EP. 5: Clinical Trial Evidence for the Myeloprotective Benefit of Trilaciclib for Chemotherapy-Induced Myelosuppression

In February 2021, trilaciclib received United States Food and Drug Administration approval for use in patients with extensive-stage small cell lung cancer (ES-SCLC) to help decrease the occurrence of chemotherapy-induced myelosuppression (CIM) in adult patients when given prior to a platinum and etoposide-containing or topotecan-containing chemotherapy regimen.¹ Trilaciclib is a cyclin-dependent kinase (CDK)4/6 inhibitor that arrests CDK4/6-dependent hematopoietic stem and progenitor cells in the G1 phase of the cell cycle during chemotherapy exposure, resulting in a reduction of chemotherapy-induced damage.^2-4 Unlike other interventions currently used for the management of CIM, trilaciclib is administered intravenously prior to chemotherapy.³ Three randomized controlled phase 2 trials have investigated the myeloprotective effects of trilaciclib and have reported data demonstrating the efficacy associated with the administration of trilaciclib prior to chemotherapy.^2-4

Pivotal Study: Trilaciclib With First-Line Etoposide, Carboplatin, and Atezolizumab

In this randomized, double-blind, multicenter phase 2 study (NCT03041311), 107 patients with ES-SCLC were randomized 1:1 to receive trilaciclib (n = 54) or placebo (n = 53) prior to treatment with etoposide, carboplatin, and atezolizumab.^2,5 Eligible patients had a confirmed diagnosis of ES-SCLC with measurable disease by RECIST v1.1 and an ECOG performance status of 0 to 2.² Patients who presented with symptomatic brain metastases and those who had been treated with prior systemic therapy for limited-stage or ES-SCLC were excluded from the study.²

Primary myelosuppression end points included the percentage of patients who experienced severe neutropenia (SN, defined as absolute neutrophil count < 0.5×10⁹ cells/L) during treatment and duration of severe neutropenia (DSN) during cycle 1.² The incidence of SN was significantly lower in the trilaciclib arm vs placebo arm (1.9% vs 49.1%; aRR, 0.04; 95% CI, 0.008-0.195; P < .0001). The mean duration of grade 4 SN was significantly reduced in the trilaciclib arm with 0 days (SD, 1.0) compared with 4 days in the placebo arm (SD, 4.7) during the first cycle of treatment (mean difference, -3.6 days; 95% CI, -4.9 to -2.3; P < .0001).²

Key secondary end points included total all-cause chemotherapy dose reductions, occurrence of red blood cell (RBC) transfusions on week 5 or later, and occurrence of granulocyte colony-stimulating factor (G-CSF) administration.² In the trilaciclib group, the rate of all-cause chemotherapy dose reductions was significantly lower than in the placebo group with 2.1 events per 100 cycles vs 8.5 events per 100 cycles in the placebo group (raw P = .0195, multiplicity-adjusted P = .0065). Compared with placebo, patients treated with trilaciclib also had a reduced need for RBC transfusions and a decreased rate of G-CSF use; however, the difference between the groups was not statistically significant.²

Febrile neutropenia adverse events (AEs) during induction were noted in 1 patient (1.9%) in the trilaciclib group and 3 patients (5.7%) in the placebo group. Infection serious AEs occurred in 3 patients (5.6%) and 7 patients (13.2%) in the trilaciclib and placebo groups, respectively, with 10 patients (18.5%) in the trilaciclib arm requiring intravenous antibiotics vs 12 patients (22.6%) in the placebo arm.²

Trilaciclib With First-Line Etoposide and Carboplatin

This 2-part, randomized, placebo-controlled phase 2 study (NCT02499770) included 122 patients with histologically or cytologically confirmed ES-SCLC with adequate organ function, measurable disease by RECIST v1.1, and an ECOG performance status of 0 to 2.^3,6 Part 1 (n = 19) of the study included an open-label dose-finding portion; part 2 (n = 75) was a dose expansion phase in which patients were randomized 1:1 to receive chemotherapy and trilaciclib or placebo.^3,6 All patients were treated with carboplatin on the first day of treatment and 100 mg/m² of etoposide on days 1 through 3. With subsequent dosing, patients in part 1 received trilaciclib at a dose of 200 mg/m² or 240 mg/m², whereas patients in part 2 were randomly assigned to trilaciclib at a dose of 240 mg/m² (n = 39) or placebo (n = 38).³ In both parts of the study, treatment continued until disease progression, unacceptable toxicity, or the completion of chemotherapy, which would typically be 4 to 6 cycles.³

Numerous myelosuppression end points across hematopoietic lineages were utilized to assess the efficacy of trilaciclib. The primary end points for the study included the number of patients with dose-limiting toxicities, incidence of treatment-emergent AEs, and occurrence of DSN (grade 4).^3,6

In part 2 of the study, the relative dose intensities of etoposide and carboplatin were higher in the trilaciclib group vs the placebo group (mean etoposide, 91.8% vs 89.3%; mean carboplatin, 95% vs 90.4%), which was consistent with the lower incidence of dose reductions (7.9% vs 35.1%, P = .0033) and cycle delays (39.5% vs 67.6%, P = .0170) for etoposide and carboplatin in the trilaciclib arm vs the placebo arm.³ DSN in cycle 1 (0 days vs 3 days, P = .0003) and the occurrence of SN (5.3% vs 43.2%, P = .0001) were both significantly improved with the use of trilaciclib.³ The trilaciclib arm also demonstrated significant improvements in the percentage of patients receiving RBC transfusions on or after week 5 (5.3% vs 24.3%, P = .0338) and the overall rate of RBC transfusions per 100 weeks (0.5% vs 2.0%, P = .041).³

Moreover, trilaciclib was associated with a clinically meaningful decrease in toxicities grade 3 or higher (primarily related to the decrease of hematologic AEs), and patients across the trilaciclib and placebo groups experienced comparable rates of serious AEs (28.9% vs 24.3%, respectively).³

Trilaciclib with Second- and Third-Line Topotecan

In this double-blind, placebo-controlled phase 2 trial (NCT02514447) of patients with ES-SCLC being treated in the second- or third-line settings, a total of 61 patients were randomized to receive 240 mg/m² of trilaciclib (n = 32) or placebo (n = 29) prior to topotecan on days 1 through 5 of each 21-day cycle until disease progression or unacceptable toxicity.^4,7 Patients previously treated with topotecan for SCLC and those who had brain metastases requiring immediate treatment were excluded from the study.⁴

Primary end points included the percentage of patients who experienced SN and the DSN (absolute neutrophil count < 0.5×10⁹ cells/L) in the first cycle.⁴ The occurrence of SN was significantly improved in the trilaciclib arm compared with the placebo arm (40.6% vs 75.9%, P = .016), and patients who received trilaciclib also demonstrated a lower mean DSN in cycle 1 (2 days vs 7 days, P < .0001).⁴

Key secondary end points for the study included the occurrence of RBC transfusions during week 5 or later, platelet transfusions, G-CSF administration, and the number of all-cause dose reductions.⁴ Both the percentage of patients who received RBC transfusions on or after week 5 and those who received platelet transfusions were lower in the trilaciclib vs placebo arm (31.3% vs 41.4% and 25.0% vs 31.0%, respectively). Patients receiving trilaciclib also experienced a lower percentage of G-CSF administration compared with placebo (50.0% vs 65.5%).⁴ Furthermore, all-cause dose-reductions were lower in the trilaciclib arm (18.8%) vs the placebo arm (31.0%).⁴

Regarding safety, almost all patients experienced at least 1 AE during the study, although the incidence of grade 3 to 4 AEs, including high-grade hematologic AEs, was higher in the placebo group compared with the trilaciclib arm.⁴ There was a numerically lower incidence of hospitalization due to CIM or sepsis in the trilaciclib arm vs the placebo arm (9.4% vs 21.4%).⁴

Conclusions

Chemotherapy continues to serve an important role in the treatment of SCLC; however, regimens containing platinum agents (carboplatin or cisplatin) and etoposide or those containing topotecan can lead to the development of CIM.^2,4 Historically, CIM has been treated responsively following the onset of symptoms using G-CSF, erythrocyte-stimulating agents, and blood transfusions, all of which are lineage-specific therapies associated with their own risks.³ The CDK4/6 inhibitor trilaciclib helps manage CIM by preventing cytotoxic damage to hematopoietic stem and progenitor cells when given prior to chemotherapy, which can result in multilineage benefits.^1,3

References

1. Cosela. Prescribing information. G1 Therapeutics, Inc; 2021. Accessed March 14, 2022. https://www.g1therapeutics.com/cosela/pi/
2. Daniel D, Kuchava V, Bondarenko I, et al. Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: a multicentre, randomized, double-blind, placebo-controlled phase II trial. Int J Cancer. 2020;148(10):2557-2570. doi:10.1002/ijc.33453
3. Weiss JM, Csoszi T, Maglakelidze M, et al. for the G1T28-02 Study Group. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial. Ann Oncol. 2019;30(10):1613-1621. doi:10.1093/annonc/mdz278
4. Hart LL, Ferrarotto L, Andric ZG, et al. Myelopreservation with trilaciclib in patients receiving topotecan for small cell lung cancer: results from a randomized, double-blind, placebo-controlled phase II study. Adv Ther. 2021;38(1):350-365. doi:10.1007/s12325-020-01538-0
5. Carboplatin, etoposide, and atezolizumab with or without trilaciclib (G1T28), a CDK 4/6 inhibitor, in extensive stage small cell lung cancer (SCLC). ClinicalTrials.gov. Updated January 27, 2021. Accessed March 9, 2022. https://clinicaltrials.gov/ct2/show/NCT03041311
6. Trilaciclib (G1T28), a CDK 4/6 inhibitor, in combination with etoposide and carboplatin in extensive stage small cell lung cancer (SCLC). ClinicalTrials.gov. Updated August 21, 2020. Accessed March 9, 2022. https://clinicaltrials.gov/ct2/show/NCT02499770
7. Trilaciclib (G1T28), a CDK 4/6 inhibitor, in patients with previously treated extensive stage SCLC receiving topotecan chemotherapy. ClinicalTrials.gov. Updated January 27, 2021. Accessed March 9, 2022. https://clinicaltrials.gov/ct2/show/NCT02514447