This is a first-in-human (FIH), phase Ⅰ/Ⅱa, open-label, multicenter clinical study of HMPL-A251 monotherapy in adult participants with unresectable, advanced or metastatic HER2-expressing solid tumors.

• To evaluate the safety and tolerability and to determine the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE) of HMPL-A251 in participants with previously treated HER2+ solid tumors
• To characterize the safety and preliminary efficacy of HMPL-A251 at RDEs to determine recommended dose(s) for phase 2 (RP2D) or phase 3 (RP3D) in participants with selected HER2-expressing solid tumors

Inclusion Criteria:

1. Histologically confirmed unresectable advanced or metastatic disease.
2. Have at least one measurable lesion per RECIST v1.1;
3. Life expectancy ≥ 12 weeks;
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1;
5. Weight ≥ 35 kg;

Exclusion Criteria:

1. An established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus.
2. Use of strong inhibitors of cytochrome P450 3A4 enzyme (CYP3A4), and inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) within 5 elimination half-lives or 2 weeks (whichever is longer) before the first dose of study drug;
3. Toxicity from prior anti-tumor therapy has not recovered to Grade 1 or baseline prior to the first dose of study drug (except alopecia). Participants with chronic Grade 2 toxicities may be eligible after discussion between the investigator and Sponsor Medical Monitor (e.g., Grade 2 chemotherapy-induced neuropathy);
4. Baseline blood amylase or lipase exceeds the normal range and are judged by the investigators to be clinically significant;
5. Spinal cord compression, leptomeningeal disease, or clinically active central nervous system (CNS) metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms;
6. Major surgery within 28 days prior to the first dose of study drug. Participants must have recovered adequately from the toxicity and/or complications from the intervention prior to the first dose of study drug(s);