Pegfilgrastim Plus Plinabulin Reduces Chemo-Induced Neutropenia in TAC-Treated Patients

Douglas W. Blayney, MD

The combination of pegfilgrastim (Neulasta) and plinabulin demonstrated a reduction in chemotherapy-induced neutropenia (CIN) versus pegfilgrastim alone in patients treated with docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy, according to results from the phase II trial Study 106.

Now, an ongoing confirmatory phase III study, also titled Study 106 (NCT03294577), is further investigating the novel combination, explained lead study author Douglas W. Blayney, MD.

"It is important to point out that chemotherapy is not going away, even in this era of immunotherapy," said Blayney. "Many of the checkpoint inhibitor regimens are combined with chemotherapy. Also, patients who [develop resistance] to immunotherapy are often given chemotherapy as the next mode of treatment."

In the phase II study, the rates of grade 3/4 neutropenia were 81% with single-agent pegfilgrastim versus 50% with the combination regimen (P <.05); grade 4 neutropenia, specifically, was 57% versus 38%, respectively.

Additionally, bone pain typically associated with single-agent pegfilgrastim was majorly absent for patients treated with the combination. Bone pain for ≥1 day was experienced in 6% of patients treated with pegfilgrastim/plinabulin compared with 95% of those treated with pegfilgrastim alone (P <.001). The rates of bone pain for ≥4 days occurred in 0% of patients on the combination compared with 33% of those receiving single-agent pegfilgrastim (P <.01).

In an interview with OncLive, Blayney, a professor of medicine (oncology) at Stanford Medical Center, discussed these phase II results and the importance of controlling CIN for patients.

OncLive: Why is it important to control CIN?

Blayney: The chemotherapy that is used to treat patients with cancer has myelotoxicity as a main adverse event. Myelotoxicity results from damaged fast-growing cells in the bone marrow. It can cause low white blood cell counts and particularly low neutrophil counts. This puts the patient at risk for life-threatening infections.

Infections manifest as fever; fever with neutropenia is a biomarker for a life-threatening infection. Patients should be hospitalized or started on antibiotics to treat these potentially [deadly] infections; however, this leads to a lot of unnecessary hospitalization and antibiotic use.

What is the rationale behind combining pegfilgrastim and plinabulin?

The chemotherapy regimens utilized today are divided into high, intermediate and low risk for febrile neutropenia risk. High risk is defined by the National Comprehensive Cancer Network (NCCN) guidelines as more than 20%. [High-risk patients] are recommended for routine use of pegfilgrastim with each chemotherapy cycle.

The NCCN also recommends that pegfilgrastim should be given on the first cycle of chemotherapy rather than waiting until the patient develops febrile neutropenia.

In other research, plinabulin was tested in patients with intermediate risk for febrile neutropenia risk. Results showed that it not only reduced the risk of low neutrophil counts, but it changed the time course of when the nadir occurred compared with pegfilgrastim alone.

Pegfilgrastim has a low neutrophil count on day 7 or 8 after chemotherapy. Plinabulin has a low neutrophil count much later after chemotherapy and [the counts] do not [drop as low]. In this current study, we combined pegfilgrastim and plinabulin to see if the effects of different time courses—and, as it turns out, different mechanisms of action—could be taken advantage of.

What were the results of the phase II study?

We set out to combine plinabulin and pegfilgrastim for patients with high-risk febrile neutropenia. In this study, we used the TAC chemotherapy regimen that is used in many parts of the world to treat patients with metastatic breast cancer.

Plinabulin was given at a 20-mg/m2 dose on the same day as chemotherapy. That dose was established in our earlier work. A 1.5-mg dose of pegfilgrastim was added on the second day after chemotherapy. That dose was escalated to 3 mg and then 6 mg, which is the full dose. Neutrophil counts were measured daily; we found that this dose combination gave the optimal protection against neutropenia.

The nadir of neutrophils [occurred on] day 7 with pegfilgrastim alone, and on day 11 with the combination of pegfilgrastim and plinabulin. Additionally, [the nadir with the combination] was not as deep, meaning the neutrophils did not [drop] as low as with pegfilgrastim alone.

Remarkably, we found an absence of bone pain in the combination arm. [Historically], pegfilgrastim has been associated with bone pain occurring 2 to 3 days after treatment in almost all patients who receive pegfilgrastim.

In our study, bone pain was nearly absent with the combination of plinabulin on day 1 and pegfilgrastim on day 2 after chemotherapy. [That is in addition] to the increased neutropenia protection.

Could you speak to the mechanisms of action with these agents?

Pegfilgrastim accelerates maturation of neutrophil precursor and demarginates existing mature neutrophil from circulation. Typically, when we give chemotherapy, the neutrophil nadir is on day 10 to day 14. The neutrophil recovery is complete by day 21. Chemotherapy is given every 21 days to allow the neutrophils time to recover.

With pegfilgrastim being given on day 2 or 3 after chemotherapy, the neutrophil nadir occurs on day 7 or day 8 and recovery is complete by day 14.

Plinabulin on the other hand does not accelerate the maturation of neutrophils. Instead, it seems to protect the neutrophils in the bone marrow from the damage [of chemotherapy]. The neutrophil nadir occurs around day 11 and recovery is complete by day 14.

In short, pegfilgrastim protects against low neutrophil counts in the second week after chemotherapy, and plinabulin protects against low neutrophil counts in the first week. Combining them allows for increased protection during the complete chemotherapy cycle.

Were there any additional safety signals found with the combination?

We confirmed that the bone pain typically associated with pegfilgrastim was not seen with the combination of pegfilgrastim and plinabulin. Additionally, we did not see the transient hypertension associated with higher doses of plinabulin.

Furthermore, the expected adverse events of chemotherapy including nausea, vomiting, hair loss, and infections were evenly distributed among the treatment arms.

Were there any additional findings that are important to highlight?

We saw a hint that the combination protects against low platelet counts that are seen with some chemotherapies. The TAC chemotherapy does not cause dangerously low platelet counts, but we observed that the combination had a higher platelet count throughout the chemotherapy cycle.

Similarly, quality of life appears to be superior with the combination [compared with pegfilgrastim alone].

Finally, pegfilgrastim monotherapy causes an overshoot of neutrophils in the first few days of treatment. This overshoot of neutrophils may be immunosuppressive. The biomarker for that immunosuppression is the neutrophil-lymphocyte ratio. We will further explore all of these elements in the phase III study.

Bayney DW, Huang L, Mohanlal R. A randomized phase 3 clinical trial of the combination of plinabulin (plin) + pegfilgrastim (peg) versus (vs) peg alone for TAC (docetaxel, doxorubicin, cyclophosphamide) induced neutropenia (cin). Blood. 2019;134(suppl_1):3590. doi: 10.1182/blood-2019-127310.