Distinct Mechanism of Action Makes Plinabulin a Potentially Powerful Therapy in Treating Breast Cancer

Plinabulin, an investigational, first-in-class, selective immunomodulating microtube binding agent (SIMBA), has demonstrated a potential capability to prevent chemotherapy-induced neutropenia (CIN) as well as serve as an anticancer agent in treating non-small cell lung cancer (NSCLC). ¹ The drug’s status as a potential preventative and active drug is based on its highly differentiated mechanism of action.

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

References

1. Plinabulin. BeyondSpring Pharmaceuticals. 2021. Accessed July 14, 2021. https://bit.ly/3rjFXPu.
2. BeyondSpring announces US FDA acceptance and priority review of new drug application for plinabulin and G-CSF combination for the prevention of chemotherapy-induced neutropenia (CIN). News release. BeyondSpring. June 1, 2021. Accessed July 14, 2021. https://bit.ly/2SQVl8U.
3. Blayney DW, Huang L, Mohanlal R. Superior and clinically meaningful protection against profound neutropenia with the plinabulin/pegfilgrastim (Plin/Peg) combination versus peg in breast cancer patients receiving TAC chemotherapy: phase 3 results from Protective-2 (BPI-2358-106). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PS13-53-01.
4. BeyondSpring announces new positive PROTECTIVE-2 phase 3 registrational trial results at the 2020 San Antonio Breast Cancer Symposium. News release. BeyondSpring. December 10, 2020. Accessed July 14, 2021. https://bit.ly/36CltI7.
5. Blayney DW, Shi Y, Adamchuk H, et al. Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention. J Clin Oncol. 2021;39(suppl 15):533. doi:10.1200/JCO.2021.39.15_suppl.533
6. Docetaxel + plinabulin compared to docetaxel + placebo in patients with advanced NSCLC. ClinicalTrials.gov. Updated May 21, 2021. Accessed July 14, 2021. https://clinicaltrials.gov/ct2/show/NCT02504489.
7. Nivolumab in combination with plinabulin in patients with metastatic non-small cell lung cancer (NSCLC). ClinicalTrials.gov. Updated February 23, 2021. Accessed July 14, 2021. https://clinicaltrials.gov/ct2/show/NCT02812667.
8. A phase I/II study of nivolumab, ipilimumab and plinabulin in patients with recurrent small cell lung cancer. ClinicalTrials.gov. Updated May 28, 2021. Accessed July 14, 2021. https://clinicaltrials.gov/ct2/show/NCT03575793.

This article was originally published on OncLive as “Unique Mechanism of Action Positions Plinabulin as a Preventive and Active Therapy in Breast Cancer, NSCLC”