Background: PYR (an irreversible pan-HER inhibitor) plus H+T has promising anti-tumor activity for HER2+ BC, both in the neoadjuvant and 1L settings. Similar to other HER2i, diarrhea is the most common side effect with PYR. Here, we report the outcomes of different anti-diarrhea strategies when HER2+ mBC pts were treated with PYR plus H+T. Material and Methods: Eligible pts received PYR (from C1D7, QD, oral) plus H (8 mg/kg in C1 and 6 mg/kg from C2, IV) and T (75 mg/m2 , IV) on D1 of each 21-day cycle. This study consisted of 5 cohorts. Cohort 1: pts received 400 mg PYR, without loperamide prophylaxis; Cohort 2: pts received 400 mg PYR, with loperamide prophylaxis; Cohort 3: pts received 320 mg PYR, with loperamide prophylaxis; Cohort 4: pts received 320 mg PYR, with use of loperamide for diarrhea management; Cohort 5: PYR dose escalation from 320 mg in the first 3 cycles to 400 mg thereafter was planned, with loperamide prophylaxis. Loperamide for primary prophylaxis of diarrhea was given in the first 2 cycles (C1D7, 4 mg TID; and then 2 mg QID). Results: Totally, 97 pts were enrolled, with 14, 20, 20, 20, and 23 in each cohort. Of them, 0, 35.0%, 30.0%, 15.0%, and 26.1% had received prior antitumor therapy(ies) in the m setting, respectively. Incidence of G3 diarrhea in cohorts with loperamide use was lower than that in the cohort without loperamide prophylaxis (8.7-35.0% in Cohorts 2 to 5 vs. 64.3% in Cohort 1; Table 1). In the 3 cohorts with loperamide prophylaxis, dose escalation of PYR seemed to reduce the incidence of G3 diarrhea compared with a fixed dose of PYR (8.7% in Cohort 5 vs. 30.0% in Cohort 3 and 35.0% in Cohort 2). No G4 or G5 diarrhea was reported. ORR in all pts with measurable lesion was 80.0%, with 85.7%, 83.3%, 78.9%, 80.0%, and 73.7% in Cohort 1 to 5, respectively.