• Phase III study (N = 345) of 1^st-line afatinib vs cisplatin/pemetrexed in EGFR-mutant advanced NSCLC
• Median PFS 11.1 vs 6.9 mo, ORR 56% vs 23%
• Rash, diarrhea and stomatitis common with afatinib, but patient-reported outcomes favored afatinib with better control of cough, dyspnea and pain

Afatinib is an irreversible EGFR TKI developed in the hope that it would offer greater activity than erlotinib and gefitinib. This study is similar to prior trials with reversible agents and compares chemotherapy — in this case cisplatin/pemetrexed — to afatinib as first-line therapy. Not surprisingly, short-term variables were once again improved with the TKI, which supported afatinib's recent approval by the FDA. Interestingly, at this point, aside from the early evidence of synergy with cetuximab, it is difficult to determine whether a major difference exists between irreversible and reversible agents. However, for reasons that are unclear, erlotinib and gefitinib add no benefit when combined with EGFR antibodies, so this may turn out to be important. But clearly additional studies are needed to determine the optimal sequence and/or role of these and other systemic strategies.