Background: Peg is standard of care (SoC) for the prevention of CIN. Peg’s mechanism of action leaves patients vulnerable to FN in week 1 of the chemo cycle(C), as the absolute neutrophil count (ANC) does not normalize until week 2. Plin is a first-in-class, non-G-CSF small molecule agent, which received breakthrough designation from FDA in CIN. It prevents CIN by protecting progenitor cells in bone marrow from chemo assault and has normal ANC in week 1 (Blayney JAMA Onc 2020). Phase 2 testing showed the combination of Plin and Peg achieved CIN protection throughout the entire cycle vs Peg alone (Blayney: St Gallen 2019, ASCO 2019). Methods: Plin is given on Day (D)1 after Chemo, has a favorable safety profile, and also has anticancer activity. A separate phase 3 study evaluating Plin as an anticancer agent (DUBLIN-3; NCT02504489) in NSCLC pts is underway, with anti-cancer results in OS expected in 2021. In PROTECTIVE-2 (Study 106; NCT0329457), we added Plin (on D1) to Peg (on D2), testing superiority of the combination for CIN prevention vs Peg alone. Study 106, is a global multicenter randomized (1:1) double-blind study to evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Placebo (Plac) (Arm 2) in preventing Severe Neutropenia (N), (defined as ANC <0.5 cells × 10E9/L) in early-stage BC (node positive or node negative with a high risk of recurrence) pts. 221 pts with ECOG status 0 or 1 received Docetaxel (75 mg/m2), Doxorubicin (50 mg/m2), and Cyclophosphamide (500 mg/m2) (TAC) on D1 for four 21 D cycles and study treatment. Central laboratory ANC was assessed at Covance in Cycle 1 (C1) on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Primary objective was to compare the percentage (%) of pts with a Duration of Severe Neutropenia (DSN) of 0 days [that is % of pts with no Grade (Gr) 4 neutropenia (N)] in C1 in each arm. Key secondary endpoints were DSN and ANC Nadir in C1. We also evaluated safety (AE frequency and Grade). Conclusions: Adding Plin to Peg offers superior CIN protection compared to Peg alone and also has a superior safety profile by lowering over 20% of grade 4 AE. The effect size of the CIN protection in the combination is also correlated to clinical meaningful FN reduction compared to peg alone. Clinical trial information: NCT03531099