Trilaciclib Before Gemcitabine/Carboplatin Misses OS End Point in Metastatic TNBC

Treatment with the CDK4/6 inhibitor trilaciclib (Cosela) prior to gemcitabine and carboplatin did not lead to a statistically significant improvement in overall survival (OS) compared with placebo plus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer (TNBC), missing the primary end point of the phase 3 PRESERVE 2 trial (NCT04799249).¹

Topline findings announced by G1 Therapeutics showed that in the intention-to-treat population (n = 187), patients administered trilaciclib plus gemcitabine and carboplatin experienced a median OS of 17.4 months compared with 17.8 months for those given placebo plus gemcitabine and carboplatin (HR, 0.91; P = .884).

Notably, OS numerically favored the trilaciclib regimen in both the PD-L1–positive and –negative subgroups; however, neither reached statistical significance.

Data from the study will be submitted for presentation at a future medical conference.

“The unexpected results from PRESERVE 2 underscore the challenge of developing new therapies for TNBC,” Jack Bailey, chief executive officer of G1 Therapeutics, stated in a news release. “We are disappointed that this trial did not deliver the benefit that we anticipated to people living with TNBC. We are also grateful to the patients who participated in this trial, their families, and their health care teams including the clinicians and their staff.”

PRESERVE 2 was a multicenter, randomized, double-blind, placebo-controlled study that enrolled patients at least 18 years of age with evaluable, locally advanced or metastatic TNBC. The study featured 2 cohorts with identical treatment arms and end points.²

In cohort 1, patients were required to be naive to prior systemic therapy in the locally advanced or metastatic setting, including chemotherapy, targeted therapy, immunotherapy, or investigational agents. Prior treatment with a PD-1/PD-L1 inhibitor was not allowed in any setting. For patients in cohort 1, at least 6 months needed to have elapsed since last curative-intent treatment and first metastatic recurrence.

In cohort 2, patients needed to have a documented PD-L1 status, and prior treatment with a PD-1/PD-L1 inhibitor for at least 4 months in the locally advanced or metastatic setting was required. Treatment with the immune checkpoint inhibitor needed to be the most recent line of therapy.

Other key inclusion criteria for all patients included an ECOG performance status of 0 or 1 and adequate organ function. Prior radiation for metastatic disease was permitted.

Patients were excluded if they had received prior gemcitabine in any setting or carboplatin in the locally advanced or metastatic setting; had central nervous system metastases and/or leptomeningeal disease requiring immediate treatment with radiation therapy or steroids; had a QTcF interval of more than 480 msec at screening; or had undergone prior hematopoietic stem cell or bone marrow transplantation.

Investigators randomly assigned patients to receive intravenous trilaciclib at 240 mg/m2 or placebo administered over 30 minutes prior to chemotherapy on days 1 and 8 of each 21-day cycle. Gemcitabine at 1000 mg/m2 plus carboplatin at area under the curve 2 were given on days 1 and 8 of each cycle.

OS in cohorts 1 and 2 served as the trial’s primary end points. Secondary end points included progression-free survival, quality of life, and myeloprotective effects.

Trilaciclib plus gemcitabine and carboplatin demonstrated a safety profile comparable with that seen in prior studies of the regimen, and no new safety signals were identified. Myeloprotection was observed in the experimental arm, which included a reduction in the rate of severe neutropenia. Severe neutropenia was reported in 8% of patients in the trilaciclib arm vs 29% of patients in the placebo arm.¹

“We will now further our focus on both accelerating and expanding the growth of the extensive-stage small cell lung cancer business to achieve anticipated company profitability in the second half of 2025 and evaluating other myeloprotection uses for trilaciclib. We are also pursuing ex–United States partners to expand the use of trilaciclib globally,” Bailey added in the news release.

References

1. G1 Therapeutics provides update on phase 3 PRESERVE 2 trial in patients receiving trilaciclib prior to first line chemotherapy in metastatic triple negative breast cancer (MTNBC). News release. G1 Therapeutics. June 24, 2024. Accessed June 24, 2024. https://investor.g1therapeutics.com/news-releases/news-release-details/g1-therapeutics-provides-update-phase-3-preserve-2-trial
2. Trilaciclib, a CDK 4/​6 inhibitor, in patients receiving gemcitabine and carboplatin for metastatic triple-negative breast cancer (TNBC) (PRESERVE 2). ClinicalTrials.gov. Updated January 16, 2024. Accessed June 24, 2024. https://www.clinicaltrials.gov/study/NCT04799249