Background: Pyrotinib (an irreversible pan-ErbB inhibitor) combined with SHR6390 (a novel oral small molecule CDK4/6 inhibitor) had shown anti-tumor activity in pyrotinib-resistant PDX models. A phase Id trial was conducted to evaluate the safety and efficacy of pyrotinib combined with SHR6390 in the treatment of refractory advanced HER2 positive gastric cancer or solid tumors (NCT03480256). Methods: A standard “3+3” design was conducted in this trial. Patients (Pts) received pyrotinib (qd, d1-28; q4w) combined SHR6390(qd, d1-21; q4w) at dose of 400/100mg (cohort A), 320/100mg (cohort E) and 400/75mg (cohort F) until disease progression or intolerable toxicity. The primary endpoint was safety and maximum tolerated dose. Results: From Sep. 2019 to Dec. 2020, 19 pts (14 gastric cancer, 3 colorectal cancer, 2 other solid tumors) were enrolled (A: n = 6; E: n = 6; F: n = 7). 15 pts received and progressed on Herceptin before enrollment. In cohort A, one DLT was observed (Grade 4 neutropenia), and another 3 pts suffered G3 neutropenia, anemia or thrombocytopenia. Considered of safety, the dose levels were decreased and designed as cohort E and F. In cohort E, one DLT was observed (G4 neutropenia). No DLT was observed in cohort F. The most common hematologic toxicities were neutropenia (95%), anemia (74%) and thrombocytopenia (74%). The most common non-hematologic toxicities were diarrhea (53%), mucositis (26%) and nausea (21%). The most common G3/4 AEs were leukopenia (37%) and anemia (16%). No G3/4 non-hematologic toxicity was observed. 18 pts were included in efficacy analysis. The overall response rate was 38.9%, with 7 PR (A: n = 3; E: n = 2; F: n = 2) and 7 SD. The median PFS was 3.83 months, with 2 pts received treatment over 12 months (A: n = 1; F: n = 1). Conclusions: Pyrotinib combined with SHR6390 had shown acceptable safety profile and encouraging efficacy in refractory advanced HER2 positive solid tumors. Further study would be carried out at the dose in cohort A. Clinical trial information: NCT03480256