Background: The combining of HER2 targeted therapy and endocrine therapy (ET) has been demonstrated to be a reasonable therapeutic approach and recommended for highly selected patients (pts) with HR+/HER2+ MBC. CDK4/6 inhibitors could sensitize HER2 targeted therapies in multiple patient-derived xenograft models and delay tumor recurrence in a transgenic model of HER2+ breast cancer. The aim of this phase Ib/II study was to investigate the safety and efficacy of adding a CDK 4/6 inhibitor to the combination. Primary phase Ib results were reported. Methods: Patients with HR+/HER2+ MBC who were eligible for first- or second-line treatment were enrolled, and orally received letrozole, pyrotinib, and a novel CDK4/6 inhibitor SHR6390. In the “3+3” dose-exploring phase, letrozole was given at a fixed dose of 2.5mg/d. Pyrotinib and SHR6390 were initially given at a dose of 400mg/d and 125 mg/d respectively (Level _I). If the initial dose level could be tolerated, subsequent pts were assigned to the higher level (Level _H) with pyrotinib 400 mg/d and SHR6390 150mg/d; otherwise, simultaneously to Level _L1 with pyrotinib 400 mg/d, and SHR6390 100 mg/d, or Level _L2 with pyrotinib 320mg/d, and SHR6390 125 mg/d. Primary endpoints of phase Ib included dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and efficacy. Results: As of 4 Jan 2021, a total of 15 pts (Level _I 5 pts, Level _L1 6 pts, and Level _L2 4 pts) were enrolled in phase Ib and received the study treatment. 6 of them had received systemic therapies in the advanced stage, and 10 of them had been previously treated with trastuzumab. The most frequent grade 3/4 adverse events included neutrophil count decreased (n = 6), white blood cell count decreased (n = 4), stomatitis (n = 4) and diarrhea (n = 3). 3 pts (2 in Level _I, and 1 in Level _L1) had experienced DLTs, all of which were grade 3 stomatitis. Of the 15 pts evaluable for response, 7 pts（46.7%） had achieved confirmed partial responses (1 in Level _I, 3 in Level _L1, and 3 in Level _L2) and 7 pts (46.7%) had stable disease. Based on DLTs and clinical efficacy, pyrotinib 320mg/d, SHR6390 125mg/d, and letrozole 2.5mg/d was declared as RP2D. Conclusions: Data from phase Ib showed the triplet combination of pyrotinib, letrozole, and SHR6390 had an acceptable safety profile and encouraging preliminary efficacy, potentially offering a chemotherapy sparing treatment option for patients with HR+/HER2+ MBC. Enrollment on phase II is ongoing. Clinical trial information: NCT03772353.