FDA Grants Priority Review to Plinabulin Plus G-CSF for CIN Prevention

The FDA has granted a priority review to the new drug application (NDA) seeking approval of plinabulin plus granulocyte colony-stimulating factor (G-CSF) for the prevention of chemotherapy-induced neutropenia (CIN).¹

The NDA includes findings from the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577), along with 5 supportive trials that enrolled over 1200 patients. Notably, PROTECTIVE-2 demonstrated that the combination of plinabulin and pegfilgrastim (Neulasta) was 53% more effective in reducing the incidence of CIN compared with pegfilgrastim alone in patients who were receiving chemotherapy.²

The plinabulin regimen resulted in less neutropenia than pegfilgrastim alone, at 21.6% and 46.4%, respectively (P = .0001) in patients with breast cancer who were receiving a chemotherapy regimen that included docetaxel, doxorubicin, and cyclophosphamide (TAC). The addition of plinabulin improved the rate of prevention of grade 4 neutropenia in cycle 1 vs pegfilgrastim alone, going from 13.6% to 31.5% (P = .0015), meeting the primary end point of the trial.

The doublet also reduced the risk of febrile neutropenia by 41% compared with pegfilgrastim alone. Moreover, those in the investigative arm experienced a 50% reduction in the mean duration of profound neutropenia vs those in the control arm, at 0.3 days and 0.6 days, respectively (P = .0004).

“We are pleased that the FDA has accepted with priority review our NDA filing for plinabulin, which is one of the key milestones for this product in 2021. We look forward to continue to work closely with the FDA through the review process,” Lan Huang, PhD, co-founder, chief executive officer, and chairwoman of BeyondSpring Inc., stated in a press release.

In the double-blind, active-controlled, international phase 3 trial, 221 patients were randomized to receive TAC (day 1 dose) in a 21-day treatment cycle in combination with 40 mg of plinabulin (day 1 dose) and 6 mg of pegfilgrastim (day 2 dose; n = 11) or a single dose of pegfilgrastim at 6 mg (day 2 dose; n = 110).

Previously, the addition of plinabulin to pegfilgrastim was found to improve the duration of severe neutropenia (DSN) cycle 1 on days 1 through 8 (absolute neutrophil count [ANC] <0.5 x 109 cells/L; P = .0065), DSN cycle 1 (P = .03); mean ANC nadir cycle 1 (P = .0002), and duration of profound neutropenia cycle 1 (ANC <0.1 x 109 cells/L; P = .0004).³

Full data also indicated that key secondary end points were also met, including DSN cycle 1, days 1 to 8; DSN cycle 1, and mean ANC nadir cycle 1. A lower frequency of grade 4 adverse effects was also reported with plinabulin regimen compared with pegfilgrastim alone, at 58.6% and 80.0%, respectively.

In the phase 2 portion of the trial, the doublet reduced CIN compared with single-agent pegfilgrastim in those given TAC chemotherapy.⁴ Specifically, plinabulin/pegfilgrastim resulted in a 50% rate of grade 3 neutropenia vs 81% with pegfilgrastim alone (P <.05). Moreover, the plinabulin regimen also led to lower rates of grade 4 neutropenia than pegfilgrastim alone, at 38% vs 57%, respectively.

Patients who were given the plinabulin combination also reported less bone pain than those who were given pegfilgrastim by itself. Six percent of patients in the investigative arm vs 95% of those in the control arm experienced bone pain for day 1 or longer (P <.001). Additionally, 0% and 33% of those in the investigative and control arms, respectively, reported bone pain that persisted for 4 days or longer (P <.01).

“Chemotherapy is a very important therapy regimen for [patients with] cancer, even more so with its approval in combination with checkpoint inhibitors. With COVID-19, the National Comprehensive Cancer Network panel had updated the guidelines to potentially double the patient population included in CIN prevention,” Huang added. “If approved, plinabulin and G-CSF combination would be an important new and improved option to prevent CIN for approximately 467,500 [patients with] cancer in the United States annually.”

References

1. BeyondSpring announces US FDA acceptance and priority review of new drug application for plinabulin and G-CSF combination for the prevention of chemotherapy-induced neutropenia (CIN). News release. BeyondSpring Inc. June 1, 2021. Accessed June 1, 2021. https://bit.ly/2SQVl8U
2. 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: phase 3 results from Protective-2 (BPI-2358-106). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PS13-53-01.
3. BeyondSpring announces positive topline results from its PROTECTIVE-2 phase 3 registrational trial of plinabulin in combination with pegfilgrastim for prevention of chemotherapy-induced neutropenia. News release. BeyondSpring Therapeutics. November 16, 2020. Accessed June 1, 2021. https://bit.ly/35BVosZ
4. 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. BeyondSpring Pharmaceuticals. June 15, 2020. Accessed June 1, 2021. https://bit.ly/3fval2d