Data from the Phase III PROTECTIVE-2 (Study 106) demonstrated a 53% reduction of profound neutropenia (PN; defined as Absolute Neutrophil Count (ANC) of <0.1×10E9 cells/L) as well as a 50% reduction in the mean duration in patients diagnosed with breast cancer undergoing chemotherapy treatment who received plinabulin in combination with standard of care vs. standard of care alone. The data also demonstrated the combination reduced the odds of febrile neutropenia (FN) by 41% vs. standard of care alone, due to its ability to reduce patients’ exposure to profound neutropenia.

The trial results were presented by BeyondSpring Therapeutics in a poster during the virtual San Antonio Breast Cancer Symposium (SABCS), held December 8 – 11, 2020.[1]

Cytotoxic chemotherapy suppresses the hematopoietic system, and, as a result, impairs host protective mechanisms and limiting the doses of chemotherapy that can be tolerated. Chemotherapy-induced neutropenia or CIN, also called febrile neutropenia (FN), is the most serious hematologic toxic side effect that increases the risk of life-threatening infection with fever and necessitates ER/hospital visits. [3]

“It is well recognized that CIN is directly related to chemotherapy’s ability to kill rapidly dividing cells. Unfortunately, fast dividing neutrophils in the bone marrow are adversely affected regardless of the chemotherapy type,” explained Gordon Schooley, Ph.D., BeyondSpring’s Chief Regulatory Officer.

CIN is considered the primary cause of reductions in dose or duration of chemotherapy, which may ultimately lead to limiting the delivery of the chemotherapy at full dose and on schedule and, in turn, compromising effective cancer treatment and long-term survival in patients with potentially curable malignancies. Chemotherapy-induced neutropenia is also associated with lengthy hospitalizations and high medical costs.[3][4]

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Profound neutropenia is the most severe form of chemotherapy-induced neutropenia and a well-known risk factor to increase the rates of infection, febrile neutropenia (FN), and hospitalization among patients undergoing chemotherapy. Both CIN and PN can occur when chemotherapy kills too many white blood cells needed to keep the body healthy.

The incidences of CIN and its complications vary by type of malignancy. One study reported incidence rates of 15% to 65% in patients diagnosed with one of five major tumor types: breast cancer, colon cancer, lymphoma, lung cancer, and ovarian cancer.

In the United States, each year, up to 65% of the near 650,000 Americans who receive chemotherapy each year experience CIN.

Profound neutropenia, an exploratory endpoint representing the most severe form of CIN, is associated with significant risk to patients and may require antibacterial or antifungal prophylaxis. [5] It is attributed to both febrile neutropenia (48%) and infection (50%).[6]

Plinabulin is a small molecule therapy that is administered through an IV. Topline Phase III data announced in November 2020 showed plinabulin significantly decreased the incidence of chemotherapy-induced neutropenia (CIN) when used with standard of care.

PROTECTIVE-2
The Phase III PROTECTIVE-2 (Study 106) trial (NCT0329457) a global, multicenter, randomized, double-blinded study in patients with breast cancer in early-stage (Stage I and II) and Stage III BC (node-positive or node-negative with a high risk of recurrence) pts with ECOG status 0 or 1 undergoing myelosuppressive chemotherapy with TAC (docetaxel at 75 mg/m2, doxorubicin at 50 mg/m2, and cyclophosphamide at 500 mg/m2) for the evaluation of protection against CIN, comparing plinabulin (40 mg) in combination with pegfilgrastim (Neulasta®; Amgen; 6 mg) in 111 patients to pegfilgrastim alone (6 mg) in 110 patients.

Patients participating in the trial received TAC and plinabulin or placebo on day 1 and on day 2, they received pegfilgrastim.

New data from the study demonstrated that plinabulin in combination with pegfilgrastim offers greater protection against chemotherapy-induced neutropenia (CIN) than the standard of care, pegfilgrastim alone.

The study not only met the primary and key secondary objectives but also demonstrated that the combination was 53% more effective than pegfilgrastim alone in reducing the incidence of profound neutropenia (absolute neutrophil count or ANC < 0.1 x 10E9 cells/L), 21.6% vs. 46.4%, respectively, p=0.0001, in patients with breast cancer undergoing chemotherapy with TAC (docetaxel, doxorubicin, and cyclophosphamide).

Of clinical importance, the combination has shown to reduce the odds of having FN by 41% in comparison to pegfilgrastim, based on the reduction of profound neutropenia.

“It is clinically meaningful to reduce FN risk by 41% in the combination, compared to pegfilgrastim alone, which is the only major breakthrough advancement in CIN prevention in the last 30 years. The CIN protection from plinabulin added to pegfilgrastim, particularly in the first week of chemotherapy when 75% of CIN-related complications occur before the effect of pegfilgrastim kicks-in in Week 2, fills the treatment gap in the current standard of care,” said Douglas Blayney, MD, Professor of Medicine at Stanford Medical School, and global PI for the plinabulin CIN studies.

“The combination of plinabulin with pegfilgrastim represents a major advancement in offering protection against CIN, with the potential to reduce FN risk, in the care of cancer patients,” Blayney said.

“Based on these results, we believe these outcomes are universally applicable to any chemotherapy and are independent of cancer types,” BeyondSpring’s Schooley added.

“As both the United States. the Food and Druf Administration (FDA) and in China the National Medical Products Administration (NMPA) (国家药品监督管理局), formerly the China Food and Drug Administration, or CFDA, awarded BeyondSpring’s Plinabulin CIN program with Breakthrough Therapy Designation status based on the interim phase III data of PROTECTIVE-2, and the Company now completing the PROTECTIVE-2 trial with positive and consistent results to the interim, we are well on track to submit our NDA for CIN in Q1 2021. The improved CIN prevention benefit of the Plinabulin/G-CSF combination would have the potential for CIN prevention of the myelosuppressive effects of different chemotherapeutic agents in millions of patients with multiple tumor types,” said Ramon Mohanlal, M.D., Ph.D., BeyondSpring’s Chief Medical Officer, and Executive Vice President, Research and Development.

“Plinabulin represents a new treatment paradigm for CIN prevention, an area wherein G-CSF has established efficacy, but with short-comings due to its delayed onset of action, next day dosing requirement, bone pain induction, and platelet count reduction. Plinabulin has a fast onset mechanism of action, without causing relevant bone pain or thrombocytopenia, and can be given on the same day as chemotherapy. Plinabulin added to G-CSF offers superior prevention of CIN, and has the potential to avoid life-threatening infections and to improve short-term and long-term survival. Plinabulin’s anticancer activity from its immune-enhancing mechanism of action, together with its CIN preventive effects, has the potential to become a universal add-on to anti-cancer treatments in general,” Mohanlal concluded.

Guideline
The updated National Comprehensive Cancer Network (NCCN) guidelines expanded the use of prophylactic G-CSFs, such as pegfilgrastim, to include not only high- risk patients (chemo FN rate>20%), but also intermediate-risk patients (FN rate between 10-20%) to avoid hospital/ER visits during the COVID-19 pandemic.

The revision of the NCCN guidelines effectively doubles the addressable market of patients who may benefit from treatment with plinabulin, if approved, to approximately 440,000 cancer patients in the U.S. annually. Plinabulin is designed to provide protection against the occurrence of CIN and its clinical consequences in week 1, for early onset of action after chemotherapy. CIN is the primary dose-limiting toxicity in cancer patients who receive chemotherapy treatment.

Clinical trials
Plinabulin vs. Pegfilgrastim in Prevention of TAC Induced Neutropenia | PROTECTIVE-2 Study 106 – NCT03294577

Highlights of prescribing information
Pegfilgrastim (Neulasta®; Amgen) [Prescribing Information]

Reference
[1] 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.
[2] Blayney DW, Mohanlal R, Huang L. Protective-2 (BPI-2358-106): A Confirmatory Trial to Demonstrate Superiority of the Plinabulin+Pegfilgrastim (Plin/Peg) Combination Versus Standard of Care Pegfilgrastim for the Prevention of Chemotherapy-Induced Neutropenia (CIN) in Breast Cancer (BC) Patients (pts). Blood (2020) 136 (Supplement 1): 16. doi.org/10.1182/blood-2020-141110 [Article]
[3] 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.
[4] Ozer H. The timing of chemotherapy-induced neutropenia and its clinical and economic impact. Oncology (Williston Park). 2006 Apr;20(5 Suppl 4):11-5. PMID: 16736983.
[5] Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, Kuderer NM, Langston AA, Marr KA, Rolston KV, Ramsey SD. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013 Feb 20;31(6):794-810. doi: 10.1200/JCO.2012.45.8661. Epub 2013 Jan 14. PMID: 23319691.
[6] Bodey GP, Rodriguez V, Chang HY, Narboni. Fever and infection in leukemic patients: a study of 494 consecutive patients. Cancer. 1978 Apr;41(4):1610-22. doi: 10.1002/1097-0142(197804)41:4<1610::aid-cncr2820410452>3.0.co;2-b. PMID: 346201.

Featured image: Attendees during morning sessions of the 2018 San Antonio Breast cancer Symposium. Photo courtesy: © 2019 – 2020. AACR/San Antonio Breast Cancer Symposium (SABCS). Used with permission.

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