FDA Rejects Drug Preventing Low Blood Counts in Patients on Chemotherapy

The FDA delivered a blow on Wednesday to the millions of cancer patients who face the prospect of declines in white blood cell counts during chemotherapy — a condition known as chemotherapy-induced neutropenia (CIN) — when it denied approval for a promising new agent that has been under Priority Review: Plinabulin. But the news is not all bad. The agency has asked the manufacturer to provide additional data to support its application, indicating that plinabulin might still play a part in future cancer care.

Neutropenia increases the risk for infections; hospitalizations for major complications, including dangerously low blood pressure, renal and respiratory challenges, and heart failure; as well as in-hospital death. Data published in May 2018 in the Journal of Clinical Oncology suggested that over 100,000 cancer patients receiving chemotherapy are hospitalized with CIN annually. In addition, almost 11 percent of all hospitalizations due to receipt of systemic therapy between 2006 and 2016 were related to CIN, according to a study published in April 2021 in Scientific Reports.

Plinabulin is derived from seawater bacteria and has been shown to prevent CIN in a variety of cancers, including breast, prostate, and non-small-cell lung cancer, in part by enhancing white blood cells ability to survive, according to a June 2021 press release by BeyondSpring, the pharmaceutical company developing plinabulin.

Most recently, it was studied in a phase 3 clinical trial (PROTECTIVE-2) that examined plinabulin in combination with another agent, Neulasta (pegfilgrastim), which helps stimulate white blood cell production, to prevent CIN in women with breast cancer receiving a combination regimen known as TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy.

Study findings from PROTECTIVE-2 presented this past June at the American Society of Clinical Oncology’s Annual Meeting highlight how plinabulin — if approved for marketing — has the potential to alter the CIN landscape.

In those results, which tested the combination of plinabulin and Neulasta against Neulasta alone, “the combination not only protected [against CIN] in the first week after chemotherapy, but also in week two without interfering with the protective effect of pegfilgrastim,” said Douglas Blaney, MD, a professor at Stanford Health and the lead investigator on the PROTECTIVE-2 study.

This is important because “the first week after chemotherapy [is when] most of the hospitalizations and emergency department visits occur,” Dr. Blaney says. “So, there’s this neutropenia protection gap.” The neutropenia protection gap (also called the neutropenia vulnerability gap) refers to the immediate eight-day time period after chemotherapy when neutrophils (the most common type of white blood cells) are most depleted.

Not only did PROTECTIVE-2 findings show that the plinabulin added to pegfilgrastim reduced the incidence of CIN in general, but the percentage of patients experiencing febrile neutropenia (FN), a neutropenia-induced fever higher than 101 degrees F, declined by roughly 50 percent, compared with those receiving pegfilgrastim alone. In addition, patients receiving the combination were able to leave the hospital a day sooner.

FN accounts for up to one-third of major complications and up to 11 percent of overall deaths, and when accompanied by severe blood infections (sepsis) up to 50 percent of hospital deaths due to CIN. In PROTECTIVE-2, significantly fewer patients receiving combination therapy experienced severe FN and the hospitalization rate was reduced by about 3 percent.

“The other thing that we observed was that there was less bone pain with the combination” notes Blaney, explaining that patients receiving pegfilgrastim often complain of an unusual bone pain described as “my skin is too small or my bones are expanding from the middle.” The sensation is due to pegfilgrastim stimulating the bone marrow cells to make white blood cells, says Blaney.

The FDA’s current decision blocking plinabulin for marketing at this time leaves an important treatment gap for patients who experience CIN each year. But the company remains convinced that its agent will eventually meet its promise to raise the standard of care in treatment of CIN.

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