Phase 2 Trial Suggests Trilaciclib Before Chemo Significantly Improves OS in Metastatic TNBC

Final data from a phase 2 trial suggested that the administration of trilaciclib before chemotherapy comprised of gemcitabine and carboplatin resulted in a significant improvement in overall survival in previously treated patients with metastatic triple-negative breast cancer.

In previously treated patients with metastatic triple-negative breast cancer (mTNBC), the administration of the CDK4/6 inhibitor trilaciclib before chemotherapy comprised of gemcitabine and carboplatin (GCb) led to a significant improvement in overall survival (OS), according to final data from a randomized phase 2 trial (NCT02978716).1

These study results, presented during the 2020 San Antonio Breast Cancer Symposium (SABCS), also revealed that OS benefits were maintained across subgroup analyses and observed in patients irrespective of CDK4/6 dependence, immune signature, and PD-L1 expression status.

“Subgroup analyses suggest that administering trilaciclib prior to GCb enhances antitumor efficacy, regardless of CDK4/6 dependence and PD-L1 expression. Furthermore, adding trilaciclib prior to GCb appears to preserve and enhance immune system function,” Joyce O’Shaughnessy, MD, said in a poster presentation of the final analysis. “These data support further investigation of the association between enhanced antitumor immunity and improved survival in patients with TNBC receiving trilaciclib prior to chemotherapy.”

The randomized, open-label, multicenter study enrolled patients with mTNBC who had previously received up to 2 prior lines of chemotherapy for recurrent or metastatic disease. Patients were randomized equally to 1 of 3 groups: group 1 received gemcitabine and carboplatin chemotherapy alone on days 1 and 8, group 2 received trilaciclib prior to chemotherapy on days 1 and 8, and group 3 received trilaciclib on days 1 and 8 and prior to chemotherapy on days 2 and 9.

Treatment consisted of gemcitabine 1000 mg/m2 and carboplatin area under the curve 2 with or without intravenous trilaciclib 240 mg/m2 given over 30 (±5) minutes prior to chemotherapy; the regimens were administered in 3-week cycles until progressive disease or unacceptable toxicity.

Progression-free survival (PFS) and OS were key secondary end points, but the primary end point of the study was the duration of severe neutropenia in cycle 1 and occurrence of severe neutropenia at any time during treatment. Additional analyses explored outcomes based on CDK4/6 and immune subtyping as well as by PD-L1 status.

A total of 102 patients were enrolled in the study, including 34 in group 1, 33 in group 2, and 35 in group 3. Baseline characteristics were considered to be similar between the arms.

Preliminary results of the study demonstrated that the mean duration of severe neutropenia was 0.8 days in group 1, 1.5 days in group 2, and 1.0 day in group 3. Severe neutropenia was reported in 26%, 36%, and 23% of the 3 groups, respectively.2

Although the myelosuppression was not significantly different with the addition of trilaciclib prior to chemotherapy, the OS results were encouraging.

The final results showed that the addition of trilaciclib prior to chemotherapy resulted in higher objective response rates (ORRs), longer PFS, and statistically significant improvements in OS compared with chemotherapy alone. “Mature data from this study were consistent with the primary analysis,” said O’Shaughnessy, who is co-chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center and The US Oncology Network.

As of the earlier May 15, 2020, data cutoff, the ORR was 29.2% in group 1, 50.0% in group 2, and 38.7% in group 3. Among all 68 patients who were treated with trilaciclib, the overall ORR was 44.3%.

In group 1, the median PFS was 5.7 months (95% CI, 3.3-9.9) compared with 9.4 months (95% CI, 6.1-11.9) in group 2 (HR, 0.62; 95% CI, 0.32-1.20; = .2099) and 7.3 months (95% CI, 6.2-13.9) in group 3 (HR, 0.63; 95% CI, 0.32-1.22; = .1816). The median PFS for all patients treated with trilaciclib was 9.0 months (95% CI, 6.4-11.3) (HR, 0.62; 95% CI, 0.36-1.10; = .1291).

With the final data cutoff of July 17, 2020, the final OS results showed a median OS of 12.6 months (95% CI, 6.3-15.6) for patients in group 1. The median OS was not reached (NR; 95% CI, 10.2-NR) in group 2 (HR, 0.31; 95% CI, 0.15-0.63; = .0016) and 17.8 months (95% CI, 12.9-32.7) in group 3 (HR, 0.40; 95% CI, 0.22-0.74; P = .0004). For all patients treated with trilaciclib, the median OS was 19.8 months (95% CI, 14.0-NR) (HR, 0.37; 95% CI, 0.21-0.63; <.0001).

Tumors were retrospectively characterized for CDK4/6 subtyping by the PAM50 and Lehmann TNBCtype-4 signatures as either CDK4/6 dependent, independent, or variable/indeterminate. By the PAM50 signature, basal-like tumors have known CDK4/6 independence and HER2-enriched, normal-like, and luminal A/B tumors have variable dependence. According to the Lehmann TNBCtype-4 signature, luminal androgen receptor types have a known dependence and some basal-like and mesenchymal tumors have variable dependence.

By the PAM50 signature, in group 1 the median OS was 10.1 months. In group 2, the median OS was NR (HR, 0.30; 95% CI, 0.1-0.8; = .0164). The median OS in group 3 was 22.3 months (HR, 0.32; 95% CI, 0.1-0.8; P = .0095). For groups 2 and 3 combined, the median OS was 22.3 months (HR, 0.33; 95% CI, 0.2-0.7; = .003).

According to the Lehmann signature, the median OS in group 1 was 9.7 months. In group 2, the median OS was NR (HR, 0.18; 95% CI, 0.0-0.7; = .0052). For group 3, the median OS was 15.3 months (HR, 0.49; 95% CI, 0.2-1.3; = .1397). In groups 2 and 3 combined, the median OS was 15.3 months (HR, 0.32; 95% CI, 0.1-0.8; = .008).

“Antitumor efficacy outcomes were similar in patients with tumors characterized as CDK4/6 dependent, confirming that trilaciclib did not antagonize the antitumor effects of GCb in the CDK4/6-dependent population,” O’Shaughnessy said.

Of 85 patients evaluable for PD-L1 expression, 49 (57.6%) were positive. The benefit of trilaciclib treatment was seen irrespective of PD-L1 status, but a larger OS benefit was seen for patients who were PD-L1 positive.

Within the PD-L1–positive population, the median OS in group 1 was 10.5 months compared with 20.1 months in group 2 (HR, 0.38; 95% CI, 0.2-1.0; = .037) and 32.7 months for group 3 (HR, 0.30; 95% CI, 0.1-0.8; = .01). The combined trilaciclib groups had a median OS of 32.7 months (HR, 0.34; 95% CI, 0.2-0.7; = .004).

In the PD-L1–negative population, the median OS was 13.9 months in group, NR in group 2 (HR, 0.35; 95% CI, 0.1-1.2), 17.8 months in group 3 (HR, 0.55; 95% CI, 0.2-1.4; = .198) and 17.8 months in combined groups 2 and 3 (HR, 0.48; 95% CI, 0.2-1.2; = .093).

Both PFS and OS were increased with added trilaciclib prior to GCb regardless of patients’ immune subtypes or high/low immune-related gene expression.

“When we assessed the effect of trilaciclib on the peripheral T-cell repertoire, we saw a significant decrease in Simpson clonality among patients receiving trilaciclib [interaction = .012]. When patients were stratified above or below median Simpson clonality at baseline, there was a significant improvement in survival among patients with decreased clonality receiving trilaciclib [= .02],” O’Shaughnessy said. “Survival also appeared to be improved among patients with a higher fraction of newly expanded T-cell clones who received trilaciclib [= .3]. These data suggest the addition of trilaciclib to GCb activates T-cell immunity, potentially leading to the antitumor benefit observed in the study.”

In a spotlight poster presentation, Cristina Saura Manich, MD, PhD, head of the Breast Cancer Program at the Vall d’Hebron University Hospital in Barcelona, Spain, noted that the trial was not powered to detect differences in OS, so a powered trial is needed to confirm these results.

As such, the developer of trilaciclib, G1 Therapeutics, has announced that a registrational trial for trilaciclib in combination with GCb chemotherapy in patients with mTNBC will begin in 2021. The combination will be explored in patients with mTNBC who have not received a PD-1/PD-L1 inhibitor being treated in the frontline setting, and in patients who have received a PD-1/PD-L1 inhibitor being treated in the second-line setting. A total of 250 patients are expected to be enrolled, with the majority in the frontline cohort.3

The primary end point of this randomized, double-blind trial will be OS with secondary end points of patient-reported outcomes, safety, tolerability, myelopreservation, and PFS.


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: Final analysis of a randomized phase 2 trial. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-12, 2020; Virtual. Abstract PD1-06.

2. 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

3. G1 Therapeutics Presents Final Phase 2 Clinical Data on Trilaciclib in Combination with Chemotherapy in Metastatic Triple-Negative Breast Cancer Demonstrating Significant Improvement in Overall Survival at 2020 San Antonio Breast Cancer Symposium. News release. G1 Therapeutics. December 9, 2020. Accessed December 10, 2020.

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