Rapid Readouts: Final Results From the Phase 3 PROTECTIVE-2 Trial

Douglas W. Blayney, MD, discusses data from the following presentation:

• Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention.(Blayney, ASCO 2021, Abstract 533)
  • The objective of this study is to report the final results of the combination treatment of Plin and Peg compared with Peg alone inpatients with breast cancer with chemotherapy that have an increased risk for high febrile neutropenia from the phase 3 PROTECTIVE-2 trial (NCT03294577).
  • Phase 3 superiority trial:
    • Comparator arm: Docetaxel, Doxorubicin, and Cyclophosphamide + Plin (40 mg) + Peg (6 mg) on day 1 of cycle 1
    • Control arm: Docetaxel, Doxorubicin, and Cyclophosphamide + Peg (6 mg)on day 1 of cycle 1
    • Primary end point: percentage of patients with no grade 4 neutropenia during cycle 1 in each treatment arm
    • Secondary end point: days of severe neutropenia (DSN) and absolute neutrophil count (ANC) nadir
  • Conclusions: Efficacy
    • Plin is a first-in-class, selective immunomodulating microtubule-binding agent thatdemonstrated significantly meaningful clinical benefits in all explored end points.
      • The combination treatment of Plin and Peg (n = 111) protected 31.53% of patients from rade 4 neutropenia compared with 13.64% of patients treated with Peg alone (n = 110) in cycle 1 (P = .001).
      • Clinically, febrile neutropenia was noted in 3.60% of patients treated with the combination of Plin and Peg vs 6.36% of patients treated with Peg alone in cycle 4. ANC benefit of the combination treatment improves clinical benefit by nearly 50%.
      • Treatment with Plin and Peg resulted in significantly lower rates of DSN compared with Peg treatment alone from days 1 to 15 (1.24 and 1.51 days, respectively; P = .03). This benefit was noted during the first week of treatment (days 1-8) with 1.1 vs 1.4 DSN in the combination arm vs Peg alone, respectively (P = .006).
      • ANC nadir values were significantly improved for the combination arm vs Peg treatment alone (0.54 and 0.31, respectively; P = .0002).
      • The duration of febrile neutropenia was 1.25 and 2.28 days for Plin and Peg treatment vs Peg treatment alone. Notably, not all patients in the combination arm required hospitalization compared with those treated with Peg only (75% and 100%, respectively).
  • Conclusions: Safety and Quality of Life
    • The adverse event (AE) profile was decreased with the combination treatment of Plin and Peg.
      • There were 20% lower rates of grade 4 treatment-related AEs with the combination treatment.
      • A significantly lower rate of bone pain AEs was noted in the combination treatment arm (P = .03).
    • The combination treatment of Plin and Peg greatly decreased the severity of AEs that are often associated with TAC treatment.
    • Safety results in the PROTECTIVE-2 trial were similar to those seen in the phase 2 trial of the combination of Plin and Peg treatment
    • In the PROTECTIVE-2 trial, the combination of Plin and Peg demonstrated superior CIN protection vs Peg treatment alone, resulting in increased rates of neutrophils and diminished rates of AEs and of associated treatment toxicities.