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.

Keywords: chemotherapy; myelopreservation; myelosuppression; small cell lung cancer (SCLC); trilaciclib.

Conflict of interest statement

Dr Davey Daniel has received research funding from G1 Therapeutics, Inc and Genentech. Dr Jana Jaal has received research funding from AstraZeneca, and has been an adviser to AstraZeneca, Boehringer Ingelheim and MSD. Dr Lowell Hart has received research funding, consultancy and travel expenses from G1 Therapeutics, Inc. Dr Yili Pritchett and Dr Jessica A. Sorrentino are paid employees and shareowners of G1 Therapeutics, Inc. Dr Shannon R. Morris and Joyce M. Antal were employees of G1 Therapeutics, Inc at the time of manuscript preparation and submission. Dr Vladimer Kuchava, Prof. Igor Bondarenko, Dr Oleksandr Ivashchuk, Dr Sreekanth Reddy, Dr Iveta Kudaba and Dr Amiran Matitashvili have no conflicts of interest to declare. Dr Jerome Goldschmidt has participated in speakers bureau and received honoraria from Amgen and Bristol Myers Squibb.

2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Figures

FIGURE 1

Summary of myelosuppression endpoints. Data are from the induction phase. P values are raw one‐sided or multiplicity‐adjusted. *Multiplicity adjusted P value. AEs, adverse events; C, cycle; E/P/A, etoposide, carboplatin and atezolizumab; ESA, erythropoiesis‐stimulating agent; FN, febrile neutropenia; G‐CSF, granulocyte colony‐stimulating factor; RBC, red blood cell; SN, severe neutropenia

FIGURE 2

Median time to confirmed deterioration in patient‐reported outcomes. Data are from the time of DBL1. DBL1, first database lock (data cutoff: August 17, 2018); EWB, emotional well‐being; FACT‐An, Functional Assessment of Cancer Therapy‐Anemia; FACT‐G, Functional Assessment of Cancer Therapy‐General; FACT‐L, Functional Assessment of Cancer Therapy‐Lung; FWB, functional well‐being; LCS, Lung Cancer Subscale; NYR, not yet reached; PWB, physical well‐being; SWB, social well‐being; TOI, trial outcome index; TTD, time to deterioration

FIGURE 3

Antitumour efficacy. Kaplan‐Meier estimates of A, Probability of progression‐free survival and B, Probability of overall survival. Data are from the overall treatment period. OS data are not yet mature. E/P/A, etoposide, carboplatin and atezolizumab; HR, hazard ratio; OS, overall survival; PFS, progression‐free survival

FIGURE 4

Flow cytometry and T‐cell receptor immunosequencing analysis. A and B, T‐cell populations in whole blood were analysed by flow cytometry at the indicated time points. A, CD8+/regulatory T cells and B, activated CD8+/regulatory T cells. Regulatory T‐cell population was defined as CD45+CD25+CD127lowCD3+CD4+. Error bars represent 95% CI. C‐H, Immunosequencing analysis of T‐cell clones. C, Change from baseline in the number of expanded T‐cell clones was determined by differential abundance analysis of T‐cell receptor β sequences in whole blood from patients at baseline (iC1D1) and the start of maintenance (mC1D1). Horizontal bars indicate median number of expanded clones in each group. D‐F, Peripheral expansion assessed in patients receiving trilaciclib or placebo, according to response to treatment. G and H, Patients were stratified by high (equal or above median, solid lines) and low (below median; dashed lines) fraction of newly detected expanded clones (median fraction 0.429 for all patients) for Kaplan‐Meier estimates of probability of OS and probability of PFS. HR indicates ratio of high relative to low. C, cycle; CI, confidence interval; D, day; E/P/A, etoposide, carboplatin and atezolizumab; HR, hazard ratio; i, induction; m, maintenance; OS, overall survival; PFS, progression‐free survival; PVT, posttreatment visit +90 days