The FDA has issued a complete response letter to the new drug application seeking the approval of plinabulin in combination with granulocyte colony-stimulating factor for the prevention of chemotherapy-induced neutropenia.
The FDA has issued a complete response letter (CRL) to the new drug application (NDA) seeking the approval of plinabulin in combination with granulocyte colony-stimulating factor (G-CSF) for the prevention of chemotherapy-induced neutropenia (CIN).1
The regulatory agency completed their review of the application and has decided that the NDA cannot be greenlighted in its current form. Specifically, they did not find the data from the single registrational phase 3 trial to sufficiently demonstrate the benefit of the agent. They have requested that a second well-controlled trial be conducted to provide the substantial evidence needed to support this indication.
The NDA comprises data from the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577), along with 5 supportive trials that enrolled more than 1200 patients. These findings indicated that the addition of plinabulin to pegfilgrastim (Neulasta) proved to be 53% more effective in reducing CIN incidence vs pegfilgrastim alone in those who were receiving chemotherapy.2
Those who received plinabulin experienced less neutropenia than those who did not, at 21.6% and 46.4%, respectively (P = .0001) in those with breast cancer who were receiving a chemotherapy regimen that comprised docetaxel, doxorubicin, and cyclophosphamide (TAC). Plinabulin also improved the prevention of grade 4 neutropenia in cycle 1 compared with pegfilgrastim alone, meeting the primary end point of the trial; these rates were 13.6% and 31.5%, respectively (P = .0015).
“BeyondSpring strongly believes that plinabulin in combination with G-CSF has significant potential to raise the standard of care in CIN, a devastating side effect of chemotherapy,” Lan Huang, PhD, co-founder, chief executive officer, and chairwoman of BeyondSpring, stated in a press release. “The Company plans to request a meeting with the FDA and remains committed to its goal of bringing plinabulin to [patients with] cancer [who are] in need globally.”
A selective immunomodulating microtubule-binding agent, plinabulin, was designed to trigger the release of the immune defense protein GEF-H1, which results in 2 effects: durable anticancer benefit because of the maturation of dendritic cells activating tumor antigen–specific T cells to target cancer cells, and the early onset of action in CIN prevention following chemotherapy by increasing the number of hematopoietic stem/progenitor cells.
The double-blind, active-controlled, international phase 3 trial enrolled 221 patients who were randomized to TAC (day 1 dose) in a 21-day treatment cycle plus plinabulin at 40 mg (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 combination was found to improve the duration of severe neutropenia (DSN) on days 1 through 8 of cycle 1 (absolute neutrophil count [ANC] <0.5 x 109 cells/L; P = .0065), in cycle 1 (P = .03); the agent also improved the mean ANC nadir in cycle 1 (P = .0002) and duration of profound neutropenia in cycle 1 (ANC <0.1 x 109 cells/L; P = .0004).3
Key secondary end points of the research were also met, with improvements in DSN cycle 1, days 1 to 8 with the addition of plinabulin, as well as in the DSN cycle 1, and mean ANC nadir cycle 1. The plinabulin combination also resulted in fewer grade 4 adverse effects (AEs) vs pegfilgrastim alone, at 58.6% and 80.0%, respectively.
Data from the phase 2 portion of the research indicated that the combination reduced CIN vs pegfilgrastim monotherapy in patients who had received TAC.4 Specifically, the addition of plinabulin resulted in a better rate of grade 3 neutropenia vs pegfilgrastim alone, at 50% vs 81%, respectively (P < .05), and a lower rate of grade 4 neutropenia, at 38% and 57%, respectively.
Patients in the investigative arm also reported less bone pain vs those in the control arm. Rates of bone pain with the plinabulin regimen or pegfilgrastim monotherapy at day 1 or longer were 6% and 95%, respectively (P < .001). Moreover, no patients who received plinabulin experienced bone pain that lasted for 4 days or longer vs 33% of those on the control arm (P < .01).
Previously, plinabulin was granted a breakthrough therapy designation5 and priority review6 for use as a potential option for CIN prevention, in both the United States and China.
Moreover, the addition of plinabulin to docetaxel was found to significantly improve overall survival(OS) when used in the second- or third-line treatment of patients with EGFR wild-type non–small cell lung cancer who had progressed on a previous platinum-based regimen.7 Data from the phase 3 DUBLIN-3 trial (NCT02504489), which were presented during the 2021 ESMO Congress, showed that the combination resulted in a median OS of 10.5 months (95% CI, 9.3-11.9) vs 9.4 months (95% CI, 8.4-10.7) with docetaxel alone (HR, 0.82; 95% CI, 0.68-0.99; P = .0399).
The pharmaceutical company announced that they “remain confident in the efficacy and safety data for plinabulin in combination with G-CSF for the prevention of CIN.” Moreover, the company will be working closely with the regulatory agency to consider the “possible future clinical pathway for CIN, which may include a second study.”