 countries were randomized to trilaciclib (n = 96) or placebo (n = 91) prior to GCb. Median age was 58 years (range, 30–82), and 39.6% of pts had PD-L1–positive disease (trilaciclib, 38.5%; placebo, 40.7%). DFI was < 12 months in 20.9% of pts and > 12 months (or de novo disease) in 79.1%. Pts completed a median of 6 (range, 1–41) treatment cycles. Median (95% CI) OS was 17.4 (12.4–21.3) versus 17.8 (13.3–22.5) months (hazard ratio [HR], 0.91 [95% CI, 0.62–1.33]; P = 0.884) in the trilaciclib and placebo groups, respectively, with a median follow-up of 12.1 and 14.9 months. In pts with PD-L1–positive disease, median OS with trilaciclib versus placebo was 23.1 versus 21.8 months (HR, 1.0 [95% CI, 0.51–1.96]; P = 0.923), and in pts with PD-L1–negative disease was 15.7 versus 14.9 months (HR, 0.92 [95% CI, 0.57–1.49]; P = 0.913), respectively. Median (95% CI) PFS was 6.3 (4.4–8.3) months with trilaciclib and 6.4 (5.2–8.1) months with placebo (HR, 1.17 [95% CI, 0.80–1.69]; P = 0.434), and ORR was 29.5% and 38.2%, respectively. Overall, safety was comparable between treatment arms; 128 pts (92.3%) had an adverse event (AE), including 143 pts (78.6%) with grade ≥ 3 AEs. Trilaciclib-/placebo-related AEs were reported in 109 pts (59.9%). The most common (≥ 40% of pts) any-grade AEs, irrespective of causality, were anemia (trilaciclib, 58.1%; placebo, 62.9%) and neutrophil count decreased (trilaciclib, 40.9%; placebo, 39.3%). Compared with placebo, fewer pts receiving trilaciclib had grade 4 neutropenia (8.6% vs 25.8%), any-grade thrombocytopenia (38.7% vs 53.9%), and chemotherapy dose reductions (49.5% vs 64.0%). Conclusions: Data from PRESERVE 2 show that compared with placebo, administering trilaciclib prior to GCb did not improve survival in pts with mTNBC. The safety profile of trilaciclib was consistent with previous studies. Some myeloprotective effects were observed, consistent with the known mechanism of action of trilaciclib. Citation Format: Shom Goel, Joyce O’Shaughnessy, Binghe Xu, Zhongsheng Tong, Shusen Wang, George Emile, Ekaterine Arkania, Gia Nemsadze, Iurie Bulat, Rodryg Ramlau, Aleksandra Grela-Wojewoda, Mafalda Oliveira, Valerii Cheshuk, Philip Lammers, Michael Danso, Hope S. Rugo, Debra Patt, Timothy Pluard, Julio Ruiz, Rajesh Malik, Antoinette R. Tan. PRESERVE 2: A randomized, phase 3, double-blind trial of trilaciclib or placebo in patients (pts) receiving first-line gemcitabine/carboplatin (GCb) for locally advanced or metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS2-05.