Comparison of pegfilgrastim (Peg), plinabulin (Plin), and the combination for chemotherapy (Chemo) induced neutropenia (CIN) prevention: Rationale for the combination.

Abstract

e12030 Background: Peg is used for prevention of CIN. Plin, a novel non-GSF small molecule with anti-cancer activity has equal efficacy against CIN as Peg; Plin does not cause bone pain and mitigates thrombocytopenia and the immune suppressive hematologic profile (Blayney ASCO, ESMO, SITC 2018). Plin has a mechanism of action (MoA) consistent with IL-6 -dependent granulocyte progenitor cell expansion, increased neutrophil demargination and transit from the bone marrow (Suwa, Am J Physiol 2000; Blayney SLB/IEIIS 2018). In single agent (SA) Peg and Plin phase (Ph) 2 data, CIN with Peg occurs in the 1st week (~day (D) 7) post Chemo, and with Plin in the 2nd week (~ D15) post Chemo, presumably due to different MoAs (NCT03102606, NCT03294577). We evaluated whether combining these two agents/MoAs would protect against CIN throughout the entire Chemo cycle (C). Methods: Early stage Breast Cancer Ph 2 patients received high febrile neutropenia (FN) risk TAC (docetaxel, doxorubicin, cyclophosphamide) and either SA standard dose Peg 6 mg (Peg; n=22) or SA Plin (20 mg/m2; n= 15), or Peg 6mg combined with Plin 20 mg/m2 (Peg/Plin; n=16). Peg was given ~24 hrs after TAC, and Plin ~30 min after TAC. Blood draws for ANC were taken daily from predose to Day (D)15, and validated bone pain assessments were done from predose D1 to D8 in C1. Results: On D7 (week 1) of C1, Plin but not Peg maintained mean ANC within normal; P<0.0001 for Plin vs Peg mean ANC. On D15 (week 2 of C1) Peg, but not Plin maintained ANC within normal; P<0.0001 for Peg vs Plin mean ANC. Plin added to Peg maintained mean and median ANC within normal throughout C1. (ANC normal range is 1.5 - 8 x10E9/L.) Frequency of Grade (Gr) 4 and 3/4 CIN was ~35 % lower (P<0.05 for Gr3/4) and median ANC nadir was 2 times higher (1.00 vs 0.46) in Peg/Plin vs Peg in C1. FN occurred in 1 pt each with Peg and Peg/Plin. Incidence of bone pain was 95% vs 6% with Peg vs Peg/Plin (P<0.0001). Conclusions: Adding Plin to standard dose Peg offers superior CIN protection throughout the entire high FN risk Chemo cycle, while almost eradicating bone pain vs Peg alone. Clinical trial information: NCT03294577 .[Table: see text]