Objective(s):To investigate the efficacy and safety of afatinib in EGFR, HER 2 and HER3 mutated cancers, regardless of cancer type, excluding EGFR mutated non-small cell lung cancer.

Methodology:Open label, genomic driven trial (basket trial)

No. of patients total entered:Optimal Simon two stage design for the three genetic driven cohorts: 10 patients will be enrolled per cancer type in the first stage and an additional 19 in the second stage (maximum total 87 patients)

Indication : cancers harbouring an EGFR mutation(excluding non-squamous non- small cell lung cancer, a registered indication), a HER2 mutation or a HER3 mutation

Test product(s) : Afatinib At progression paclitaxel will be added for those patients that have no contra-indications

dose: Starting dose of afatinib at 40 mg/day. Dose increase to 50 mg in the absence of adverse events. Stepwise dose reduction to 30,20, 10 mg/day according to drug-related adverse events.

At progression, addition of paclitaxel 80 mg/m2 weekly 3w/4 to afatinib 40 mg/day .

mode of admin. : Oral for afatinib Intravenous for paclitaxel

Duration of treatment: Continuous treatment until progression or unacceptable adverse events or withdrawal of consent.

At disease progression, add paclitaxel until progression or unacceptable adverse event or withdrawal of consent if no contra-indications.

Criteria for efficacy: Primary Endpoint:

• Response rate (CR+ PR) via RECIST v1.1

Secondary Endpoints:

• Disease control rate (CR+PR+SD)
• Progression free survival
• Overall survival
• To correlate tumor response with findings on tumor biopsies
• To investigate resistance mechanisms
• response rate (CR+ PR) determined by RECIST and progression free survival on the combination therapy of afatinib and paclitaxel

Criteria for safety: Incidence and intensity of adverse events according CTCAE v4.0

Inclusion Criteria:

• Women and men with locally advanced or metastatic cancers harboring either an activating EGFR mutation or a HER2 mutation or a HER3 mutation
• Failure of at least one line of standard systemic therapy
• No eligibility for other open genomic driven phase I, II or III trial available for these tumor genotypes
• ECOG performance status ≤2
• Patient with a life expectancy >3 months
• Patients able to provide written informed consent prior to enrollment into the clinical trial.
• Adequate organ function

Exclusion Criteria:

• Non squamous non-small cell lung cancer harbouring an EGFR mutation (registered indication)
• Chemotherapy, biological therapy or investigational agents within four weeks prior to the start of study treatment
• Known hypersensitivity to afatinib or the excipients of any of the trial drugs
• Prior treatment with afatinib