Addressing Myelotoxicity as a Consequence of Treatment for Extensive-Stage Small Cell Lung Cancer

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

This article presents key findings on the safety and efficacy of trilaciclib for the management of chemotherapy-induced myelosuppression in patients with extensive-stage small cell lung cancer.

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