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

Background: Chemotherapy-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 methods: This 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.

Results: A 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).

Conclusion: Trilaciclib 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 number: NCT02499770.

Keywords: CDK4/6; anemia; myelopreservation; neutropenia; small-cell lung cancer; trilaciclib.

Figure 1.

Myelosuppression end points. Assessment of myelosuppression end points across hematological lineages. (A) Occurrence of specified end point per treatment group represented as percent (number of patients with at least one event/total number of patients per group). (B) Summary of the duration of SN in cycle 1 and the total units of RBCs or platelets transfused per treatment group. (C) Number of episodes of specified end point reported as event rate per 100 weeks or 100 cycles (number of events/cumulative number of weeks or cycles). Statistical significance: * ≤0.05, ** ≤0.01, *** ≤0.001, **** ≤0.0001. NE, not estimable; orange, E/P + Placebo (E/P); blue, E/P + Trilaciclib 240 mg/m² (T/E/P); SN, severe (grade 4) neutropenia; FN, febrile neutropenia; RBC, red blood cell; ESA, erythropoietin-stimulating agent; G-CSF, granulocyte-colony stimulating factor; d, day; w, with. ^‡Analysis only includes RBC transfusions on/after 5 weeks of treatment. ^#Mean duration of SN in cycle 1 per treatment group (including patients without an event, whose duration is 0 days).

Figure 2.

Hematology assessments. Hematological assessments were scheduled on days 1, 3, 8, 10, 15, and 22 of each cycle. (A) Mean nadir values (with 95% CI) for ANC for each cycle for patients who did not receive G-CSF. Dark blue dots represent the nadir for patients receiving G-CSF in each group, but the data are not included in the mean±95% CI calculations. The dotted line represents the value required to start each new cycle, i.e. 1.5×10⁹/l. The number of patients receiving G-CSF for each cycle is overlaid on the graph. Comparison of cycle 1 ANC nadir was made using Student’s t-test. (B) Mean (with 95% CI) change from baseline in hemoglobin in g/l. Patients who received transfusions or ESAs were excluded. The number of patients receiving RBC transfusions per cycle is overlaid in the graph. (C) and (D) Mean counts (with 95% CI) over time for platelet and lymphocytes, respectively. The dotted line on (C) represents the value required to start each new cycle, i.e. 100×10⁹/l. The dotted line on (D) represents a CTCAE grade 3 lymphocyte count decreased value, i.e. 0.5×10⁹/l. orange, E/P + Placebo (E/P); blue, E/P + Trilaciclib 240 mg/m² (T/E/P); C, cycle; D, day; ENDC, end of cycle which is defined as the last value measured prior to the first day of dosing in the subsequent cycle; CI, confidence interval; Gr, grade; G-CSF, granulocyte colony stimulating factor; l, liter; g, gram; N, number of patients.

Figure 3.

Safety end points and major adverse hematological events (MAHE) composite. (A) Occurrence of grade 3 or 4 TEAEs (all, hematologic, lineage specific; see supplementary Methods, available at Annals of Oncology online for description) per treatment group represented as percent (number of patients with at least one TEAE/total number of patients per group). (B) Event rate over time for modified MAHE defined using the following events: (1) hospitalization for any reason, (2) febrile neutropenia, (3) death for any reason, (4) dose reduction for any reason, (5) duration of severe (grade 4) neutropenia >5 days, and (6) RBC transfusions occurring on/after 5 weeks after start of treatment. Event rates were calculated using the Poisson method accounting for the ECOG status (0-1 versus 2) as the stratification factor. Events occurring between the first dose and 60 days after the last dose of study drug were included in the event rate over time analysis. orange, E/P + Placebo (E/P); blue, E/P + Trilaciclib 240 mg/m² (T/E/P). TEAEs, treatment emergent adverse events; MAHE, major adverse hematologic event; RBC, red blood cell.

Figure 4.

Progression-free and overall survival. (A) Kaplan–Meier analysis of progression-free survival. The x-axis depicts months from first dose of study drug administration and number of patients at risk. The y-axis depicts the probability of being progression-free. (B) Kaplan–Meier analysis of overall survival. The x-axis depicts months from first dose of study drug administration and number of patients at risk. The y-axis depicts the probability of being alive. The HR and its 80% CI are calculated using the Cox regression model and the P-value is calculated using the stratified log-rank method. Baseline ECOG status (0-1 versus 2) was used as the stratification factor for both the HR and P-value calculations. orange, E/P + Placebo (E/P); blue, E/P + Trilaciclib 240 mg/m² (T/E/P); HR, hazard ratio; CI, confidence interval; mg, milligram; m², meter squared.