Background: Next generation sequencing of solid tumors will increasingly reveal mutations in cancer genes, including EGFR, HER2 and HER3 mutations. Afatinib is a small molecule, which selectively and irreversibly inhibits EGFR, HER2 and HER4 and which blocks transphosphorylation of HER3. Afatinib monotherapy has shown activity in EGFR and HER2 mutated lung cancer and preclinical activity in rare HER3 mutated lung cancer. In addition, synergy has been reported between afatinib and paclitaxel. The aim of this Belgian multicentre multicohort basket trial is to study the activity of afatinib in cancers of any type with an EGFR, a HER2 or a HER3 mutation and to study the efficacy of adding paclitaxel to afatinib at disease progression, regardless of tumor type. Methods: Methods: This is a multicenter, open-label, phase 2 study of afatinib in three cohorts of patients with advanced cancer harbouring an EGFR mutation, a HER2 mutation or a HER3 mutation. For each cohort an optimal Simon’s two-stage design is used (p0 = 0.10; p1 = 0.30; alpha = 0.05; power 80%). The primary endpoint for each cohort is objective response as determined according to RECIST 1.1. Secondary endpoints are progression free survival, overall survival and toxicity. At progression, paclitaxel weekly will be added to afatinib and response rate, progression free survival and toxicity will be evaluated. In addition to genotype specific response determination, the activity of afatinib in each cancer type will also be evaluated. Rebiopsy will be performed at progression. Major eligibility criteria are: Patients with locally advanced or metastatic cancers harbouring an EGFR, HER2 or a HER3 mutation, excluding EGFR mutated lung cancer. Failure of at least one line of standard systemic therapy. ECOG performance status ≤2. Adequate organ function. This study is in progress and has currently recruited 4 patients (2 lung cancers, 2 breast cancers) in the HER2 mutated cohort. No patients have yet been recruited in the EGFR or HER3 mutated cohorts. EudraCT No.: 2016-003411-34 Clinical trial information: 2016-003411-34.