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November 16, 2020 - The combination of plinabulin and pegfilgrastim showed a statistically significant improvement in the rate of prevention of grade 4 neutropenia versus pegfilgrastim alone in patients with cancer undergoing chemotherapy.
The combination of plinabulin and pegfilgrastim (Neulasta) showed a statistically significant improvement in the rate of prevention of grade 4 neutropenia versus pegfilgrastim alone in patients with cancer undergoing chemotherapy, according to full topline results of the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577).1
The full findings reported that the improvement in preventing grade 4 chemotherapy-induced neutropenia (CIN) was statistically significant in cycle 1 at 31.5% with the combination versus 13.6% with pegfilgrastim alone (P = .0015), and key secondary end points were also met, including duration of severe neutropenia (DSN) cycle 1 D1 to 8, DSN cycle 1, and mean absolute neutrophil count (ANC) nadir cycle 1.
“These data clearly demonstrate the potential for this combination to offer superior therapy compared to standard of care in the prevention of CIN,” said lead study author Douglas W. Blayney, MD, professor of medicine at the Stanford University School of Medicine. “With current therapy, grade 4 neutropenia still occurs in more than 80% of patients after chemotherapy, primarily in week 1 after chemotherapy, which increases emergency room visits and hospitalizations due to infection and febrile neutropenia. Grade 4 neutropenia is also associated with increased mortality and reduced long-term survival due to reduction, delay, or interruption of chemotherapy.”
In September 2020, the FDA granted a breakthrough therapy designation to the combination of plinabulin, which is a differentiated immune and stem cell modulator, in combination with pegfilgrastim for the treatment for patients with chemotherapy-induced neutropenia. The designation for plinabulin was based on clinical evidence from PROTECTIVE-2 trial and other CIN studies.2 China’s National Medical Products Administration (NMPA) also granted plinabulin breakthrough status in September 2020.
In the double-blind, active-controlled, international, phase 3 PROTECTIVE-2 study, 221 patients were randomized to receive docetaxel, doxorubicin, and cyclophosphamide (day 1 dose) in a 21-day cycle along with 40 mg of plinabulin (day 1 dose) and 6 mg pegfilgrastim (day 2 dose; n = 111) versus a single 6-mg dose of pegfilgrastim (day 2 dose; n = 110).
Results showed that pegfilgrastim also improved the following secondary end points: DSN cycle 1 on days 1 through 8 (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).
Moreover, there was a lower frequency of grade 4 adverse events with the combination versus pegfilgrastim alone, at 58.6% and 80.0%, respectively.
In the phase 2 portion of the trial, the combination resulted in a reduction in CIN compared with pegfilgrastim monotherapy in patients who received TAC chemotherapy.3 Here, rates of grade 3 neutropenia were 81% versus 50% in the control and investigational arms, respectively (P <.05). Lower rates of grade 4 neutropenia were also observed in the combination arm compared with the monotherapy arm, at 38% vs 57%, respectively.
Moreover, patients who received treatment with the plinabulin combination experienced less bone pain compared with those who received single-agent pegfilgrastim. Bone pain for day 1 or longer was reported in 6% of those on the combination versus 95% of those on the monotherapy (P <.001). Rates of bone pain that persisted for 4 days or longer were 0% vs 33% in the investigational and control arms, respectively (P <.01).
The PROTECTIVE-2 results were further supported by other CIN studies that were conducted, data of which showed the early onset action of agent in week 1 with regard to neutrophil protection in various cancer types and several chemotherapies.
“We are pleased to have received breakthrough therapy designation from both the US FDA and China NMPA for the plinabulin combination in CIN, underscoring the unmet medical need and potential benefit of the combination,” said Ramon Mohanlal, MD, PhD, chief medical officer and executive vice president of Research and Development at BeyondSpring Pharmaceuticals, the developer of plinabulin. “We are working with regulatory agencies on the NDA submission, which is expected in [quarter 1 of] 2021 and have also begun preparation for commercialization. In addition to plinabulin being developed as a treatment option for the prevention of CIN, it is also being investigated as a direct anticancer agent in a global phase 3 trial of plinabulin + docetaxel for non-small cell lung cancer, with final data read-out in [the first half of] 2021.”