Preclinical data from patient-derived (PDX) cancer models presented at the 2021 AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics, held October 7-10, 2021, supports the use plinabulin (Previously known as NPI-2358; BeyondSpring Pharmaceuticals), a vascular disrupting agent (VDA) against tubulin-depolymerizing with IC50 of 9.8~18 nM in tumor cells, in small cell lung cancer (SCLC).

This preclinical data is based on a study in which plinabulin’s anti-cancer effects were tested against approximately 80 patient-derived tumor models with small cell lung cancer (SCLC) tumor types being the most sensitive to plinabulin monotherapy at IC70 of 35 nM

The preclinical study data is consistent with clinical data in SCLC: plinabulin, in combination with nivolumab (Opdivo®; Bristol-Myers Squibb) and ipilimumab (Yervoy®; Bristol-Myers Squibb), shows a 46% objective response rate (ORR) in 13 evaluable patients with PD-1/PD-L1 naïve or resistant tumors in 2nd line and beyond in SCLC.

SIMBA
Plinabulin is a selective immunomodulating microtubule-binding agent (SIMBA), which is a potent antigen presenting cell (APC) inducer.

Plinabulin triggers the release of the immune defense protein, GEF-H1, which leads to two distinct effects: first is a durable anticancer benefit due to the maturation of dendritic cells resulting in the activation of tumor antigen-specific T-cells to target cancer cells, and the second is early-onset of action in CIN prevention after chemotherapy by boosting the number of hematopoietic stem/progenitor cells (HSPCs). It is being developed as a “pipeline in a drug” in multiple cancer indications.

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Single agent
This study demonstrates plinabulin’s direct single agent anti-cancer tumor effects in PDX models of SCLC and additional cancer types, including glioblastoma multiforme, bladder cancer, gastric cancer, sarcoma and triple-negative breast cancer.

“The positive PDX preclinical data increases our confidence in pursuing SCLC as an indication for plinabulin, which has shown high response rate data in human studies. This is supplemental to the maturation of dendritic cells in the cancer immune system and the induction of downstream mechanisms in specific cancer cell types,” said Kenneth Lloyd, Ph.D., Chief Scientific Officer of BeyondSpring.

“The fact that plinabulin has already been associated with tumor responses in SCLC patients in a Phase 1 study presented at the 2021 Annual Meeting of the American Society of Clinical Oncology (ASCO) is a good indication that these PDX models are predictive. The preclinical data presented here supports our intended strategy for developing an option for cancer patients by combining plinabulin and checkpoint inhibitors in SCLC,” Lloyed added.

Susceptibility to plinabulin
The study was intended to screen cancer cells for susceptibility to plinabulin. For this purpose, PDX models of cancer established from patient tumor biopsies were used in a manner that results in minimal chance for changes in cancer cell genetics, and hence, these models are considered more predictive of clinical response than common cancer models. Eighty PDX three-dimensional culture models were tested. Data showed that the cancer types most sensitive to plinabulin included SCLC (mean absolute IC70 = 35 nM; n = 7), bladder cancer (mean absolute IC70 = 38 nM; n = 9) and soft tissue sarcoma (mean absolute IC70 = 57 nM; n = 10).

“We have been developing plinabulin in multiple cancer indications based on its effects on dendritic cells and macrophages. Plinabulin’s anti-cancer effect is supported by the positive Phase 3 DUBLIN-3 non-small cell lung cancer study with evidence of the extension of overall survival,” concluded Lan Huang, Ph.D., the co-founder, Chief Excecutive Officer and chairwoman of BeyondSpring.

In addition, results from a prior phase 2 clinical trial (NCT00630110) demonstrated that plinabulin in combination with docetaxel led to a median OS of 11.3 months in patients with advanced NSCLC with a measurable lesion versus 6.7 months with docetaxel alone. [1] In this study, the median progression-free survival was 3.7 months with an objective response rate of 18% versus 2.9 months and 10.5%, respectively, with docetaxel alone. Furthermore, the duration of response was 12.7 months in the combination arm compared with 1 month in the docetaxel-only arm (<.05).

“Plinabulin’s single agent anti-cancer activity in PDX SCLC models and the relevant positive immuno-oncology combo preliminary clinical data in SCLC could potentially expand its cancer indications,” Huang added.

Chemotherapy-induced neutropenia
Chemotherapy suppresses the hematopoietic system, impairing host protective mechanisms and limiting the doses of chemotherapy that can be tolerated by patients. One of the most serious hematologic toxicities is neutropenia, which is associated with the risk of life-threatening infections as well as chemotherapy dose reductions, leading to delays in treatment that may, in turn, compromise treatment outcomes.[2]

Plinabulin has also shown efficacy in preventing chemotherapy-induced neutropenia, which has received Breakthrough Designation and Priority Review from the U.S. FDA.

“We look forward to continuing to expand these anti-cancer indications in the clinic and to validate plinabulin as a ‘pipeline in a drug,” Huang concluded.

Clinical trials
Phase 1/2 Study of Vascular Disrupting Agent NPI-2358 + Docetaxel in Patients With Advanced Non-Small Cell Lung Cancer – NCT00630110
Nivolumab in Combination With Plinabulin in Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC) – NCT02812667
A Phase I/II Study of Nivolumab, Ipilimumab and Plinabulin in Patients With Recurrent Small Cell Lung Cancer – NCT03575793

Highlights of prescription information
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescribing Information]
Ipilimumab (Yervoy®; Bristol-Myers Squibb)[Prescribing Information]

References
[1] Mohanlal RW, Lloyd K, Huang L, et al. Plinabulin as a novel small molecule clinical stage immuno-oncology agent for NSCLC. J Clin Oncol. 2017;35(suppl 7):139. doi:10.1200/JCO.2017.35.7_suppl.139
[2] Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer. 2004 Jan 15;100(2):228-37. doi: 10.1002/cncr.11882. Erratum in: Cancer. 2004 May 1;100(9):1993-4. PMID: 14716755.

Featured image: Lung radiography | Doctor examining a lung radiography. Photo courtesy: © 2016 – 2021 Fotolia / Adobe. Used with permission.

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