Patients with advanced non–small cell lung cancer (NSCLC) who have wild-type EGFR fare better with conventional chemotherapy instead of tyrosine kinase inhibitors (TKIs) as first-line treatment [Lee JK et al. JAMA. 2014]. In contrast, 70% of patients with NSCLC harboring EGFR mutations show tumor regression from the EGFR TKIs erlotinib and gefitinib [Jackman D et al. J Clin Oncol. 2010]. The majority of these patients eventually acquire resistance to erlotinib and gefitinib, contributing to disease progression.

Because of tumor cell heterogeneity, inclusion of an EGFR TKI in postprogression therapy improves outcomes. For instance, a combination of gefitinib or erlotinib plus pemetrexed has been shown to improve outcomes in 27 patients with EGFR mutation-positive NSCLC who had disease progression on gefitinib/erlotinib monotherapy; an overall response rate of 25.9% (95% CI, 62.1% to 95.5%) was achieved with the combination [Yoshimura N et al. J Thorac Oncol. 2013]. Afatinib, an irreversible ErbB TKI (including EGFR, HER2, HER4), increases survival outcomes as monotherapy and overcomes resistance in patients who had disease progression after gefitinib/erlotinib [Katakami N et al. J Clin Oncol. 2013; Sequist LV et al. J Clin Oncol. 2013].

Martin Schuler, MD, West German Cancer Center, Essen, Germany, shared results of LUX-Lung 5 [Schuler M et al. Ann Oncol. 2015], a randomized, open-label, 2-stage design, phase 3 trial that assessed continued afatinib plus paclitaxel vs investigator’s choice of single-agent chemotherapy (ICC). The study consisted of 2 parts. In part A, patients with NSCLC who had failed ≥ 1 line of chemotherapy (including platinum/pemetrexed) and erlotinib/gefitinib after ≥ 12 weeks of treatment (n = 1154) were treated with afatinib 50 mg/d. In part B, patients who had been treated with afatinib for ≥ 12 weeks followed by disease progression after part A of the study were eligible to be randomized 2:1 to afatinib 40 mg/d plus paclitaxel 80 mg/m²/wk or ICC. The primary end point was progression-free survival, whereas the secondary end points included overall survival, objective response rate, safety, and health-related quality-of-life outcomes.

Of the 1154 patients who had disease progression on erlotinib/gefitinib and afatinib 50 mg/d, 202 patients derived ≥ 12 weeks of benefit on afatinib monotherapy. These selected patients were randomized 2:1 to receive afatinib plus paclitaxel (n = 134; 40 mg/d; 80 mg/m²/wk) or ICC (n = 68). Baseline patient characteristics (included sex, age, ECOG performance status, race, smoking status, clinical stage, and tumor histology) were well balanced between both arms. Progression-free survival increased from 2.8 months with ICC to 5.6 months with afatinib plus paclitaxel (HR, 0.60; 95% CI, 0.43 to 0.85; P = .0031). Afatinib plus paclitaxel, as fourth-line treatment, was also more effective than ICC in reducing tumor size (15.1% vs 1.2%).

Although disease control rate (OR, 3.4; P < .0001) and objective response rate (OR, 3.1; P = .0049) were superior with afatinib plus paclitaxel, overall survival did not show any statistical difference between the 2 treatment arms (12.2 months in each arm; HR, 1.00; 95% CI, 0.70 to 1.43; P = .994), possibly attributed to differences in postprogression treatment between the arms. More patients in the ICC arm received 2 postprogression lines of therapy compared with the afatinib plus paclitaxel arm (36% vs 15%).

Despite prolonged exposure time to afatinib plus paclitaxel compared with ICC (133 vs 51 days), discontinuation due to treatment-related adverse events was low, and quality of life was comparable between arms (HR, 0.97; 95% CI, 0.6 to 1.5). The most common adverse events in afatinib plus paclitaxel vs ICC arms included diarrhea (53.8% vs 6.7%), alopecia (32.6% vs 15%), and asthenia (27.3% vs 28.3%).

Prof Schuler concluded that afatinib plus paclitaxel was superior to ICC and improved outcomes in patients who had an acquired resistance to erlotinib/gefitinib and had disease progression on afatinib monotherapy after an initial benefit. It should, however, be noted that this study did not include a mutational analysis. Future studies should include a mutational status analysis (including EGFR mutations) to evaluate how the efficacy of treatments differs based on mutational status.