The highly differentiated mechanism of action of plinabulin, an investigational, first-in-class, selective immunomodulating microtubule binding agent, has positioned the drug as a potential preventive treatment for chemotherapy-induced neutropenia, as well as an anticancer agent in non–small cell lung cancer.
The highly differentiated mechanism of action of plinabulin, an investigational, first-in-class, selective immunomodulating microtubule binding agent (SIMBA), has positioned the drug as a potential preventive treatment for chemotherapy-induced neutropenia (CIN), as well as an anticancer agent in non–small cell lung cancer (NSCLC).1
Plinabulin binds to the vicinity of the colchicine binding domain of the ß-tubulin in αβ-tubulin heterodimers. The binding occurs at a site and with kinetics that is unique from other tubulin targeting agents.
Moreover, by binding to tubulin, GEF-H1, an immune defense protein, is released by plinabulin. This activates a signaling transduction pathway that leads to dendritic cell (DC) maturation. In turn, DC maturation elicits innate and adaptive immune activity. DC maturation also results in increased antigen presentation and T-cell activation, which appears to contribute to plinabulin’s anticancer activity.
On June 1, 2021, the FDA granted a priority review designation to a new drug application for plinabulin plus granulocyte colony-stimulating factor (G-CSF) for the prevention of CIN.2 The regulatory designation is based on findings from the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577), as well as 5 supportive trials that enrolled over 1200 patients.
In PROTECTIVE-2, the combination of plinabulin and pegfilgrastim (Neulasta) was 53% more effective in reducing the incidence of CIN vs pegfilgrastim alone in patients with early-stage or stage III breast cancer receiving high–febrile neutropenia risk chemotherapy (n = 221).3,4
The final results of the study, which were presented during the 2021 ASCO Annual Meeting, confirmed that the combination elicited superior CIN protection compared with pegfilgrastim alone.5 The addition of plinabulin also reduced adverse clinical sequalae, did not add toxicity, reduced the severity of grade 4 treatment-emergent adverse effects (AEs), and significantly reduced bone pain (P = .03) among patients.
“We think that the combination protects [patients] throughout the chemotherapy cycle. We know from a long experience that there is a vulnerability or lack of protection within the first week after chemotherapy with pegfilgrastim. Adding plinabulin to pegfilgrastim seems to mitigate that vulnerability or increase the protection in the first week after chemotherapy,” said lead study author of the PROTECTIVE-2 study Douglas W. Blayney, MD, a medical oncologist at Stanford Health Care and a professor of medicine at Stanford Medicine, in an interview during an episode of OncLive® News Network: On Location.
“This will help oncologists and their patients receive more chemotherapy during both weeks of the chemotherapy cycle before the bone marrow recovers normally,” Blayney added.
Plinabulin’s activity has also been evaluated in lung cancer. The agent is currently being evaluated in combination with docetaxel for patients with advanced NSCLC who have measurable lung lesions in the phase 3 DUBLIN-3 trial (Study 103; NCT02504489).6 The anticancer results for overall survival are expected in the final quarter of 2021, according to Blayney.5
Plinabulin is also being evaluated in combination with the PD-1 inhibitor nivolumab (Opdivo) with the rationale that adding the agent will elicit synergistic immune-enhancing effects.1 Historically, cumulative toxicity has been a concern with nivolumab in combination with other checkpoint inhibitors; however, it is thought that plinabulin/nivolumab may demonstrate improved antitumor activity vs nivolumab alone without significantly increased toxicity. An ongoing phase 1/2 study (NCT02812667) is evaluating the combination in patients with metastatic NSCLC.7
Triplet combinations are also under study with plinabulin.1 The combination of plinabulin, nivolumab, and ipilimumab (Yervoy) is being evaluated in a phase 1/2 study (NCT03575793) in patients with recurrent small cell lung cancer to determine whether plinabulin will be synergistic with nivolumab and ipilimumab while limiting immune-related AEs associated with the agents.1,8
Finally, research is ongoing to test the potential benefits of adding plinabulin to PD-1 inhibitors and radiation therapy.1
“Given the high incidence of progression with PD-1/PD-L1 antibody therapies in the majority of cancers, we believe this novel triplet approach will restore or enable the immune targeting of cancer in patients that have progressed on checkpoint [inhibitor] therapy,” according to BeyondSpring Pharmaceuticals.1