Trilaciclib Prior to Sacituzumab Govitecan Shows Early Potential in Metastatic TNBC

Administration of trilaciclib (Cosela) followed by sacituzumab govitecan-hziy (Trodelvy) showed early signals of efficacy and may reduce the incidence of adverse effects (AEs) in heavily pretreated patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC), according to preliminary results from a phase 2 single-arm study (NCT05113966) presented at the 2023ESMO Breast Cancer Annual Congress.¹

At a median follow-up of 5.5 months (range, 1-13), the median progression-free survival (PFS) in the overall population (n = 30) was 4.1 months (95% CI, 1.6-7.3). The regimen also elicited a confirmed overall response rate (ORR) of 25% in the response-evaluable population (n = 28), which consisted entirely of partial responses (PRs; n = 7).

Of those who responded, 7 had a confirmed PR, 1 had an unconfirmed PR, and 1 achieved a PR after initial progressive disease (PD). Moreover, 46.4% of these patients achieved stable disease (SD), and 25% experienced PD. One patient was not evaluable. The clinical benefit rate (CBR) with the regimen was 32.1%, and the median duration of response (DOR) was 5.7 months (95% CI, 4.0-not evaluable [NE]).

In the 17 patients with PD-L1–positive tumors, the confirmed ORR with the doublet was higher, at 35.3%. All 6 responders had PRs to treatment; 35.3% and 29.4% of patients had SD and PD, respectively. These patients experienced a CBR of 47.1%, and the median DOR was not yet reached (NR; 95% CI, 4.0-NE).

“With a median follow-up of 5.5 months, it is too early to fully determine the efficacy of trilaciclib prior to sacituzumab govitecan in this patient population, [but] current data show that ORR is higher in patients with PD-L1–positive mTNBC, relative to the overall study population,” lead study author Lasika Seneviratne, MD, of Los Angeles Cancer Network in Los Angeles, California, and colleagues, wrote in a poster on the data.

The authors also noted that the early data suggest that trilaciclib was well tolerated when given before the antibody-drug conjugate (ADC).² Trilaciclib was reported to demonstrate a clinically meaningful on-target effect to reduce the rates of several toxicities that had been observed with the ADC alone in the phase 3 ASCENT trial (NCT02574455).

“Although cross-trial comparisons should be made with caution, lower frequencies of neutropenia, anemia, nausea, and diarrhea were observed with trilaciclib plus sacituzumab govitecan in this study compared with historical data for sacituzumab govitecan alone,” the authors wrote.¹

Prior data from the ASCENT trial showed that sacituzumab govitecan monotherapy improved median PFS over single-agent chemotherapy in patients with previously treated mTNBC without brain metastases (n = 468), at 5.6 months vs 1.7 months, respectively.^2,3 The median overall survival (OS) in these groups was 12.1 months vs 6.7 months, respectively. In the overall population, the ORR achieved with the ADC was 34.9%; in those who were and were not pretreated with a PD-1/PD-L1 inhibitor, these rates were 28.4% and 37.5%, respectively.² Notably, increased incidence of neutropenia, anemia, alopecia, and gastrointestinal AEs was observed with sacituzumab govitecan vs single-agent chemotherapy.¹

“The mechanism of action of sacituzumab govitecan may complement the observed positive impact of trilaciclib on antitumor immune modulation in this patient population,” the study authors wrote. To this end, the single-arm, open-label phase 2 study was designed to evaluate the ability of trilaciclib to enhance antitumor immunity and reduce myelotoxicity through on-target effects without decreasing the efficacy of the ADC.

The trial enrolled patients aged 18 or older with unresectable, locally advanced TNBC or mTNBC who had received 2 or more prior systemic treatments, 1 or more of which must have been in the metastatic setting. Patients must have had hormone receptor–negative, HER2-negative disease. Other key eligibility criteria included measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and no brain metastases at the time of enrollment.

All study participants received a 240-mg/m² dose of intravenous trilaciclib followed by 10 mg/kg of sacituzumab govitecan on days 1 and 8 of each 21-cycle. Treatment continued until PD or intolerable toxicity. Patients underwent tumor assessments every 6 weeks beginning at initial screening and continuing until week 36. At this time, assessments were conducted every 9 weeks until PD or subsequent anticancer therapy was needed.

The trial’s primary end point was PFS according to RECIST v1.1 criteria. Key secondary end points included ORR, CBR, DOR, OS, myeloprotection, as well as safety and tolerability.

At a data cutoff dateof April 3, 2023, 30 patients were enrolled in the trial and had already received at least one dose of any study drug.

All patients were female, and the median age was 56 years (range 30-75). Eighty-seven percent of patients were White, 10% were Black or African American, and 3.3 % were Asian. In terms of ECOG performance status, 66.7% of patients had a status of 0, and 33.3% had a status of 1. The majority (93.3%) of patients had metastatic disease at screening, and the remaining 6.7% had locally advanced disease. At the time of diagnosis, 83.3% had TNBC.

Although the study protocol did not require identification of PD-L1 and BRCA mutational status, these data were obtained from 90% and 76.7% of patients, respectively. Of these patients, 63.3% were PD-L1 positive and 26.7% were PD-L1 negative. Additionally, 56.7% of patients harbored a BRCA1/2 mutation and 20% did not; 10% of patients did not have that data available.

Notably, 73.3% of the patient population had previously progressed on treatment with a PD-1 or PD-L1 agent and had been treated with 2 or 3 prior regimens. The percentage of patients who had been treated with more than 3 previous anticancer therapies was 26.7%.

Twenty-two patients currently remain in the study, 11 of which have continued to receive study treatment. A total of 17 patients discontinued treatment due to disease progression. One patient discontinued treatment due to AEs, which included oropharyngeal candidiasis, acute respiratory failure, dyspnea, pneumonitis, and pulmonary embolism. An additional patient made the individual decision to withdraw.

Treatment-related AEs (TRAEs) were experienced by 76.7% of patients. The most common TRAEs occurring in at least 10% of patients included fatigue (any-grade, 46.7%; grade 3/4, 0%) alopecia (33.3%; 0%), nausea (30%; 3.3%), diarrhea (26.7%; 3.3%), vomiting (16.7%; 3.3%), decreased appetite (16.7%; 0%), headache (16.7%; 0%), constipation (13.3%; 0%), and abdominal pain (10%; 3.3%).

Any-grade hematologic AEs were seen in 43.3% of patients; 16.7% of these effects were grade 3/4. These toxicities included neutropenia (30%; 13.3%), leukopenia (23.3%; 13.3%), and anemia (10%; 0%).

Serious TRAEs occurred in 10% of patients, including 1 patient with sacituzumab govitecan‒related febrile neutropenia, diarrhea, nausea, and vomiting; 1 patient with sacituzumab govitecan‒related acute respiratory failure; and 1 patient with gait disturbance associated with the combination.

Ten percent of patients required a dose reduction of sacituzumab govitecan, and 46.7% required a dose delay. Additionally, 16.7% of patients received growth factors.

Assessment of the regimen’s efficacy in this trial is ongoing and will further elucidate the potential of trilaciclib to improve OS in patients with mTNBC when combined with an ADC rather than gemcitabine/carboplatin.

OS end points are expected to be met in the first quarter of 2024.²

Disclosures: Dr Seneviratne reports having financial and personal interests, working as an invited speaker, receiving payment or honoraria for lectures, conducting presentations, serving on speakers bureaus, and involvement with manuscript writing or educational events with Novartis. She also discloses financial and personal interests, as well as serving on an advisory board with AstraZeneca.

References

1. Seneviratne L, Harnden KK, Mardones M, et al. Trilaciclib combined with sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC): Preliminary phase 2 results. Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 201P.
2. New results from phase 2 trial confirm benefit of trilaciclib in reducing adverse events related to an antibody drug conjugate (ADC). News release. G1 Therapeutics. May 10, 2023. Accessed May 11, 2023. http://investor.g1therapeutics.com/news-releases/news-release-details/new-results-phase-2-trial-confirm-benefit-trilaciclib-reducing
3. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485