Gefi tinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on fi rst-line gefi tinib (IMPRESS): a phase 3 randomised trial

Summary Background Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefi ned. We aimed to assess the effi cacy and safety of continuing gefi tinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to fi rst-line gefi tinib. Methods The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacifi c region. Eligible patients were aged at least 18 years with histologically confi rmed, chemotherapynaive, stage IIIB–IV EGFR-mutation-positive advanced NSCLC with previous disease control with fi rst-line gefi tinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1:1) by central block randomisation to oral gefi tinib 250 mg or placebo once daily in tablet form; randomisation did not include stratifi cation factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m² plus pemetrexed 500 mg/m² on the fi rst day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179. Findings Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefi tinib group and 132 to the placebo group. At the time of data cutoff (M ay 5, 2014), 98 (74%) patients had disease progression in the gefi tinib group compared with 107 (81%) in the placebo group (hazard ratio 0·86, 95% CI 0·65–1·13; p=0·27; median progression-free survival 5·4 months in both groups [95% CI 4·5–5·7 in the gefi tinib group and 4·6–5·5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefi tinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefi tinib group and fi ve [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefi tinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events.