FDA Grants Fast Track Status to Trilaciclib Plus Chemo in Locally Advanced or Metastatic TNBC


The FDA has granted a fast track designation to trilaciclib for use in combination with chemotherapy in patients with locally advanced or metastatic triple-negative breast cancer

Raj Malik, MD,

Raj Malik, MD,

The FDA has granted a fast track designation to trilaciclib (Cosela) for use in combination with chemotherapy in patients with locally advanced or metastatic triple-negative breast cancer (TNBC), according to an announcement from G1 Therapeutics, Inc.1

The agent is now under evaluation as part of the multicenter, double-blind, placebo-controlled phase 3 PRESERVE 2 trial (NCT04799249). Here, investigators will examine the safety and efficacy of trilaciclib compared with placebo, given before gemcitabine plus carboplatin, in patients with advanced or metastatic TNBC who are receiving first- or second-line treatment.2

“Fast track designation underscores the urgent need for innovative drugs that can significantly improve outcomes [for patients with] TNBC,” Raj Malik, MD, chief medical officer of G1 Therapeutics, Inc., stated in a press release. “It provides an important pathway to help expedite the development and regulatory review of [trilaciclib] in this indication. We look forward to working closely with the FDA as we advance this pivotal program in TNBC and continue to work to unlock the broader potentially of this pipeline-in-a-molecule compound that we hope will help patients across multiple tumor types.”

Although chemotherapy, alone or in combination with immune checkpoint inhibitors, continues to be the standard approach for patients with metastatic TNBC, not all patients with PD-L1 positivity are eligible to receive checkpoint inhibitors. Moreover, those with PD-L1–negative disease may not clinically benefit from this approach.

Trilaciclib is a CDK4/6 inhibitor that is delivered intravenously, before chemotherapy. The agent was designed to transiently arrest hematopoietic stem and progenitor cells and immune cells that are in G1 of the cell cycle during chemotherapy exposure; the agent protects these cells from chemotherapy-induced damage.

In February 2021, the FDA approved trilaciclib to reduce the frequency of chemotherapy-induced bone marrow suppression in adults who are receiving certain types of chemotherapy for extensive-stage small cell lung cancer.3

A phase 2 trial (NCT02978716) had examined trilaciclib before gemcitabine/carboplatin vs gemcitabine/carboplatin alone in patients with TNBC and showed that although the primary end point of myeloprotection had not been met, trilaciclib did meaningfully improve overall survival (OS) in the intent-to-treat population, irrespective of PD-L1 status.4 Specifically, in patients who received trilaciclib followed by gemcitabine/carboplatin, the median OS was 20.1 months vs 12.6 months with gemcitabine/carboplatin alone (HR, 0.36).

PRESERVE 2 was designed to confirm the OS benefit observed in the phase 2 trial and to further examine the efficacy of this approach in a post–checkpoint inhibitor patient population.

To be eligible for participation, patients needed to be at least 18 years of age, have confirmed locally advanced unresectable or metastatic TNBC, available tumor tissue, an ECOG performance status of 0 or 1, acceptable organ function, a predicted life expectancy of at least 3 months, and resolution of nonhematologic adverse effects from previous therapy to grade ≤1.

If patients previously received gemcitabine, had malignancies other than TNBC within 3 years before randomization, had symptomatic central nervous system metastases and/or leptomeningeal disease that needed immediate treatment with radiation or steroids, they were excluded.

Other exclusion criteria included having received any cytotoxic chemotherapy or PD-1/PD-L1 inhibitor therapy within 14 days before the first dose of study treatment, a known hypersensitivity to carboplatin or other platinum-containing compounds, or mannitol, or previous treatment with carboplatin if completed 6 months or less before the first metastatic recurrence.

Cohort 1 of the trial will enroll a total of 170 patients who will receive gemcitabine/carboplatin in the frontline setting; these patients will be naïve to checkpoint inhibition. Cohort 2 will enroll a total of 80 patients who will receive gemcitabine/carboplatin in the second-line setting; these patients received previous treatment with a PD-1 or PD-L1 inhibitor. Patients in cohort 1 were stratified based on PD-L1 status, their disease-free interval, and the country they resided in.

Patients will be randomized 1:1 to receive trilaciclib before gemcitabine/carboplatin or placebo before gemcitabine/carboplatin on days 1 and 8 of every 21-day cycle. Treatment was administered until intolerable toxicity, disease progression, withdrawn consent, discontinuation per investigator decision, or the end of the study.

The primary end point of the trial is OS, and an important secondary end point was time to confirmed deterioration with regard to fatigue, as measured by FACIT-F. Other end points focused on OS in PD-L1–positive or –negative subgroups (cohort 1); progression-free survival; antitumor activity with regard to objective response rate, clinical benefit rate, duration of response, and best overall response per RECIST v1.1 criteria; chemotherapy-induced myelosuppression–related symptoms; myeloprotection effects; and safety.

Investigators will also evaluate the pharmacodynamic effects of the approach in the tumor and blood and antitumor efficacy by CDK4/6-dependence status.

The trial was initiated in April 2021, and data are anticipated to read out in the second half of 2023.5


  1. G1 Therapeutics receives fast track designation from US Food and Drug Administration for COSELA (trilaciclib) in combination with chemotherapy for the treatment of locally advanced or metastatic triple negative breast cancer. News release. G1 Therapeutics, Inc. July 19, 2021. Accessed July 19, 2021. https://bit.ly/3zdQgHl
  2. Goel S, O’Shaughnessy J, Tan AR, et al. Trial in progress: a phase 3, randomized, double-blind trial of trilaciclib versus placebo in patients receiving first- or second-line gemcitabine and carboplatin for locally advanced unresectable or metastatic triple-negative breast cancer (PRESERVE 2). J Clin Oncol. 2021;39(suppl 15):TPS1107. doi:10.1200/JCO.2021.39.15_suppl.TPS1107
  3. FDA approves drug to reduce bone marrow suppression caused by chemotherapy. FDA. News release. FDA. February 12, 2021. Accessed July 19, 2021. http://bit.ly/379OETw
  4. Tan AR, Wright GS, Thummala AR, et al. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2019;20(11):1587-1601. doi:10.1016/S1470-2045(19)30616-3
  5. G1 Therapeutics announces initiation of phase 3 registrational study of COSELA (trilaciclib) in triple-negative breast cancer (TNBC). News release. G1 Therapeutics, Inc. April 28, 2021. Accessed July 19, 2021. https://bit.ly/2UUMJPp
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