Patient-derived cancer model for plinabulin monotherapy supports treatment of SCLC


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

These preclinical data are based on a study in which the anticancer effects of plinabulin were tested in approximately 80 patient-derived tumor models, with small cell lung cancer (SCLC) tumor types being the most sensitive to monotherapy. to plinabulin in IC.70 of 35 nM

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

SIMBA
Plinabulin is a selective immunomodulatory microtubule binding agent (SIMBA), which is a potent inducer of antigen presenting cells (APC).

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

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Single agent
This study demonstrates the direct anticancer tumor effects of plinabulin in PDX models of SCLC and other types of cancer, including glioblastoma multiforme, bladder cancer, gastric cancer, sarcoma, and triple negative breast cancer.

“The positive preclinical data from PDX increases our confidence in the continuation of SCLC as an indication for plinabulin, which has shown high response rate data in human studies. This is complementary 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., Scientific Director of BeyondSpring.

“The fact that plinabulin has previously 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 planned strategy to develop an option for cancer patients by combining plinabulin and checkpoint inhibitors in SCLC, ”added Lloyd.

Sensitivity to plinabulin
The study aimed to screen cancer cells for plinabulin sensitivity. To this end, PDX models of cancer established from tumor biopsies of patients have been used in such a way as to minimize the risk of genetic changes in cancer cells. Therefore, these models are considered to be more predictive of clinical response than common cancer models. Eighty three-dimensional PDX culture models were tested. Data showed that the cancer types most sensitive to plinabulin included SCLC (mean absolute CI70 = 35 nM; n = 7), bladder cancer (mean absolute CI70 = 38 nM; n = 9) and soft tissue sarcoma (mean absolute CI70 = 57 nM; n = 10).

“We have developed plinabulin for multiple cancer indications based on its effects on dendritic cells and macrophages. The anticancer effect of plinabulin is supported by the positive Phase 3 study DUBLIN-3 in non-small cell lung cancer with evidence for extension of overall survival, ”concluded Lan Huang, Ph.D. ., co-founder, CEO and president of BeyondSpring.

In addition, the results of a previous phase 2 clinical trial (NCT00630110) demonstrated that plinabulin in combination with docetaxel resulted in a median OS of 11.3 months in patients with advanced NSCLC with measurable injury 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. In addition, the duration of response was 12.7 months in the combined arm versus 1 month in the docetaxel alone arm (P <.05>

“The anti-cancer activity in monotherapy of plinabulin in PDX SCLC models and positive preliminary clinical data of the relevant immuno-oncology combination in SCLC could potentially extend its indications against cancer,” Huang added.

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

Plinabulin has also been shown to be effective in preventing chemotherapy-induced neutropenia, which has received breakthrough designation and priority review from the US FDA.

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

Clinical tests
Phase 1/2 Study of Vascular Disruptor 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

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

The 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. January 15, 2004; 100 (2): 228-37. doi: 10.1002 / cncr.11882. Erratum in: Cancer. 2004 May 1; 100 (9): 1993-4. PMID: 14716755.

Featured Image: Chest X-ray | Doctor examining a chest x-ray. Photo courtesy: © 2016 – 2021 Fotolia / Adobe. Used with permission.

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