Three randomized, open-label, multinational, phase 2b  or phase 3 [17, 18] trials have compared the efficacy of oral afatinib with that of gefitinib (LUX-Lung 7) , pemetrexed + cisplatin (LUX-Lung 3)  or gemcitabine + cisplatin (LUX-Lung 6)  in the first-line treatment of patients with EGFRactMUT+ advanced lung adenocarcinoma. Eligible patients had stage IIIB or IV disease that was EGFRactMUT+, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, measurable disease and adequate organ function. Data for afatinib in this setting are also now available from real-world studies [19,20,21] and a noncomparative phase 3b trial reflective of real-world practice .
Compared with gefitinib
First-line treatment with afatinib prolonged progression-free (PFS) and time to treatment failure (TTF) to a significantly greater extent than gefitinib in both the primary  and updated  analysis of these coprimary endpoints in LUX-Lung 7 (Table 2). By contrast, median OS (co-primary endpoint) did not significantly differ between the treatment groups at the time of the primary  or updated  OS analysis (Table 2), although LUX-Lung 7 was not powered to show a between-group difference (BGD) in this outcome. The objective response rate (ORR; assessed by independent review) was significantly (p < 0.01) higher with afatinib than with gefitinib [16, 23], including in the updated analysis (72.5 vs 56.0%) .
Subgroup analyses were generally consistent with these findings. PFS [16, 25] and TTF  favoured afatinib over gefitinib across various prespecified patient subgroups (including EGFR mutation type, ethnic origin, sex, presence or absence of brain metastases, ECOG PS, age < 65 or ≥ 65 years)  and exploratory subgroups (age < 75 or ≥ 75 years) . OS generally did not significantly differ between the treatments across the prespecified subgroups, although it was significantly more favourable with afatinib than gefitinib in patients aged < 65 years (p = 0.0228 for age interaction) . Of note, afatinib and gefitinib recipients with the Leu858Arg mutation had a median PFS of 10.9 and 10.8 months  and a median OS of 25.0 and 21.2 months , and the corresponding values in recipients with Del19 were 12.7 and 11.0 months (PFS)  and 30.7 and 26.4 months (OS) .
Afatinib dose reduction did not appear to affect PFS, with no significant difference between patients receiving afatinib < 40 mg once daily and those receiving afatinib ≥ 40 mg once daily . The afatinib dosage was reduced to 30 mg once daily in 39% of patients, with 13% experiencing a further dose reduction to 20 mg once daily .
Health-related quality of life (HR-QOL) did not significantly differ between afatinib and gefitinib, as measured by changes from baseline to the end of follow-up (median 56 weeks) in EuroQoL-5D health status self-assessment questionnaire and EuroQol EQ visual analogue scale scores .
In a post hoc analysis of the patients (19 of 160; i.e. 12%) who remained on afatinib for ≥ 3 years (i.e. long-term responders), the ORR was 89% and there were too few deaths during the follow-up (median 42.1 months) for median OS to be calculated. Baseline characteristics of these patients were generally consistent with those of the overall trial population, although numerically more of the long-term responders had Del19 .
Compared with chemotherapy
First-line treatment with afatinib prolonged PFS to a significantly greater extent than pemetrexed + cisplatin  or gemcitabine + cisplatin  in the LUX-Lung 3  and 6  trials (primary endpoint; Table 2). The ORR was also significantly (p ≤ 0.001) higher with afatinib than with pemetrexed + cisplatin (56 vs 23%)  or gemcitabine + cisplatin (67 vs 23%) , with the median duration of response of 11.1 versus 5.5 months with afatinib and pemetrexed + cisplatin in LUX-Lung 3 , and 9.7 versus 4.3 with afatinib and gemcitabine + cisplatin in LUX-Lung 6 . The median duration of OS did not significantly differ between afatinib and either comparator regimen (Table 2) .
In subgroup analyses of these trials, PFS generally favoured afatinib over chemotherapy across various patient subgroups, including ethnic origin , sex [17, 18], age (< 65 or ≥ 65 years) [17, 18] and ECOG PS [17, 18]. Similarly, patients with common EGFR mutations (i.e. Del19 or Leu858Arg) had significantly (p ≤ 0.001) longer median PFS with afatinib than with chemotherapy in both LUX-Lung 3 (13.6 vs 6.9 months)  and LUX-Lung 6 (11.0 vs 5.6 months)  in prespecified analyses.
Further prespecified analyses of each trial found that median OS significantly favoured afatinib versus chemotherapy in patients with Del19, whereas no significant BGD was evident in patients with Leu858Arg (Table 2), with these findings corroborated by an exploratory pooled analysis of the studies . Several subgroup analyses were consistent with these findings, including a prespecified analysis of Japanese patients from LUX-Lung 3 , an analysis of non-Asian patients from LUX-Lung 3  and an exploratory pooled analysis of Asian patients from LUX-Lung 3 and 6 . Afatinib also provided significant (p < 0.01) OS benefit over chemotherapy in patients aged ≥ 65 years with Del19 in LUX-Lung 3, but not LUX-Lung 6 .
According to a prespecified analysis of patients with asymptomatic brain metastases and common EGFR mutations (35 patients from LUX-Lung 3 and 46 patients from LUX-Lung 6), results were generally consistent with the overall trial findings, although the difference in median PFS between afatinib and pemetrexed + cisplatin (11.1 vs 5.4 months) or gemcitabine + cisplatin (8.2 vs 4.7 months) did not reach statistical significance, most likely due to the small sample sizes . However, in a post hoc pooled analysis, median PFS was significantly longer with afatinib than with chemotherapy in this patient population (8.2 vs 5.4 months; p = 0.0297). No significant difference in OS was seen between afatinib and chemotherapy in the individual or pooled analyses .
The efficacy of afatinib has also been assessed in patients with uncommon EGFR mutations (n = 75) in a pooled post hoc analysis  of LUX-Lung 2 (a noncomparative phase 2 trial) , LUX-Lung 3  and LUX-Lung 6 . Afatinib appeared more active in patients with point mutations and/or deletions in exons 18–21 (commonly Gly719Xaa alone, Leu861Gln alone and Gly719Xaa + either Ser768Ile or Leu861Gln) than in patients with de novo Thr790Met mutations in exon 20 (alone or with other mutations) or exon 20 insertions. The respective mutation groups had median PFS durations of 10.7, 2.9 and 2.7 months and median OS durations of 19.4, 14.9 and 9.2 months .
Median PFS did not significantly differ between patients whose afatinib dosage was reduced to 30 mg once daily because of treatment-related adverse events (TRAEs) during the first 6 months of therapy and those whose afatinib dosage remained at 40 mg once daily in LUX-Lung 3 (11.3 vs 11.0 months) and LUX-Lung 6 (12.3 vs 11.0 months), according to post hoc analyses . In LUX-Lung 3 and 6, dosage reductions occurred in 53 and 28% of afatinib recipients, with > 80% of reductions occurring in the first 6 months of treatment .
In terms of HR-QOL [assessed using the European Organisation for the Research and Treatment of Cancer core cancer questionnaire (QLQ-C30) and its module specific to lung cancer (QLQ-LC13)], significantly (p ≤ 0.01) more afatinib than chemotherapy recipients had improvements in dyspnoea in LUX-Lung 3 , and in dyspnoea, cough and pain in LUX-Lung 6 . In a longitudinal analysis of LUX-Lung 3, significantly (p < 0.01) better scores for global health status/quality of life and physical, role and cognitive functioning were seen with afatinib versus chemotherapy . In LUX-Lung 6, significantly (p < 0.05) more afatinib than chemotherapy recipients had improvements in global health status/quality of life and in physical, role and social functioning .
Among long-term afatinib responders in LUX-Lung 3 (n = 24 of 229; i.e. 10%) and 6 (n = 23 of 239; i.e. 10%), the ORR was 71 and 78% and the median OS could not be calculated as too few deaths occurred during the follow-up period (median 64.6 and 57.0 months) . Baseline characteristics of these patients were generally consistent with those of the overall trial populations, although numerically more long responders were women and had Del19 .
In the real-world setting
Various studies (of retrospective design, where specified [19, 20]) have confirmed the efficacy of afatinib in the first-line treatment of advanced EGFRactMUT+ NSCLC in clinical practice [19,20,21]. Of these, comprehensive data are available from a Taiwanese cohort study in which 67.2% of the 140 afatinib recipients achieved a partial response, 26.4% stable disease and 6.4% progressive disease . The median PFS was 11.8 months overall, but was significantly (p < 0.05) shorter in patients with brain metastases or > 10% pretreatment weight loss than in patients without these characteristics. Outcomes were not significantly affected by the dosage of afatinib in the first 6 months of treatment (81 patients received 40 mg and 59 received < 40 mg) or by the type of EGFR mutation [i.e. classical (Del19 and/or Leu858Arg), classical + complex (e.g. Leu858Arg + Thr790Met), or rare (e.g. G719A) ± complex mutation] .
Among the other studies, a South Korean analysis (n = 165) found that median PFS (19.1 months overall) differed significantly (p = 0.01) by EGFR mutation type (19.1 months for Del19, 15.8 months for Leu858Arg, 4.7 months for Thr790Met and ‘not reached’ for uncommon mutations); nost patients with non-irradiated brain metastases (75.9% of 29) responded significantly to treatment . Moreover, in a Taiwanese study (in which 95.7% of the 467 patients were EGFR TKI naïve), TTF did not significantly differ across afatinib, gefitinib and erlotinib overall (12.2, 9.8 and 11.4 months, respectively), although it significantly favoured afatinib versus gefitinib specifically (p = 0.035) . TTF with afatinib, gefitinib and erlotinib was 12.2, 9.4 and 12.0 months, respectively, in patients with Del19, 11.7, 10.4 and 10.9 months in patients with Leu858Arg and 19.7, 7.5 and 7.0 months in patients with uncommon EGFR mutations, with no significant differences across the regimens in any of the mutation subgroups .
First-line use of afatinib is further supported by an interim analysis of a noncomparative phase 3b Asian trial conducted in a broad population of patients with EGFR TKI-naïve advanced EGFRactMUT+ NSCLC (60% of whom had received no prior chemotherapy). The median PFS was 12.1 months and the median time to symptomatic disease progression was 15.3 months in the 479 patients treated with afatinib 40 mg/day . Values for the respective outcomes were 12.6 and 15.8 months in patients with common EGFR mutations and 9.1 and 10.0 months in patients with only uncommon EGFR mutations .