Trilaciclib Reduces Sacituzumab Govitecan–Related AEs in Locally Advanced or Metastatic TNBC

The administration of trilaciclib (Cosela) prior to treatment with sacituzumab govitecan-hziy (Trodelvy) meaningfully reduced adverse effects (AEs) related to the antibody-drug conjugate (ADC) in patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC), according to initial data from a phase 2 trial (NCT05113966).¹

Findings from the first 18 patients enrolled on the trial showed a clinically meaningful on-target effect of trilaciclib to reduce the rates of multiple AEs by more than 50% vs the previously published safety data for patients treated with sacituzumab govitecan monotherapy (n = 258) during the phase 3 ASCENT trial (NCT02574455).

Improvements in instances of any-grade AEs were seen with fatigue (44% and 52% for the phase 2 trial and ASCENT, respectively), nausea (39% and 62%), constipation (28% and 37%), diarrhea (28% and 65%), neutropenia (22% and 64%), and decreased appetite (22% and 28%). Rates of any-grade leukopenia were 17% in both trials, and any-grade headache occurred in 28% of patients on the phase 2 trial compared with 18% for those on ASCENT.

The only grade 3/4 AEs reported in the phase 2 trial were neutropenia (17%) and leukopenia (17%). Those rates were 52% and 10%, respectively, in the ASCENT trial. No grade 3/4 events were reported for any other AEs on the phase 2 trial, whereas at least 1 instance of a grade 3/4 event was observed for every other AE during ASCENT.

Additionally, the rates of any-grade treatment-emergent AEs (TEAEs) in the phase 2 trial with trilaciclib of anemia, febrile neutropenia, and thrombocytopenia were 6%, 0%, and 0%, respectively. No grade 3/4 events of those TEAEs were reported. In the ASCENT trial, the rates of any-grade anemia, febrile neutropenia, and thrombocytopenia were 34%, 6%, and 5%, respectively. The grade 3/4 rates were 8%, 6%, and 2%, respectively.

“Though the data are preliminary, we are seeing encouraging and consistent reductions in the rate of adverse events related to use of sacituzumab govitecan when trilaciclib is administered prior to the ADC, relative to the previously published single agent safety profile of this ADC, including those related to myelosuppression,” Raj Malik, MD, chief medical officer at G1 Therapeutics, stated in press release.

“We believe we are seeing on-target effects of trilaciclib in the expected reduction in the rate of myelosuppression and in the rates of diarrhea and potentially alopecia. We will continue to progress this trial and look forward to presenting a more comprehensive data set including initial efficacy results at a medical meeting in the second quarter of 2023.”

In April 2021, the FDA granted regular approval to sacituzumab govitecan for the treatment of patients with unresectable locally advanced or metastatic TNBC who have previously received 2 or more systemic therapies, at least 1 of them for metastatic disease.² The approval was based on findings from the confirmatory ASCENT trial.

The exploratory multicenter, open-label, single-arm phase 2 trial is evaluating the safety and efficacy of trilaciclib administered prior to sacituzumab govitecan for patients with TNBC who fit the requirements for treatment with the ADC indicated in the FDA approval. Patients are also required to have an ECOG performance status of 0 or 1, plus adequate organ function.³

Patients are not permitted to have prior treatment with trilaciclib, sacituzumab govitecan, irinotecan, a TROP-2 ADC, or any therapy with a topoisomerase-1 payload. Other key exclusion criteria included known brain metastasis at baseline, known Gilbert’s disease, known homozygosity for the UGT1A1*28 allele, bone-only disease, a history of gastrointestinal bleeding, intestinal obstruction, or gastrointestinal perforation within 6 months of enrollment, or treatment with high-dose systemic corticosteroids within 2 weeks of first study treatment.

Enrolled patients are administered a 30-minute intravenous infusion of trilaciclib within 4 hours prior to the start of sacituzumab govitecan on day 1 and 8 of each 21-day cycle.

The primary end point of the trial is progression-free survival. Secondary end points are comprised of objective response rate, clinical benefit rate, overall survival, neutrophil-related myeloprotective effects, red blood cell–related myeloprotective effects, platelet-related myeloprotective effects, and the safety and tolerability of trilaciclib.

References

1. Initial results from phase 2 trial demonstrate potential of trilaciclib to reduce adverse events related to an antibody drug conjugate (ADC). News release. G1 Therapeutics, Inc. November 2, 2022. Accessed November 2, 2022. http://bit.ly/3DUA6rO
2. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. News release. FDA. April 7, 2021. Accessed November 2, 2022. https://bit.ly/3fOWhUD
3. Trilaciclib in patients receiving sacituzumab govitecan-hziy for triple negative breast cancer. ClinicalTrials.gov. Updated October 26, 2022. Accessed November 2, 2022. https://clinicaltrials.gov/ct2/show/NCT05113966