Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Chemotherapy-Induced Neutropenia in Adults With Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial

Abstract

Importance: Plinabulin is a novel, non-granulocyte colony-stimulating factor (GCSF) small molecule with both anticancer and neutropenia-prevention effects.

Objective: To assess the efficacy and safety of plinabulin compared with pegfilgrastim for the prevention of chemotherapy-induced neutropenia following docetaxel chemotherapy in patients with non-small lung cancer.

Design, setting, and participants: This was a randomized, open-label, phase 2 clinical trial of 4 treatment arms that was conducted in 19 cancer treatment centers in the United States, China, Russia, and Ukraine. Participants were adult patients with non-small cell lung cancer whose cancer had progressed after platinum-based chemotherapy. Data were collected from April 2017 through March 2018 and analyzed from August 2019 through February 2020.

Interventions: All patients received docetaxel 75 mg/m2 on day 1 and were randomly assigned to 1 of 3 doses of plinabulin (5, 10, or 20 mg/m2) on day 1 or to pegfilgrastim 6 mg on day 2. Patients were treated every 21 days for 4 chemotherapy cycles.

Main outcomes and measures: The primary end point was the determination of the recommended phase 3 dose of plinabulin based on the days of severe neutropenia during chemotherapy cycle 1. Daily complete blood cell counts and absolute neutrophil counts were drawn during times of anticipated neutropenia during cycle 1.

Results: Of the 55 patients randomized and evaluated, the mean (SD) age was 61.3 (10.2) years, and 38 (69.1%) were men. With each escalation of the plinabulin dose, the incidence of any grade of neutropenia decreased. There were no significant differences in mean (SD) days of severe neutropenia among those treated with pegfilgrastim (0.15 [0.38] days) when dosed at day 2 vs plinabulin 20 mg/m2 (0.36 [0.93] days; P = .76) when dosed at day 1, and no safety signals were detected.

Conclusions and relevance: Single dose-per-cycle plinabulin has a similar neutropenia protection benefit as pegfilgrastim. Plinabulin 40 mg fixed dose, which is pharmacologically equivalent to 20 mg/m2, will be compared with pegfilgrastim 6 mg in the phase 3 portion of this trial. Noninferior days of severe neutropenia will be the primary end point, and bone pain reduction, thrombocytopenia reduction, and quality of life maintenance will be secondary end points.

Trial registration: ClinicalTrials.gov Identifier: NCT03102606.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Blayney reports receiving travel support from BeyondSpring Pharmaceuticals during conduct of the study and grants to his institution from Amgen, stock in Madora and Artelo Biosciences, and consulting fees from Diaichi, Embold Health, Ipsen, Tersera, and Lilly outside of the submitted work. Dr Huang reports being an employee and stockholder of BeyondSpring Pharmaceuticals as well as having involvement in a patent issued for use of plinabulin in reducing docetaxel-induced neutropenia. Dr Mohanlal reports being an employee and stockholder of BeyondSpring Pharmaceuticals. Dr Ibrahim reports receiving grants from Spectrum Pharmaceuticals, Incyte Corporation, Pfizer, Cellectar Biosciences, Takeda, Puma Biotechnology, Novartis, AstraZeneca, Chiesi, Eli Lilly, and Astellas Pharma outside of the submitted work. Dr Nair reports receiving grants from BeyondSpring Pharmaceuticals during the conduct of the study. Dr Shi reports receiving grants from the Chinese National New Drug Innovation Program (2017ZX09304015). No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

Disposition of the 62 patients screened for the study. aAll randomized patients received at least 1 dose of the study drug and were included in the intent-to-treat and safety sets. bOne patient randomized to the pegfilgrastim treatment arm was erroneously given plinabulin 20 mg/m2 throughout the study.

Figure 2.. Absolute Neutrophil Counts and Neutrophil Toxicity Grade in Cycle 1

A, Absolute neutrophil count (ANC) during cycle 1 of chemotherapy expressed on a logarithmic scale to better visualize the values at low ANC levels. Lower solid line is ANC grade 4 toxicity (0.5 cells × 10−6 /L), and upper solid line is ANC grade 3 toxicity (1.0 × 10−6 cells /L). B, Percentage of treated patients plotted against maximum neutrophil toxicity grade during treatment cycle 1.

Figure 3.. Quality of Life, Bone Pain, and Thrombopenia

A, Patients’ measured global health status per treatment cycle. Higher score is better. B, Patient response to the measure of bone pain at its worst in the past 24 hours each day during cycle 1 expressed as a percentage change from baseline pain using the Brief Pain Inventory Short Form. Error bars indicate 95% CIs; a negative score indicates less pain. C, Patient response to the measure of bone pain on average in the past 24 hours each day during cycle 1 expressed as a percentage change from baseline pain using the Brief Pain Inventory Short Form. Error bars indicate 95% CIs; a negative score indicates less pain. D, Platelet counts by day during treatment cycle 1 expressed as percentage change from baseline. P values were based on the mixed-model repeated measures method with the terms of treatment, baseline value, postbaseline visit, and treatment by postbaseline visit interactions. The covariance is assumed to be compound symmetry

Figure 4.. Neutrophil Toxicity in Previous Phase 2 Study of Docetaxel for Patients With Non–Small Cell Lung Cancer

Neutrophil toxicity in a previous study conducted among patients with non–small cell lung cancer who were treated with docetaxel 75 mg/m2 on day 1. Incidence of grade 4 neutropenia (absolute neutrophil count <0.5 × 109 cells/L) on day 8 in the 40 patients treated with plinabulin 20 mg/m2 (2.6%) or the 55 patients treated with plinabulin 30 mg/m2 (4.3%) was compared with 31% in 50 patients treated with docetaxel without plinabulin. Both plinabulin doses reduced grade 4 neutropenia compared with patients treated with docetaxel alone.