...1.Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic solid tumor, including primary brain tumors2.Subjects with disease types other than breast cancer, biliary tract cancer, non-squamous NSCLC, and cervical cancer: Disease progression on or after the most recent systemic therapy for locally-advanced unresectable or metastatic disease3.Subjects with any breast cancer subtype:a.Must have HER2-mutated disease which does not display HER2 overexpression/amplificationb.Must have progressed on or after ≥1 prior line of treatment (chemotherapy, endocrine therapy, or targeted therapy) for locally-advanced unresectable or metastatic breast cancerc.Subjects with metastatic HR+ HER2-mutated disease must have received a prior CDK4/6 inhibitor in the metastatic setting4.Subjects with biliary tract cancer: must have progressed on or after ≥1 prior line of treatment (chemotherapy, endocrine therapy, or targeted therapy)5.Subjects with non-squamous NSCLC: has relapsed from or is refractory to standard treatment or for which no standard treatment is available6.Subjects with cervical cancer:a.Subjects with metastatic cervical cancer must have progressed on or after ≥1 prior line of systemic therapy (platinum-based chemotherapy with or without bevacizumab) in the metastatic settingb.Subjects with locally advanced unresectable cervical cancer must have progressed on or after ≥1 prior lines of systemic therapy7.Disease demonstrating HER2 alterations (overexpression/amplification or HER2 activating mutations), as determined by local or central testing processed in a Clinical Laboratory Improvement Amendments (CLIA)- or International Organization for Standardization (ISO) accredited laboratory, according to one of the following:a.HER2 overexpression/amplification from fresh or archival tumor tissue or blood utilizing one of the following tests, in subjects with tumor types other than breast cancer, GEC, or CRC:i.HER2 overexpression (3+ immunohistochemistry IHC) (breast or gastric algorithms)ii.HER2 amplification by in situ hybridization assay (fluorescence in situ hybridization [FISH] or chromogenic in situ hybridization signal ratio ≥2.0 or gene copy number >6)iii.HER2 amplification in tissue by next generation sequencing (NGS) assayiv.HER2 amplification in circulating tumor DNA (ctDNA) by blood-based NGS assayb.Known activating HER2 mutations detected in fresh or archival tumor tissue or blood by NGS assay, including:oExtracellular domain: G309A/E; S310F/Y; C311R/S; C334SoKinase domain: T733I; L755P/S; I767M; L768S; D769N/Y/H; Y772; A775; G776; V777L/M; G778; T798; L841V, V842I; N857S, T862A, L869R, H878Y, R896CoTransmembrane/juxtamembrane domain: S653C, I655V; V659E; G660D; R678Q; V697.oSubjects with HER2 activating mutations not listed above may be eligible, if supported by scientific literature and approved by the medical monitor8.Have adequate hepatic function as defined by the following:a.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN) (≤5 × ULN if liver metastases are present)b.Total bilirubin ≤1.5 × ULN. ...

Tucatinib potently inhibits signal transduction downstream of HER2 and HER3 through the MAPK and PI3K/AKT pathways and is selectively cytotoxic in HER2-amplified breast cancer cell lines in vitro. In vivo, tucatinib is active in multiple HER2+ tumor models as a single agent and shows enhanced antitumor activity in combination with trastuzumab or docetaxel, resulting in improved rates of partial and complete tumor regression.