Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive‐stage small cell lung cancer: A multicentre, randomised, double‐blind, placebo‐controlled Phase II trial

Abstract

Trilaciclib is an intravenous CDK4/6 inhibitor administered prior to chemotherapy to preserve haematopoietic stem and progenitor cells and immune system function from chemotherapy‐induced damage (myelopreservation). The effects of administering trilaciclib prior to carboplatin, etoposide and atezolizumab (E/P/A) were evaluated in a randomised, double‐blind, placebo‐controlled Phase II study in patients with newly diagnosed extensive‐stage small cell lung cancer (ES‐SCLC) (NCT03041311). The primary endpoints were duration of severe neutropenia (SN; defined as absolute neutrophil count <0.5 × 109 cells per L) in Cycle 1 and occurrence of SN during the treatment period. Other endpoints were prespecified to assess the effects of trilaciclib on additional measures of myelopreservation, patient‐reported outcomes, antitumour efficacy and safety. Fifty‐two patients received trilaciclib prior to E/P/A and 53 patients received placebo. Compared to placebo, administration of trilaciclib resulted in statistically significant decreases in the mean duration of SN in Cycle 1 (0 vs 4 days; P < .0001) and occurrence of SN (1.9% vs 49.1%; P < .0001), with additional improvements in red blood cell and platelet measures and health‐related quality of life (HRQoL). Trilaciclib was well tolerated, with fewer grade ≥3 adverse events compared with placebo, primarily due to less high‐grade haematological toxicity. Antitumour efficacy outcomes were comparable. Administration of trilaciclib vs placebo generated more newly expanded peripheral T‐cell clones (P = .019), with significantly greater expansion among patients with an antitumour response to E/P/A (P = .002). Compared with placebo, trilaciclib administered prior to E/P/A improved patients' experience of receiving treatment for ES‐SCLC, as shown by reduced myelosuppression, and improved HRQoL and safety profiles.

Effects of Trilaciclib on Chemotherapy-Induced Myelosuppression and Patient-Reported Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer: Pooled Results from Three Phase II Randomized, Double-Blind, Placebo-Controlled Studies

“…In this analysis, patients who received trilaciclib prior to chemotherapy appeared three times less likely to require chemotherapy dose reductions than patients who received placebo, and they had numerically higher RDIs of etoposide and carboplatin. Consistent with findings from the individual studies, [20][21][22] maintaining the dose intensity of chemotherapy did not translate to an improvement in PFS or OS. This is perhaps not surprising, as studies in patients with SCLC have shown that increasing the RDI of chemotherapy beyond the SoC rarely translates into significant improvements in response rates or survival.…”

“…The G1T28-05 study was performed to confirm the myeloprotective benefits of trilaciclib in patients receiving E/P/A for the treatment of ES-SCLC. 21 Finally, the supportive G1T28-03 study was performed to investigate the administration of trilaciclib prior to topotecan, a chemotherapy regimen that is more myelosuppressive than E/P, in the second-/third-line setting. 22 All three studies demonstrated a clear multilineage myeloprotection benefit through clinically meaningful reductions in multiple measures of CIM and the need for supportive care interventions.…”

“…The effects of administering trilaciclib prior to chemotherapy have been investigated in three randomized, placebo-controlled, double-blind, phase II clinical studies in patients with ES-SCLC. [20][21][22] All three studies included clinically relevant endpoints across multiple hematopoietic lineages, including hematologic AEs, laboratory values, and use of supportive care interventions. Each clinical study included analyses of standard antitumor efficacy evaluations and validated patient-reported outcome (PRO) measures to evaluate whether trilaciclib could improve HRQoL during chemotherapy treatment.…”

Prophylaxis and treatment strategies for optimizing chemotherapy relative dose intensity

“…Despite these positive results in SCLC, a phase 2 study in 102 randomized TNBC patients treated with gemcitabine/carboplatin revealed that trilaciclib administration did not prevent myelosuppression in this patient population; however, improvements in PFS and OS were observed in the trilaciclib group [120,121]. Across the SCLC trials, trilaciclib appeared to be fairly well-tolerated with no reports of bone pain and fewer grade 3 or higher adverse events than placebo-treated groups, primarily due to fewer hematologic toxicities [117][118][119]122] Trilaciclib was approved the US. FDA in February 2021 to reduce the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecancontaining regimen for extensive-stage SCLC [123].…”

“…Phase 2 randomized, placebo-controlled clinical studies in extensive-stage small cell lung cancer (SCLC) revealed that trilaciclib administration prior to chemotherapy significantly reduced the duration of severe neutropenia in cycle 1 and the occurrence of severe neutropenia during carboplatin/etoposide, carboplatin/etoposide/atezolizumab, or topotecan treatment (77, 107 and 61 randomized patients, respectively). Improvements in red blood cell and platelet counts, and health-related quality-of-life were also observed [117][118][119]. Despite these positive results in SCLC, a phase 2 study in 102 randomized TNBC patients treated with gemcitabine/carboplatin revealed that trilaciclib administration did not prevent myelosuppression in this patient population; however, improvements in PFS and OS were observed in the trilaciclib group [120,121].…”