Plinabulin/Pegfilgrastim Combo Shows Efficacy in Prevention of Severe Neutropenia

The combination of plinabulin and pegfilgrastim (Neulasta) showed a significant enhancement in the rate of grade 4 neutropenia prevention compared with pegfilgrastim alone in patients undergoing chemotherapy, meeting the primary end point of a prespecified interim analysis of the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577).¹

The topline results of the prespecified interim analysis, which was to take place after 120 patients were accrued to the trial, demonstrated efficacy in preventing grade 4 neutropenia with the addition of plinabulin (P <.01). The trial also met a key secondary end point of duration of severe neutropenia (DSN) in cycle 1, favoring the plinabulin arm (P <.05).

Moreover, DSN in the first 8 days of cycle 1, which was another secondary end point, was also met and showed superiority in the plinabulin/pegfilgrastim arm (P <.05).

These data support plinabulin’s mechanism of action in providing early protection against severe neutropenia, as single-agent pegfilgrastim protects against severe neutropenia typically from day 9 onward, BeyondSpring, the manufacturer of plinabulin, stated in a press release, adding that the “complementary mechanism would potentially give full protection in cycle 1."

“These interim results from the PROTECTIVE-2 phase 3 study, which compares the plinabulin-Neulasta combination to Neulasta alone, have the potential to be clinically meaningful for cancer patients receiving chemotherapy,” Douglas Blayney, MD, professor of medicine at Stanford Medical School, and global principal investigator of plinabulin’s chemotherapy-induced neutropenia (CIN) studies, stated in the press release. “Since most infections, hospitalizations and other complications of CIN occur in the first week after chemotherapy, it is particularly gratifying to see the combination’s clinical benefit demonstrated. These results could help to confirm the patient benefit of plinabulin’s different mechanism of action from the G-CSF-based agents, such as Neulasta."

“Plinabulin appears to have CIN protection in week 1, and G-CSFs have protection in week 2 of chemotherapy cycles,” Blayney continued. “The combination should logically provide significantly better protection than Neulasta alone as shown in the interim readout. We are well on our way to confirming that the combination offers protection throughout the chemotherapy cycle, which is an unmet medical need.”

Pegfilgrastim, which is a long-lasting granulocyte colony-stimulating factor (G-CSF), is the current standard of care for treating patients with CIN.

In the phase 3 portion of the double-blind, active-controlled PROTECTIVE-2 study, investigators evaluated the efficacy and safety of docetaxel, doxorubicin and cyclophosphamide (TAC) in a 21-day cycle with plinabulin at 40 mg plus pegfilgrastim at 6 mg versus pegfilgrastim alone in patients with breast cancer.

In the phase 2 portion of Study 106, the combination of plinabulin and pegfilgrastim demonstrated a reduction in CIN versus pegfilgrastim alone in patients treated with TAC chemotherapy.²

In the phase 2 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 or longer was experienced in 6% of patients on pegfilgrastim/plinabulin compared with 95% of those treated with pegfilgrastim alone (P <.001). The rates of bone pain for 4 days or longer occurred in 0% of patients on the combination compared with 33% of those receiving single-agent pegfilgrastim (P <.01).

BeyondSpring noted that procedures are in place to prevent potential bias after the planned interim analysis of the phase 3 trial. Moreover, the developer chose to only be informed by independent statisticians only whether the prespecified P values were met, instead of the exact P values. The DSN in cycle 1, which was the original primary end point prior to a protocol amendment, is the current standard for CIN study regulatory approval.

“We are extremely excited about the topline results from the interim analysis of PROTECTIVE-2 phase 3,” said Lan Huang, MD, CEO and co-founder of BeyondSpring, stated in the press release. “With these breakthrough data, coupled with the consistent data generated across our six independent clinical trials on over 1,200 patients, we aim to cover new ground in developing a treatment that prevents severe neutropenia, instead of just merely reducing it, as with the current standard of care.”

References

1. BeyondSpring Announces Positive Topline Interim Results from PROTECTIVE-2 (Study 106) Phase 3 Trial Evaluating Superiority of Plinabulin in Combination with Neulasta for Chemotherapy-Induced Neutropenia Prevention [news release]; New York, NY. BeyondSpring. Published June 15, 2020. Accessed June 15, 2020. https://bit.ly/3fval2d.
2. 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.