Abstract PD1-06: Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: Final analysis of a randomized phase 2 trial
Authors: O'Shaughnessy Joyce , Wright Gail S , Thummala Anu R , Danso Michael A , Popovic Lazar , Pluard Timothy J , Han Hyo S , Vojnović Željko , Vasev Nikola , Ma Ling , Richards Donald A , Wilks Sharon T , Milenković Dušan , Xiao Jie , Sorrentino Jessica A , Horton Janet , Tan Antoinette R 
Published: February 2021

Abstract
Background
Trilaciclib is an intravenous (IV) cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Preliminary data showed that adding trilaciclib prior to gemcitabine plus carboplatin (GCb) significantly increased overall survival (OS) compared with GCb alone among patients with metastatic triple-negative breast cancer (mTNBC) (Tan et al., Lancet Oncol. 2019;20:1587-1601). Here, final antitumor efficacy results (objective response rate [ORR], progression-free survival [PFS], and OS) are reported for the whole study population, and in cohorts according to CDK4/6 dependence and level of programmed death ligand-1 (PD-L1) expression.
Methods
This was a randomized, open-label, phase 2 study of patients with mTNBC who had received ≤2 previous lines of chemotherapy in the recurrent/metastatic setting (NCT02978716). Patients were randomized (1:1:1) to receive GCb on days 1 and 8 (group 1, n=34), trilaciclib prior to GCb on days 1 and 8 (group 2, n=33), or trilaciclib alone on days 1 and 8 and prior to GCb on days 2 and 9 (group 3, n=35), in 21-day cycles. PFS and OS (prespecified secondary endpoints) were assessed in the intention-to-treat (ITT) population, and ORR in response-evaluable patients.
Patient tumors were characterized as CDK4/6 independent (basal-like) or indeterminate (HER2-enriched, normal-like, luminal A/B) according to the established PAM50 signature, or CDK4/6 dependent (luminal androgen receptor) or indeterminate (basal-like 1/2, mesenchymal) according to the established Lehmann signature. PD-L1 expression was scored as negative or positive if &lt;1% or ≥1% of the total tumor area contained PD-L1-labelled immune cells, respectively, using the Ventana SP142 assay. Association of CDK4/6 dependence and PD-L1 expression with antitumor efficacy was assessed using proportional hazards regression.
Results
Median follow-up was 8.4 months (range: 0.1-25.7) for group 1, 14.0 months (1.3-33.6) for group 2, and 15.3 months (3.5-33.7) for group 3. The ORR among response-evaluable patients was 7/24 (29.2%) in group 1, 15/30 (50.0%) in group 2, and 12/31 (38.7%) in group 3. Median PFS (95% confidence interval [CI]) in the ITT population was 5.7 (3.3, 9.9) months in group 1, 9.4 (6.1, 11.9) months in group 2, and 7.3 (6.2, 13.9) months in group 3, with hazard ratios (HRs) of 0.62 (P = 0.2099) and 0.63 (P = 0.1816), for groups 2 and 3 versus group 1, respectively. Overall, 73.5%, 39.4%, and 57.1% of patients in groups 1, 2, and 3 had died. Median OS (95% CI) was 12.6 (6.3, 15.6) months in group 1, not reached (NR) (10.2, NR) in group 2 (HR = 0.31, P = 0.0016), and 17.8 (12.9, 32.7) months in group 3 (HR = 0.40, P = 0.0004). For groups 2 and 3 combined, median OS was 19.8 (14.0, NR) months (HR = 0.37, P &lt;0.0001 vs group 1). ORR, PFS, and OS were comparable in tumors categorized as CDK4/6 dependent, independent, or indeterminate. Antitumor efficacy by PD-L1 status is provided in the Table.
Conclusions
Mature data from this study confirm that administering trilaciclib prior to GCb enhances antitumor efficacy compared with GCb alone, with statistically significant improvements in OS. Subgroup analyses suggest that adding trilaciclib prior to GCb benefits patients regardless of CDK4/6 dependence status and PD-L1 expression. Additional immune subtyping analyses are ongoing and will be presented.
Group 1Group 2Group 3PD-L1 +vePD-L1 –vePD-L1 +vePD-L1 –vePD-L1 +vePD-L1 –vePatients, n171016101616ORR, n (%)4 (23.5)3 (30.0)8 (50.0)4 (40.0)7 (43.8)4 (25.0)Median PFS, months (95% CI)3.5 (2.2, NR)9.5 (5.2, NR)7.9 (4.3, NR)11.9 (8.8, NR)9.0 (6.2, NR)6.9 (6.4, NR)P value (Wald Test)––0.3470.6040.0690.766HR (95% CI)––0.70 (0.3, 1.5)0.76 (0.3, 2.2)0.46 (0.2, 1.1)1.16 (0.4, 3.1)Median OS, months (95% CI)10.5 (6.3, 18.8)13.9 (12.6, NR)20.1 (10.2, NR)NR (9.4, NR)32.7 (15.3, NR)17.8 (12.9, NR)P value (Wald Test)––0.0280.0830.020.239HR (95% CI)––0.35 (0.1, 0.9)0.34 (0.1, 1.2)0.33 (0.1, 0.8)0.57 (0.2, 1.5)HR and P values are for comparisons between group 2 versus group 1, and group 3 versus group 1.+ve, positive; –ve, negative; CI, confidence interval; HR, hazard ratio; NR, not reached; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand-1; PFS, progression-free survival.
Citation Format: Joyce O'Shaughnessy, Gail S Wright, Anu R Thummala, Michael A Danso, Lazar Popovic, Timothy J Pluard, Hyo S Han, Željko Vojnović, Nikola Vasev, Ling Ma, Donald A Richards, Sharon T Wilks, Dušan Milenković, Jie Xiao, Jessica A Sorrentino, Janet Horton, Antoinette R Tan. Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: Final analysis of a randomized phase 2 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-06.