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As many as 40% of patients diagnosed with NSCLC may develop brain metastases during the course of their disease,1 and the risk may be greater in those who harbour an EGFR mutation.2 The presence of brain metastases is an important factor influencing the selection of the optimal first-line treatment in EGFR mutation-positive NSCLC.3
Risk of CNS progression in patients who were treated with afatinib in LUX-Lung 3,6 and 7
In patients with baseline brain metastases who were treated with afatinib in LUX-Lung 3 and 6, the cumulative incidence of CNS progression was 40% lower than that of non-CNS progression (31% vs 52%).3 In patients without brain metastases who were treated with afatinib in LUX-Lung 3,6 and 7, the cumulative incidence of CNS progression was 92% lower than that of non-CNS progression (6% vs 78%).3
Data from LUX-Lung 3 and 6 demonstrate the efficacy of afatinib vs chemotherapy in patients with stable brain metastases at baseline. Pre-planned subgroup analyses were performed in patients with brain metastases and common EGFRmutations in LUX-Lung 3 (n=35) and LUX-Lung 6 (n=46).4 In a post hoc combined analysis of patients with brain metastases from both studies (n=81), median PFS was significantly longer with afatinib than with chemotherapy (8.2 months vs 5.4 months; hazard ratio [HR]=0.50; 95% CI: 0.27–0.95; p=0.03).4
In patients with brain metastases in LUX-Lung 7, PFS was improved with afatinib versus gefitinib (HR=0.76) and the magnitude of the increase was similar to that observed in patients without brain metastases (HR=0.74).5
Real-world evidence of the efficacy of afatinib in Korean patients with EGFR mutation-positive NSCLC and brain metastases
A retrospective study was carried out in 165 Korean patients with recurrent or metastatic EGFR mutation-positive NSCLC.6 Forty-three percent of patients had brain metastases before starting first-line treatment with afatinib. In patients with brain metastases at baseline who had not received radiotherapy for brain tumours, median PFS was 15.7 months (n=39).6 Of these patients, 29 had follow-up MRI data and 55% of these patients were described as having significantly decreased brain metastases with afatinib treatment.6
GKS, Gamma Knife surgery; WBRT, whole-brain radiotherapy.
Real-world evidence of the efficacy of afatinib in Taiwanese patients with advanced EGFR mutation-positive NSCLC and brain metastases in patients with and without brain metastases.
In a retrospective study in 467 Taiwanese patients with advanced EGFR mutation-positive NSCLC, 110 patients received afatinib as first-line treatment.7 Median PFS in patients with and without brain metastases at baseline was 9.9 months and 13.1 months, respectively.7
In another retrospective Taiwanese study in patients with advanced EGFR mutation-positive lung adenocarcinoma, 42 out of 140 patients had brain metastases at baseline.8 Patients with initial brain metastases had a poorer ECOG performance status than those without brain metastases (p=0.003).8 Median PFS in patients with and without brain metastases at baseline was 9.2 months and 14.9 months, respectively (HR=2.29; 95% CI: 1.46–3.60; p<0.001).8
PFS in Taiwanese patients with and without brain metastases
Efficacy of afatinib in a smaller case series in patients with symptomatic brain metastases and in a small study in patients with leptomeningeal carcinomatosis
In a case series in patients with symptomatic brain metastases, first-line treatment with afatinib was also shown to induce complete remission that lasted ≥6 months in five EGFR mutation-positive NSCLC patients who had declined whole-brain radiation therapy.9 Afatinib has also shown efficacy in a prospective study of 11 patients with EGFR-positive NSCLC who had leptomeningeal carcinomatosis; the median cerebrospinal concentration of afatinib in this study was 1.4 ng/mL.10 This equates to a molar concentration of 2.9 nM, which is clearly above the IC50 value for the EGFR (0.5 nM).11,12
Of 600 patients treated with afatinib in the LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6 trials, 75 (12%) patients had uncommon EGFR mutations (i.e. not del19 or L858R).13 These patients were divided into three subgroups depending on the type of mutation: those with point mutations or duplications in exons 18–21 (group 1; n=38); those with de novo T790M mutations alone or in combination with other mutations (group 2; n=14); and those with exon 20 insertions (group 3; n=23). Overall, afatinib treatment was associated with decreases in tumour size that was associated with an increase in PFS. Afatinib had clinical activity in tumours that harboured uncommon EGFR mutations including G719X, L861Q, and S768I mutations (group 1). In patients receiving afatinib, median PFS and median OS were highest for patients in group 1; in particular, median PFS was longest in eight patients with S768I mutations (14.7 months). However, afatinib had little clinical activity in patients with de novo T790M and exon 20 insertion mutations.
Real-world evidence of the efficacy of afatinib in Taiwanese patients with advanced lung adenocarcinoma and uncommon EGFR mutations
A retrospective, observational study evaluated whether EGFR mutation type affected clinical efficacy in Taiwanese patients with advanced EGFR mutation-positive lung adenocarcinoma.2 Twenty-three percent of patients in this study had complex or rare EGFR mutations. After excluding patients with exon 20 insertions from the analysis, there was no significant difference in median PFS between patients who had common EGFR mutations (del19/L858R; n=108) and those who had uncommon EGFR mutations (n=22; median PFS, 12.2 vs 11.5 months; HR=0.85; 95% CI: 0.47–1.53; p>0.05).2
In another retrospective Taiwanese study in patients with advanced EGFR mutation-positive NSCLC, 110 out of 467 patients received afatinib as first-line treatment.4 Of these patients, 55% had exon 19 mutations, 23% had L858R mutations and 22% had uncommon EGFR mutations. In patients who received afatinib, median PFS was 12.2 months in the overall patient group, 12.2 months in patients with exon 19 mutations, 11.7 months in patients with L858R mutations and 19.7 months in patients with uncommon EGFR mutations.4
Real-world evidence of the efficacy of afatinib in Korean patients with uncommon EGFR mutations
A retrospective study was carried out in 165 Korean patients with recurrent or metastatic EGFR mutation-positive NSCLC.9 All patients were treated with afatinib as first-line therapy and 8.5% had an uncommon EGFR mutation. Patients with tumours that had uncommon EGFR mutations other than T790M responded to afatinib treatment: median PFS had not been reached at the data cut-off.9
Data from LUX-Lung 3 (72% Asian population) and LUX-Lung 7 (57% Asian population) indicate that efficacy of afatinib in Asian patients is in line with that seen in other study populations, with EGFR mutation status being a key predictor of efficacy, rather than ethnicity.10,18 For instance, the hazard ratio (HR) for PFS in LUX-Lung 7 was 0.72 for non-Asian patients and 0.76 for the Asian population.10
A subgroup analysis of Japanese patients who participated in LUX-Lung 3 showed a significant increase in PFS with afatinib compared with cisplatin/pemetrexed in all Japanese patients, as well as in patients with common EGFR mutations. OS was significantly longer with afatinib than with chemotherapy in patients with del19 mutations (46.9 vs 31.5 months), but did not differ significantly between treatment arms in patients with L858R mutations.19
The LUX-Lung 6 phase III trial was conducted in Asian countries with 90% of randomised patients being Chinese. A post hoc analysis of the Chinese patient subset demonstrated that afatinib significantly increased PFS compared with gemcitabine/cisplatin in all patients (11.0 vs 5.6 months) and in patients with EGFR Del19 or L858R mutations (11.0 vs 5.6 months).16 An increase in OS was also observed versus gemcitabine/cisplatin in patients with EGFR Del19 mutations (31.6 vs 16.3 months). There were no unexpected safety findings with afatinib in Chinese patients.16
Chinese patients with SqNSCLC: subgroup analysis of LUX-Lung 8
A post hoc subgroup analysis of data from 67 Chinese patients with advanced SqNSCLC in LUX-Lung 8 confirmed that the efficacy, safety and tolerability of afatinib in this subgroup are in line with that seen in the overall study population.17 Trends favouring afatinib vs erlotinib in terms of PFS (HR=0.70; 95% CI: 0.38–1.27), OS (HR=0.69; 95% CI: 0.39–1.21), tumour control and improvements in patient-reported outcomes were comparable to those in the overall study population.17
Of the patients treated with afatinib, dose reductions occurred in 53% of patients in LUX-Lung 3 and in 28% of patients in LUX-Lung 6. Tolerability-guided dose adjustment of afatinib reduced the incidence and severity of treatment-related AEs without affecting efficacy.22 Median PFS in patients who had dose reductions in the first 6 months was found to be similar to that in patients who remained on afatinib 40 mg once daily.22Similarly, in the Phase IIb LUX-Lung 7 trial of afatinib versus gefitinib, 42% of afatinib-treated patients had tolerability-guided dose reductions and experienced fewer treatment-related AEs without any loss in afatinib efficacy.23
In a single-arm, open-label, phase II study of first-line afatinib in 46 Japanese patients with EGFR mutation-positive NSCLC, afatinib was initially prescribed at 20 mg/day and then, if tolerated, the dose was increased in 10 mg increments up to 50 mg/day.24 In patients with Grade ≥3 or selected prolonged Grade 2 drug-related adverse events the afatinib dose could be reduced 10 mg at a time to a minimum of 20 mg every other day.24 In the 44 patients with a target lesion, the objective response rate (ORR) was 82%.24 In the overall patient group, median PFS was 15.2 months (95% CI: 13.2–not estimable) and median OS had not yet been reached at the data cut-off (median follow-up was 18.9 months).24 Low-dose afatinib treatment was well tolerated.24
Subgroup analyses of LUX-Lung 3 and LUX-Lung 6 patients showed that afatinib treatment results in significant PFS benefit vs comparator in patients aged at least 65 years whose tumours have common EGFR mutations. A significant increase in OS was also reported in elderly patients with del19 mutations in LUX-Lung 3.21 The safety profile of afatinib was generally similar across age groups, with a slightly higher incidence of Grade 3/4 treatment-related AEs in elderly patients; however, this was also seen in the chemotherapy arm (cisplatin/pemetrexed [Cis/Pem] in LUX-Lung 3 and cisplatin/gemcitabine [Cis/Gem] in LUX-Lung 6).21
In subgroup analyses of LUX-Lung 7, afatinib increased median PFS and OS vs gefitinib regardless of age group, although the difference between treatment arms did not reach significance in all age groups analysed.22
Patients with renal impairment
In an open-label, single-dose study that included patients with moderate (n=8) or severe (n=8) renal impairment, plasma protein binding of afatinib was similar to that in matched healthy controls. Moderate to severe renal impairment had a minor influence on the pharmacokinetics of afatinib, with a trend towards increased exposure in patients with severe renal impairment. All AEs in this study were CTCAE Grade 1.23 The recommended dose of 40 mg was considered to be safe and equally well-tolerated in these patients. Two case reports on afatinib in patients undergoing haemodialysis for chronic renal failure indicate that patients could be safely treated with 30 mg afatinib.24,25 Other case reports also suggest that afatinib is well tolerated in patients undergoing haemodialysis,26 especially when provided with dose reductions, and in an elderly patient with chronic kidney disease.27
For label information on afatinib use in patients with renal impairment, click here.
Patients with hepatic impairment
In an open-label, single-dose study that included patients with mild (n=8) or moderate (n=8) hepatic impairment, impaired hepatic function had no effect on plasma protein binding of afatinib.28 Hepatic impairment had no clinically relevant effect on the absorption, distribution or elimination of afatinib. AEs were reported in five patients with hepatic impairment and in one healthy control patient. Three patients with mild hepatic impairment had AEs that were considered to be treatment-related: Grade 3 lipase elevation, likely caused by cholecystolithiasis; Grade 2 headache and nausea; and Grade 1 diarrhoea.28
For label information on afatinib use in patients with hepatic impairment, click here.
For further information on special populations, such as renal impaired patients, polymedicated patients and patients with brain metastases, please visit the Article Library where you can search an extensive list of publications that can be sorted by patient population.
In the LUX-Lung 3, LUX-Lung 6 and LUX-Lung 7 studies, 10–12% of afatinib-treated patients were long-term responders (LTRs; treated for ≥3 years).29 In LUX-Lung 7, 12% of afatinib-treated patients versus 4% of gefitinib patients were LTRs. Long-term treatment was independent of tolerability-guided dose adjustment and of the presence of brain metastases at time of enrolment. Long-term treatment with afatinib had no detrimental impact on subsequent treatment.29
**Note: For LL7, percentages are based on total number of patients who received treatment with afatinib or gefitinib.
In LUX-Lung 8, 21 out of 398 patients in the afatinib arm were long-term responders who had received at least 12 months of afatinib treatment.31 Median treatment duration in these patients was 17.6 months (range 12.3–27.6 months). Median PFS was 16.6 months (range 2.8–25.8) and median OS was 21.1 months (range 12.9–31.6); one patient had a complete response and six patients had a partial response.31
Of the 553 patients with common EGFR mutations who received first-line afatinib in the LUX-Lung 3, 6 and 7 trials and later discontinued treatment, second-line therapy was given in 394 (71%) patients. Median time on second-line treatment was not different between del19 and L858R mutation subgroups.32 Interestingly, 37 patients received osimertinib after first-line afatinib, the majority in third-line treatment or beyond; median time on therapy was 20.2 months (95% confidence interval [CI]: 12.8–31.5 months).32 Median OS for osimertinib-treated patients is not yet evaluable.
In LUX-Lung 7 there was a trend towards improved OS with afatinib versus gefitinib in patients who received a third-generation EGFR TKI (not estimable [NE] vs 48.3 months; hazard ratio [HR]=0.49; 95% CI: 0.20‒1.19).33
T790M is the major acquired resistance mechanism for afatinib, with no clinical characteristics or EGFR mutation types described associated with the development of acquired T790M.34,35 A single-centre, retrospective analysis of 48 Austrian patients with EGFR mutation-positive stage IV adenocarcinoma of the lung who had been treated with afatinib for at least 3 months was carried out; 23% of patients had received first-generation EGFR TKIs prior to afatinib.36 In this study, ORR in all patients was 90% and the median duration of response was 12.5 months (95% CI: 9–14).36 The EGFR T790M mutation was present in 27/48 (56%) of patients who progressed after initially achieving disease control for ≥3 months with afatinib; the ORR with afatinib in these patients was 93%.36These 27 patients were then treated with osimertinib, with an ORR of 81%.36 At the time of analysis, osimertinib treatment was ongoing in 11 (41%) patients. Median time on sequential treatment with afatinib and osimertinib was 25.0 months (95% CI: 20–33 months).36
Emergence of the EGFR T790M mutation did not appear to correlate with any baseline characteristics.36
GioTag is a retrospective study on sequential therapy with afatinib followed by osimertinib in patients with EGFR mutation-positive advanced NSCLC in a real-world setting.33 The primary objective is to determine the time on treatment with first-line afatinib followed by second-line osimertinib for patients who develop a T790M resistance mutation.33 The secondary objective is to collect data on the acquired resistance mechanism to osimertinib.33 This ongoing study is based on existing data from medical records of approximately >190 pre-selected patients in 11 countries.
Find out more about GioTag.
Real-world data from patients in Austria, Canada, Japan, South Korea and Taiwan provide evidence of the efficacy and safety of afatinib in clinical practice. ORR, PFS and OS data were comparable or better than in the LUX-Lung 3, 6 and 7 clinical trials, and there were no new safety signals. Efficacy data for patients with brain metastases and patients with uncommon EGFR mutations have also been reported. Dose adjustments were necessary in many patients but did not affect efficacy.
Afatinib in Japanese patients with EGFR mutation-positive NSCLC
In a prospective, post-marketing observational study in 1602 Japanese patients with inoperable or recurrent EGFR mutation-positive NSCLC (40.1%, 46.1% and 13.8% of patients had an ECOG performance status of 0, 1, and ≥2, respectively), ORR with afatinib was higher in EGFR TKI naïve patients than in patients who had previously been treated with EGFR TKIs (68% vs 21%).38 In EGFR TKI naïve patients who started on a daily afatinib dose of 40 mg, ORR was 71% in those aged ≥75 years (n=49) and 74% in those aged <75 years (n=362).38 Adverse drug reactions were predictable, generally manageable and consistent with the known safety profile of afatinib.38
First-line afatinib in clinical practice in Korean patients with EGFR mutation-positive NSCLC
A retrospective study was carried out in 165 Korean patients with recurrent or metastatic EGFR mutation-positive NSCLC: 95% had an ECOG performance status of 0 or 1; 52% were male; 8.5% had an uncommon EGFR mutation; and 43% had brain metastases before starting treatment with afatinib.6 All patients were treated with afatinib as first-line therapy. Overall, median PFS was 19.1 months (95% CI: 12.3–25.9) and median OS had not been reached at the data cut-off.6 In patients with brain metastases at baseline who had not received radiotherapy for brain tumours, median PFS was 15.7 months (n=39).6 Of these patients, 29 had follow-up MRI data and 55% of these patients were described as having significantly decreased brain metastases with afatinib treatment.6
Patients with tumours that had uncommon EGFR mutations other than T790M responded to afatinib treatment: median PFS had not been reached at the data cut-off.6
Although 68% of patients in this study required a dose reduction due to adverse events, this did not appear to impair efficacy.2
GKS, Gamma Knife surgery; WBRT, whole-brain radiotherapy.
Clinical efficacy in relation to dose and EGFR mutation type in Taiwanese patients with advanced EGFR mutation-positive lung adenocarcinoma
A retrospective, observational study evaluated whether afatinib dose adjustment and EGFR mutation type affected clinical efficacy in Taiwanese patients with advanced EGFR mutation-positive lung adenocarcinoma (30% of patients had brain metastases; 23% had complex or rare EGFR mutations).8 59 of 140 patients received an afatinib dose of <40 mg in the first 6 months of treatment; there was no significant difference in the median PFS between the 40 mg and <40 mg groups (12.0 vs 11.0 months; HR=0.84; 95% CI: 0.53–1.31; p>0.05).8 After excluding patients with exon 20 insertions from the analysis, there was no significant difference in median PFS between patients who had common EGFR mutations (del19/L858R; n=108) and those who had uncommon EGFR mutations (n=22; median PFS, 12.2 vs 11.5 months; HR=0.85; 95% CI: 0.47–1.53; p>0.05).8
Visit the RealGiDo page for more information about afatinib dose adjustment in clinical practice.
Clinical efficacy in relation to EGFR mutation type and the presence or absence of brain metastases in Taiwanese patients with advanced EGFR mutation-positive NSCLC
In a retrospective study in 467 Taiwanese patients with advanced EGFR mutation-positive NSCLC, 110 patients received afatinib as first-line treatment.7 Of these patients, 55% had exon 19 mutations, 23% had L858R mutations and 22% had uncommon EGFR mutations.7 In patients who received afatinib, median PFS was 12.2 months in the overall patient group, 12.2 months in patients with exon 19 mutations , 11.7 months in patients with L858R mutations and 19.7 months in patients with uncommon EGFR mutations.7 Median PFS in patients with and without brain metastases at baseline was 9.9 months and 13.1 months, respectively.7
First- compared to second-generation EGFR TKIs in Canadian patients with advanced EGFR mutation-positive NSCLC
In a retrospective study of 500 Canadian patients with advanced EGFR mutation-positive NSCLC, treatment with a second-generation EGFR TKI was associated with a longer OS than treatment with a first-generation EGFR TKI (median OS: 43 months [n=110] vs 23 months [n=390]; HR=0.6; 95% CI: 0.4–0.8; p<0.01).39 The survival benefit favouring second-generation TKIs was significant in the overall patient cohort and in the exon 19 deletion patient cohort, but not the cohort with exon 21 L858R mutations.39 Skin and gastrointestinal side effects were common in patients receiving second-generation TKIs, but were manageable with dose reductions and only one patient discontinued treatment.39
In a genetic analysis of 245 patients from the LUX-Lung 8 study, 53 (21.6%) had tumours with ≥1 ERBB Family mutation.40 PFS and OS were longer with afatinib versus erlotinib in patients with ERBB wild-type tumors (median PFS, 3.0 months vs 2.4 months; median OS, 8.1 months vs 6.4 months). These effects were more pronounced in patients with ERBB mutation-positive tumors (median PFS, 4.9 months vs 2.7 months; median OS, 10.6 months vs 7.2 months), with the most marked effect seen in patients with HER2 mutations.40
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*Afatinib is approved in more than 80 markets including the EU, Japan, Taiwan, and Canada under the brand name GIOTRIF®, in the US under the brand name GILOTRIF® and in India under the brand name Xovoltib®; for the full list please see here. Registration conditions differ internationally; please refer to locally approved prescribing information.
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