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

Abstract

BackgroundChemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.Patients and methodsThis was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.ResultsA total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).ConclusionTrilaciclib demonstrated an improvement in the patient’s tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib’s myelopreservation benefits.Clinical Trail numberNCT02499770.

CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy

“…15 43 While preclinical and correlative data from patients with SCLC have demonstrated that trilaciclib can enhance T-cell activity, direct mechanistic evidence to explain the improved OS results in mTNBC is still needed. 4 Given the clinical proof-of-concept findings that trilaciclib can reduce chemotherapy-induced multi-lineage myelosuppression in patients with SCLC, 3 improve OS when added to chemotherapy in patients with mTNBC 4 on October 31, 2020 by guest. Protected by copyright.…”

“…Nine-week-old female C57BL/6 (C57BL/6NCrl) and BALB/c mice were implanted subcutaneously with 5×10 5 MC38 22 or CT26 American Type Culture Collection (ATCC) tumor cells, respectively (cell lines supplied by Charles River Laboratories). Two to 3 weeks after tumor injection and prior to treatment start (day 1 of the study), animals with individual tumor volumes from 80 to 120 mm 3 were sorted into the appropriate number of treatment groups, with group mean tumor volumes of 100 mm 3 .…”

“…Patients received trilaciclib or placebo prior to E/P on days 1-3 of each cycle. 3 During part 2 of the study, whole blood was collected from those patients who received at least four cycles of chemotherapy for analysis of immune subsets by flow cytometry at Covance Central Laboratory Services (CLS). For patients treated with E/P and trilaciclib prior to E/P (T/E/P), samples were collected on day 1 of cycles 1 (C1D1; 30 and 28 samples, respectively), 3 (C3D1; 24 and 27 samples, respectively) and 5 (C5D1; 19 and 22 samples, respectively), and at the post-treatment visit (28 and 19 samples, respectively).…”

“…1 2 In a phase II trial (NCT02499770) evaluating trilaciclib administered prior to etoposide and carboplatin (E/P) therapy in patients with newly diagnosed extensive-stage small cell lung cancer (SCLC), trilaciclib demonstrated myelopreservation across multiple hematopoietic lineages (including neutrophils, RBCs and lymphocytes), resulting in fewer supportive care interventions and dose reductions, an improved safety profile and no detriment to antitumor efficacy. 3 In addition to improving the safety of chemotherapy, trilaciclib improved overall survival (OS) among patients with metastatic triple-negative breast cancer (mTNBC) when added prior to gemcitabine and carboplatin. 4 Possible mechanisms of trilaciclib-mediated Open access enhanced antitumor efficacy include maintenance of chemotherapy dose intensity (ie, fewer dose reductions), protection of lymphocyte populations and increased immune activation.…”

“… 1 2 In a phase II trial (NCT02499770) evaluating trilaciclib administered prior to etoposide and carboplatin (E/P) therapy in patients with newly diagnosed extensive-stage small cell lung cancer (SCLC), trilaciclib demonstrated myelopreservation across multiple hematopoietic lineages (including neutrophils, RBCs and lymphocytes), resulting in fewer supportive care interventions and dose reductions, an improved safety profile and no detriment to antitumor efficacy. 3 …”