Unexpected Survival Benefit Reported With Trilaciclib in Metastatic Triple-Negative Breast Cancer

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The intravenous administration of trilaciclib, the first-in-class reversible inhibitor of cyclin-dependent kinase 4/6 (CDK4/6), given with chemotherapy, led to a significant improvement in overall survival in previously treated patients with metastatic triple-negative breast cancer, compared with chemotherapy alone. The finding of a 63% reduction in the risk of death (P < .0001) is part of the final data analysis of a randomized phase II trial presented at the 2020 San Antonio Breast Cancer Symposium by Joyce A. O’Shaughnessy, MD.1 Dr. O’Shaughnessy is Chair of Breast Cancer Research and the Celebrating Women Chair in Breast Cancer at Baylor-Sammons Cancer Center, Dallas, as well as Chair of the Breast Cancer Program for the US Oncology Research Network.

At the European Society for Medical Oncology (ESMO) 2019 Congress, Dr. O’Shaughnessy presented a preliminary analysis that was simultaneously published in The Lancet Oncology.2,3 That first look at the data showed, unexpectedly, that trilaciclib improved overall survival, although it did not reduce the frequency and duration of severe neutropenia, the study’s co-primary endpoints. At the 2020 San Antonio meeting, Dr. O’Shaughnessy presented the final analysis of survival in the overall population and in various cohorts.

Joyce A. O’Shaughnessy, MD

Joyce A. O’Shaughnessy, MD

“Mature data from this study were consistent with the primary analysis, confirming that giving trilaciclib prior to gemcitabine plus carboplatin enhances antitumor efficacy compared with gemcitabine plus carboplatin alone, with statistically significant improvement in overall survival,” Dr. O’Shaughnessy reported.

Unlike the other agents in its class, trilaciclib is an intravenously delivered rather than orally available CDK4/6 inhibitor; thus, it is not considered a fitting partner for endocrine therapy. Rather, trilaciclib transiently arrests hematopoietic stem and progenitor cells and lymphocytes in the presence of chemotherapy, protecting them from damage and potentially ameliorating myelosuppression, which formed the rationale for this study.

Global Phase II Trial

The global, multicenter, phase II G1T28-04 trial randomly assigned 102 previously treated or treatment-naive patients to one of three treatment arms:

  • Group 1: Standard gemcitabine/carboplatin chemotherapy in 21-day cycles (chemotherapy-alone arm)
  • Group 2: Standard gemcitabine/carboplatin in 21-day cycles plus trilaciclib at 240 mg/m2 given prior to gemcitabine (concurrent arm)
  • Group 3: Single-agent trilaciclib on days 1 and 8, plus trilaciclib and chemotherapy on days 2 and 9 (additional trilaciclib arm).

The primary endpoint of the study was the duration of severe neutropenia in cycle 1 and the occurrence of severe neutropenia at any time during treatment. As reported previously, this endpoint was not met.2 Progression-free survival and overall survival were key prespecified secondary endpoints. Additional analyses explored outcomes based on CDK4/6 dependence, immune subtyping, and PD-L1 status.

Antitumor Effects Observed

In addition to a significant effect on overall survival, numerical improvement in progression-free survival and objective response rate was also observed with trilaciclib. The survival benefits were maintained across biomarker-defined subgroup analyses, Dr. O’Shaughnessy reported in a poster spotlight session.

Patients with both PD-L1–positive and PD-L1–negative tumors treated with the addition of trilaciclib demonstrated improvement in overall survival compared with gemcitabine plus carboplatin alone. The outcome in the PD-L1–positive subset (57.6% of those tested) was notable, with overall survival of 32.7 months vs 10.5 (hazard ratio = 0.34; P = .004).

By CDK4/6 dependency, overall survival was similar in tumors categorized as CDK4/6-dependent, -independent, or -indeterminate, showing that trilaciclib did not impair the efficacy of gemcitabine plus carboplatin regardless of CDK4/6 status. Trilaciclib also added benefit regardless of the patient’s immune subtype or high/low immune-related gene expression.

Tests that assessed the effects of trilaciclib on the peripheral T-cell repertoire showed improved survival among patients with decreased clonality and those with a higher fraction of newly expanded T-cell clones who received the drug. “These data suggest the addition of trilaciclib to gemcitabine plus carboplatin activates T-cell immunity, potentially leading to the antitumor benefit observed in the study,” Dr. O’Shaughnessy said.


  • The randomized phase II G1T28-04 trial evaluated the intravenously delivered CDK4/6 inhibitor trilaciclib given before or with chemotherapy, compared with chemotherapy alone (gemcitabine plus carboplatin), in previously treated patients with metastatic triple-negative breast cancer.
  • The drug was being evaluated not for its antitumor effects, but for its ability to ameliorate myelosuppression in this population.
  • The primary endpoint—a reduction in grade 4 neutropenia—was not met, but patients receiving trilaciclib had a significant improvement in overall survival vs chemotherapy alone: approximately 20 months vs 13 months.

Registration Trial to Begin

The study’s sponsor (G1 Therapeutics) has announced that a registrational trial of trilaciclib in combination with gemcitabine plus carboplatin in patients with metastatic triple-negative breast cancer will begin in 2021. The combination will be explored in the front-line setting in patients who have not received a PD-1/PD-L1 inhibitor and in the second-line setting in patients previously treated with a PD-1/PD-L1 inhibitor. The primary endpoint of this randomized, double-blind trial will be overall survival, with secondary endpoints of patient-reported outcomes, safety, tolerability, myelopreservation, and progression-free survival. Trilaciclib is also part of the ongoing I-SPY 2 basket trial. 

DISCLOSURE: The study was sponsored by G1 Therapeutics. Dr. O’Shaughnessy has served as a consultant for G1 Therapeutics, AbbVie, Agendia, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, Genentech, Genomic Health, GRAIL, Immunomedics, Heron Therapeutics, Ipsen Biopharmaceuticals, Jounce Therapeutics, Lilly, Merck, Myriad, Novartis, Ondonate Therapeutics, Pfizer, Puma Biotechnology, Prime Oncology, Roche, Seattle Genetics, and Syndax Pharmaceuticals.


1. O’Shaughnessy J, Wright GS, Thummala AR, et al: Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer. 2020 San Antonio Breast Cancer Symposium. Abstract PD1-06. Presented December 8, 2020.

2. O’Shaughnessy J, Wright GS, Thummala A, et al: Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple negative breast cancer in a randomized phase 2 trial. ESMO 2019 Congress. Abstract 6255. Presented September 28, 2019.

3. Tan AR, Wright GS, Thummala AR, et al: Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer. Lancet Oncol 20:1587-1601, 2019.


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