• 100 patients with EGFR-mutant, advanced NSCLC with acquired resistance to EGFR TKIs treated with afatinib/cetuximab
• 30% confirmed response rate, similar in T790M-positive and T790M-negative tumors, and a 75% disease control rate
• Toxicity was primarily Grade 1 and 2 AEs, with low rates of Grade ≥3 rash or diarrhea

Although most patients with EGFR tumor mutations respond to EGFR TKIs, disease progression is inevitable, and this study is rare in that it demonstrated treatment benefit in that setting, in this case with “total EGFR blockade.” Originally presented at ASCO 2011 and then updated at ESMO 2012, this encouraging effort documents the impressive clinical activity of the combination of the EGFR antibody cetuximab with the irreversible EGFR TKI afatinib. Importantly, responses were observed in patients with difficult-to-treat T790 mutations, which represented more than half the population of the study. Although there has been concern about dermatologic toxicity with the combination, the regimen was considered tolerable and surprisingly effective, with most patients experiencing tumor shrinkage and 30% partial responses. This encouraging combination is now being integrated rapidly into new and planned trials in both the relapsed/refractory and the up-front settings.