Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Chemotherapy-Induced Neutropenia in Adults With Non–Small Cell Lung Cancer

Abstract

IMPORTANCEPlinabulin 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/m 2 on day 1 and were randomly assigned to 1 of 3 doses of plinabulin (5, 10, or 20 mg/m 2 ) on day 1 or to pegfilgrastim 6 mg on day 2. Patients were treated every 21 days for 4 chemotherapy cycles. MAIN OUTCOMES AND MEASURESThe 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. RESULTSOf 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/m 2 (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/m 2 , 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.

Prophylaxis and treatment strategies for optimizing chemotherapy relative dose intensity

“…Preclinical studies have also revealed that plinabulin prevents the development of CIN in rodents but does not affect the bone marrow or blood G-CSF levels [111]. These findings have been confirmed in clinical studies, with noninferiority observed versus pegfilgrastim in the number of days of severe neutropenia in a phase 2 randomized study of plinabulin versus pegfilgrastim in 55 NSCLC patients treated with docetaxel [112]. Additionally, results of the phase 3 PROTECTIVE-2 study of plinabulin plus pegfilgrastim compared to pegfilgrastim alone demonstrated that the plinabulin combination results in a significant reduction in the incidence of grade 4 neutropenia, febrile neutropenia, and the duration of profound and severe neutropenia in cycle 1 during TAC treatment in 211 randomized breast cancer patients [113].…”

“…In a phase 1 study in 15 NSCLC patients treated with docetaxel plus plinabulin, the most common adverse events were fatigue, pain, nausea, diarrhea, and vomiting [115]. Furthermore, less bone pain and fewer grade 4 adverse events occurred with plinabulin plus pegfilgrastim versus pegfilgrastim alone in the PROTECTIVE-2 study, and less bone pain was also observed with plinabulin versus pegfilgrastim in the phase 2 study highlighted above in NSCLC [112,113].…”

Improving Outcomes of Chemotherapy: Established and Novel Options for Myeloprotection in the COVID-19 Era

“…This triggers downstream molecular pathways that drive dendritic cell maturation and antigen-induced T-cell activation, thereby improving antitumor immunity (59,60). In addition to its immune-potentiating effects (60,61), plinabulin can prevent CIN caused by docetaxel by boosting the number of HSPCs in the bone marrow and has demonstrated evidence of alleviating CIT (62)(63)(64)(65)(66)(67)(68)(69)(70).…”

“…In the phase 2 part of a phase 2/3 study of plinabulin plus docetaxel versus pegfilgrastim plus docetaxel in patients with NSCLC, plinabulin showed a similar effect on CIN compared with pegfilgrastim, but only plinabulin reduced the incidence of thrombocytopenia; plinabulin was also associated with less bone pain (63). A significant QoL improvement was observed with plinabulin across three of four parameters measured (global health status, symptom scales, and summary score), with additional improvements in fatigue, pain, and insomnia symptom scales (71).…”

Recent updates on the bioactive compounds of the marine-derived genusAspergillus

“…Plinabulin, a dehydrodiketopiperazine halimide analog, was terminated in phase II trials and also obtained a phase III review in 2015 for the treatment of non-small cell lung cancer (advanced metastatic) and now has become FDA-approved. [1][2][3] Reviewing the available literature concerning the genus Aspergillus marine-derived metabolites, a study was found demonstrating the bioactivities and chemical structures of 512 marine metabolites of Aspergillus origins between January 1992 and December 2014. 1 Herein, the present study surveys most of the bioactive principles isolated from the marine-derived genus Aspergillus from 2015 till December 2020 and their abundance along with pharmacological potential.…”