An analysis from the Phase 3 PROTECTIVE-2 trial, evaluating the combination of plinabulin (BeyondSpring Pharmaceuticals) and pegfilgrastim (Neulasta®; Amgen) for the prevention of chemotherapy-induced neutropenia (CIN) in breast cancer patients, confirms a significant reduction adverse event profile with the combination treatment.

The results of the analysis were presented at the San Antonio Breast Cancer Symposium (SABCS), held December 7-10, 2021.

Chemotherapy-induced neutropenia (CIN) increases the risk of infections and mortality in cancer patients. G-CSF therapies are approved for the treatment of CIN, but non-G-CSF therapies are needed to increase efficacy and minimize side effects.[1]

Plinabulin, a non-G-CSF, small molecule, selective immunomodulating microtubule-binding agent (SIMBA), which is a potent antigen-presenting cell (APC) inducer, is a synthetic analog of the marine natural product diketopiperazine phenylahistin.[2]

As a novel inhibitor of tubulin polymerization that ameliorates CIN caused in patients by the microtubule stabilizer docetaxel, the intravenous-infused treatment prevents CIN.[1]

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The investigational drug 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).

“We’ve been able to demonstrate that adding plinabulin to pegfilgrastim significantly alleviates pegfilgrastim-related bone pain, decreases toxicity, and improves health-related quality-of-life (HrQoL) through new data analysis from the PROTECTIVE-2 study,” noted Douglas W. Blayney, MD, professor of medicine at Stanford University Medical School and global principal investigator for the CIN studies.

The collective data support the concept that bone pain in patients receiving myelosuppressive chemotherapy and pegfilgrastim is a direct consequence of the accelerated drop in the nadir value of the absolute neutrophil count (ANC) in the first cycle of chemotherapy, which is considered an effective predictor of subsequent neutropenic events, and to deeper levels by pegfilgrastim, triggering an accelerated intramedullary compensatory hematopoietic response and associate pressure build-up that sensed as bone pain.

The addition of plinabulin to pegfilgrastim slowed down the Peg-induced speed and deepening of ANC decline, and consequently ameliorates this intramedullary response mechanism and bone pain generation.

Plinabulin has a fast onset mechanism of action (MoA) for CIN-prevention acting in the first week of the cycle, whereas pegfilgrastim has a slow MoA, acting in the second week of the cycle. Combining plinabulin + pegfilgrastim resulted in superior CIN prevention, the key findings of the study confirm:

  • Patients treated with pegfilgrastim and plinabulin experienced less bone pain than did patients treated with pegfilgrastim only (p=0.03);
  • Treatment with plinabulin may mitigate the need for compensatory hematopoiesis and intracavitary pressure build-up, resulting in bone pain sensations;
  • Patients treated with pegfilgrastim and plinabulin had a higher absolute neutrophil count (ANC) at the nadir (the point of their lowest ANC);
  • Treatment-emergent adverse events of bone pain, cycles 1 to 4 (% of patients): Docetaxel, doxorubicin, and cyclophosphamide (TAC) +pegfilgrastim (30%) vs TAC + pegfilgrastim + plinabulin (18%), p=0.03;
  • ANC nadir during cycle 1 (mean ANC nadir (109 cells/L)): TAC + pegfilgrastim (0.32) vs TAC + pegfilgrastim + plinabulin (0.54), p=0.0002;
  • The depth of ANC nadir was statistically significantly correlated with bone pain scores; TAC + pegfilgrastim vs TAC + pegfilgrastim + plinabulin, p=0.019.

A second poster, presented during the 2021 SABCS, showed that while the frequency of all-grade adverse events was 97% vs 96% in plinabulin+pegfilgrastim vs pegfilgrastim.

However, a shift to a lower grade was noted. Grade 4 adverse event frequency was lower with plinabulin+ pegfilgrastim vs pegfilgrastim: 59% vs 80% (p<0.03). Gr3 (18% vs 6%) and Grade 2 (19% vs 9%) frequency was higher with plinabulin + pegfilgrastim vs pegfilgrastim.

The Key Findings of this study show that adding plinabulin to pegfilgrastim:

  • Decreases toxicity and improves health-related Quality of Life (HrQoL) among patients with breast cancer receiving docetaxel, doxorubicin, and cyclophosphamide (TAC). TAC should be reevaluated for patients with early-stage breast cancer in light of the improved outcomes seen with the addition of plinabulin and pegfilgrastim;
  • Prevented a decline in HrQoL scores for mobility, self-care, daily activities, pain, and anxiety; a significant change in EQ-5D-5L utility values, Cycles 1 to 4 for TAC + pegfilgrastim vs TAC+ pegfilgrastim + plinabulin, p=0.024;
  • Shifted the adverse event profile among patients treated with plinabulin and pegfilgrastim towards lower grade adverse events.

Overall, the addition of plinabulin to pegfilgrastim for CIN prevention enables better management of TAC-induced toxicity and HrQoL. TAC should be reevaluated in early-stage BC patients in light of the improved outcomes with plinabulin+pegfilgrastim support.

“With the superior CIN prevention benefit, the bone pain reduction benefit and quality of life benefit from adding plinabulin to pegfilgrastim, the TAC regimen (docetaxel, doxorubicin, and cyclophosphamide) has the potential to become more tolerable in patients with breast cancer,” Blayney added.

“We’re pleased to be presenting at SABCS again this year and adding this new important data to our existing portfolio of CIN studies. Our goal has always been to create a better cancer treatment experience for these patients by alleviating some of the issues that can occur with CIN. We look forward to continuing to study how plinabulin can potentially make a difference in this indication,” concluded Ramon Mohanlal, MD, Ph.D., MBA, executive vice president of research and development and chief medical officer at BeyondSpring Pharmaceuticals.

Meeting Abstracts
Blayney DW, Ogenstad S, Chang M, Lelorier Y, Huang Lan, Mohanlal R. Mechanistic evidence associated with the benefit of plinabulin significantly reducing bone pain in breast cancer patients (pts) treated with TAC (docetaxel, doxorubicin, cyclophosphamide) and pegfilgrastim (Peg); Publication Number: P5-18-01. Presented during the San Antonio Breast Cancer Symposium (SABCS), held December 7-10, 2021.
Blayney DW, Lelorier Y, Mitchell D, Huang L and Mohanlal R. Combination plinabulin+pegfilgrastim (Plin+Peg) had better toxicity management and health-related quality-of-life (HrQoL) compared to Peg alone in early-stage breast cancer (BC) patients (pts) treated with taxotere, doxorubicin and cyclophosphamide (TAC); Publication Number: P5-18-04. Presented during the San Antonio Breast Cancer Symposium (SABCS), held December 7-10, 2021.

Clinical trials
Plinabulin vs. Pegfilgrastim in Prevention of TAC Induced Neutropenia – NCT03294577

[1] Tonra JR, Lloyd GK, Mohanlal R, Huang L. Plinabulin ameliorates neutropenia induced by multiple chemotherapies through a mechanism distinct from G-CSF therapies. Cancer Chemother Pharmacol. 2020 Feb;85(2):461-468. doi: 10.1007/s00280-019-03998-w. Epub 2019 Dec 6. PMID: 31811421; PMCID: PMC7015961.
[2] Ding Z, Li F, Zhong C, Li F, Liu Y, Wang S, Zhao J, Li W. Structure-based design and synthesis of novel furan-diketopiperazine-type derivatives as potent microtubule inhibitors for treating cancer. Bioorg Med Chem. 2020 May 15;28(10):115435. doi: 10.1016/j.bmc.2020.115435. Epub 2020 Mar 13. PMID: 32278711.

Featured image: Attendees during  San Antonio Breast Cancer Symposium being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. The symposium features physicians, researchers, patient advocates, and healthcare professionals from over 90 countries with the latest research on breast cancer treatment and prevention. Photo Courtesy: © 2021 AACR/SAVCS/MedMeetingImages/Scott Morgan. Used with permission.

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