Clinical Research Directory

Inclusion Criteria: * Patients must have met applicable eligibility criteria in the Master MATCH Protocol prior to registration to treatment subprotocol * Patient's tumor must have activating HER2 mutation, as determined via the MATCH Master Protocol * Additionally, any in-frame insertions in exon 20 will be considered an activating mutation * Patients must have an electrocardiogram (ECG) within 8 weeks prior to treatment assignment and must have no clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, third degree heart block) * Patients with known left ventricular dysfunction must have echocardiogram (ECHO) or a nuclear study (multiple-gated acquisition \[MUGA\] or First Pass) within 4 weeks prior to registration to treatment and must not have left ventricular ejection fraction (LVEF) \< institutional lower limit of normal (LLN). If the LLN is not defined at a site, the LVEF must be \> 50% for the patient to be eligible * NOTE: Pre-treatment LVEF determination in patients without known left ventricular dysfunction is NOT otherwise required. * Patients must have =\< grade 1 diarrhea at baseline * Patients must have =\< grade 1 renal function as defined below: * Creatinine =\< 1.5 x normal institutional limits OR * Measured creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal or as calculated by the Cockcroft-Gault equation * This should be strictly followed and will override the MATCH Master Protocol requirements Exclusion Criteria: * Patients must not have known hypersensitivity to afatinib or compounds of similar chemical or biologic composition * Patients with a history of interstitial lung disease will be excluded * Patients must not have had prior treatment with any of the following tyrosine kinase inhibitors (TKIs), which have known activity against HER2 kinase: * Neratinib * AC-480 (BMS-599626) * AST 1306 * Canertinib (CI 1033) * CUDC-101 * Lapatinib * TAK285 * Afatinib * AEE 788 * AZD8931 * CP-724714 * Dacomitinib * Pelitinib * Patients with non-small cell lung cancer will be excluded