ABSTRACT Background Many patients (patients) with epidermal growth factor receptor mutation-positive (EGFR M+) non-small-cell lung cancer (NSCLC) respond to the EGFR tyrosine kinase inhibitor gefitinib (G), but later develop ‘acquired resistance’. Optimal management strategies for such patients have not been defined. The Phase III, double-blind Iressa Mutation Positive Multicentre Treatment Beyond ProgRESsion Study (IMPRESS; NCT01544179) will assess the efficacy and safety of continuing G in addition to cisplatin and pemetrexed (cis/pem) vs cis/pem alone in patients with EGFR M+ advanced NSCLC who progressed on first-line G. Methods Patients (aged ≥18 years [≥20 years in Japan]) with cytologically or histologically confirmed, chemotherapy-naive, EGFR M + , locally advanced or metatstatic NSCLC, who initially achieved a tumor response or stable disease with a ≥6-month course of first-line G before disease progression, will be enrolled at ∼100 centers in Europe and Asia-Pacific, and randomized to G 250 mg/day plus cis/pem (recommended doses: cis 75 mg/m2, pem 500 mg/m2; ≤6 cycles), or placebo plus cis/pem. The primary objective is to evaluate PFS, defined using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, assessed radiologically every 6 weeks post randomization. It is expected that 250 patients will be randomized and followed for PFS until 190 progression events have occurred. The primary data cut off will be at ∼190 PFS events based on 90% power to demonstrate superiority of G plus cis/pem versus placebo plus cis/pem at a 2-sided 5% significance level assuming a hazard ratio of 0.63. Secondary end points will be overall survival (OS; analysed at the time of primary (PFS) analysis [estimated ∼125 OS events, i.e. 50%] and additional final OS analysis at ∼175 OS events), objective response rate, disease control rate, disease-related symptoms and health-related quality of life (Functional Assessment of Cancer Therapy for Lung Cancer [FACT-L] questionnaire), safety and tolerability. Biomarker analyses (including T790M EGFR mutation and cMET amplification) and health economic assessments will also be carried out (pre-planned exploratory objectives). Conclusions Results from IMPRESS should test the hypothesis of possible benefit of continuing G, in combination with chemotherapy, in patients with EGFR M+ NSCLC, beyond progression on first-line G.