LUX-Lung 3 is the sixth, and largest, prospective, randomized trial to evaluate targeted EGFR inhibition vs front-line platinum doublet chemotherapy for patients with EGFR mutations. LUX-Lung 3 distinguishes itself from the previous trials (see Table 1) by using afatinib (Gilotrif), a second-generation EGFR inhibitor that binds covalently to EGFR/HER1, HER 2, and HER 4; other studies have examined the first-generation inhibitors erlotinib (Tarceva) and gefitinib (Iressa). Notably, afatinib has in vitro activity against EGFR T790M, which is associated with resistance to gefitinib and erlotinib.

In addition, LUX-Lung 3 is the first trial to use cisplatin and pemetrexed (Alimta) as its comparator chemotherapy arm, the platinum doublet many would select as “best” for fit patients with adenocarcinoma. LUX-Lung 3 also adopted a more “global” approach to enrollment, with patients accrued in Asia, Europe, North/South America, and Australia, in comparison to the other trials evaluating this question, which were conducted exclusively in Asian or European countries.

LUX-Lung 3 reported impressive median progression-free survival and response rates, not only for patients treated with afatinib, but also for those who received cisplatin/pemetrexed. Patient-reported symptoms of cough and dyspnea improved more readily with afatinib than with chemotherapy. However, the vast majority of patients who received afatinib also experienced treatment-related adverse events—diarrhea, rash, and irritation of the skin, mucosa, and nails. There were four afatinib-related deaths. Yet, with supportive measures and dose reductions, fewer patients discontinued afatinib than chemotherapy (52% of patients required one dose reduction and 19% required more than one).

Unanswered Questions

Is it clinically meaningful that LUX-Lung 3 reported longer progression-free survival results with afatinib vs chemotherapy than most of the previous trials comparing EGFR inhibitors to chemotherapy in patients with EGFR mutations? The study authors suggest that afatinib may have achieved longer progression-free survival due to its ability to selectively inhibit EGFR T790M clones in addition to the more common sensitizing mutations—ie, EGFR exon 19 deletion and L858R point mutations.

I think it is still difficult to extrapolate from the existing data about the efficacy of afatinib vs gefitinib or erlotinib. Recall that the patient population in LUX-Lung 3 was different from the others in which this question has been investigated. Furthermore, each trial chose a different comparator chemotherapy regimen. A more clinically instructive trial would be a direct comparison of afatinib and erlotinib.

While that trial may never be done, a step in the right direction is LUX-Lung 7, a trial comparing afatinib to gefitinib for patients with untreated EGFR-mutant adenocarcinoma, currently recruiting patients (NCT01466660). In the meantime, LUX-Lung 3 strengthens the body of evidence supporting front-line targeted EGFR therapy for patients with EGFR mutations. ■

Dr. Johnson is Assistant Professor, Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.