Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Docetaxel-Induced Neutropenia in Patients With Solid Tumors: A Randomized Clinical Trial

Abstract

Importance: Prevention of chemotherapy-induced neutropenia (CIN) and its clinical consequences is an unmet need for which plinabulin, a selective immunomodulating microtubule-binding agent, is being tested.

Objective: To demonstrate noninferiority between plinabulin and pegfilgrastim for days of severe neutropenia in cycle 1 in patients with solid tumors treated with docetaxel.

Design, setting, and participants: The Plinabulin vs Pegfilgrastim for the Prevention of Docetaxel-Induced Neutropenia in Patients With Solid Tumors (PROTECTIVE-1) double-blind phase 3 randomized clinical trial was performed in multiple centers in China, Russia, Ukraine, and the US. Participants included patients with breast, prostate, or non-small cell lung cancer treated with single-agent docetaxel chemotherapy. Data were collected from June 1, 2018, to January 31, 2019. The database was locked on February 18, 2021. Data analysis was based on intention to treat and safety and performed from October 5, 2018, to February 23, 2021.

Interventions: Plinabulin, 40 mg, plus placebo or pegfilgrastim, 6 mg, plus placebo.

Main outcomes and measures: The primary end point was day of severe neutropenia in cycle 1. Additional end points included clinical consequences of CIN (febrile neutropenia, hospitalizations, infections, antibiotic use, and modifications of chemotherapy dose), patient-reported outcomes for bone pain score, markers for immune suppression (neutrophil-to-lymphocyte ratio [NLR] of >5), immature neutrophils (band, promyelocyte, and myelocyte counts >0), and safety.

Results: Among the 105 patients included in the analysis (65 [6.19%] women; median age, 59 [range, 31-81] years), the primary end point was met within a noninferiority margin of 0.65 days, with a mean difference of 0.52 days (98.52% CI, 0.40-0.65 days). Grade 4 neutropenia frequency in cycle 1 was not significantly different. Plinabulin had earlier onset of action with less grade 4 neutropenia in week 1 of cycle 1. Plinabulin had fewer adverse clinical consequences with rates of febrile neutropenia (0 of 52 vs 1 of 53 [1.9%]), infections (4 of 52 [7.7%] vs 8 of 53 [15.1%]), chemotherapy dose delay of more than 7 days (2 of 52 [3.8%] vs 3 of 53 [5.7%]), and permanent chemotherapy discontinuation (7 of 52 [13.5%] vs 14 of 53 [26.4%]). Patients receiving plinabulin had significantly less bone pain (difference, -0.67 [95% CI, -1.17 to -0.16]; P = .01) and a better immunosuppressive profile (NLR >5 at day 8, 2 of 52 [3.8%] vs 24 of 51 [46.0%]; P < .001). Plinabulin was well tolerated, with comparable safety to pegfilgrastim.

Conclusions and relevance: Plinabulin has comparable efficacy to pegfilgrastim for the prevention of CIN, with better safety and a better immunosuppressive profile. Plinabulin's same-day dosing compared with pegfilgrastim's next-day dosing offers distinct advantages, including reducing use of health care services.

Trial registration: ClinicalTrials.gov Identifier: NCT03102606.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Blayney reported receiving grants to his institution from BeyondSpring Pharmaceuticals, which also provided travel and lodging support during the conduct of the study, and grants to his institution from Amgen Inc and personal fees from G1 Therapeutics, Bristol Myers Squibb, Merck & Co Inc, and Eli Lilly and Company and owning stock in Madora and Artelo Biosciences Inc outside the submitted work. Dr Mohanlal reported being a stockholder in BeyondSpring Pharmaceuticals during the conduct of the study and being coinventor on a patent with BeyondSpring Pharmaceuticals. Dr Ginn reported statistical consulting for BeyondSpring Inc during the conduct of the study. Dr Huang reported owing stock in BeyondSpring Pharmaceuticals during the conduct of the study, having a patent issued for plinabulin use in reducing chemotherapy-induced neutropenia (CIN), and having a patent pending for plinabulin reducing CIN in various chemotherapy agents. No other disclosures were reported.

Figures

Figure 1.. Disposition of Study Patients

ITT indicates intention to treat.

Figure 2.. Outcomes by Time and Treatment Group in the Intention to Treat and Safety Analysis Sets

A, Semilog plot of the mean absolute neutrophil count in cycle 1 for the intention to treat analysis. B, Plot of the mean patient reported bone pain score in cycle 1 in the safety analysis.

Figure 3.. Treatment Emergent Adverse Events by Severity Grade

Grades are given in the Methods section.