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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
Pre-planned subgroup analyses were performed in patients with brain metastases and common EGFR mutations in LUX-Lung 3 (n=35) and LUX-Lung 6 (n=46).3 In a post hoc combined analysis of patients with brain metastases from both studies (n=81), median PFS was significantly longer with afatinib (8.2 months) than with chemotherapy (5.4 months; p=0.03).3
Interestingly, in patients without baseline brain metastases, median time to central nervous system progression was longer with afatinib (15.2 months in both trials) than with chemotherapy (5.7 and 7.3 months in LUX-Lung 3 and LUX-Lung 6, respectively).3 Rates of CNS progression were similar between afatinib and chemotherapy arms in patients with and in those without baseline brain metastases.3 Furthermore, the brain was typically not the site of first disease progression.3
In patients with brain metastases in LUX-Lung 7, PFS was improved with afatinib versus gefitinib and the magnitude of the increase was similar to that observed in patients without brain metastases (hazard ratio = 0.76).
In a smaller 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.4 Afatinib has also shown efficacy in a 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.5 This equates to a molar concentration of 2.9 nM, which is clearly above the IC50 value for the EGFR (0.5 nM).6,7
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).8 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). Clinical benefit was lower in patients with de novo T790M and exon 20 insertion mutations.
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.9,10 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.11
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.12 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.12 Similarly, 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.13
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.3 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.3 In the 44 patients with a target lesion, the objective response rate (ORR) was 82%.3 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).3 Low-dose afatinib treatment was well tolerated.3
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 3.14 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).14
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.15
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 1.16 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.17,18 Other case reports also suggest that afatinib is well tolerated in patients undergoing haemodialysis,19 especially when provided with dose reductions, and in an elderly patient with chronic kidney disease.20
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.21 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.21
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).22,23 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.22,23
**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.24 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.24
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.25 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).25 Median time on second-line treatment was not different between del19 and L858R mutation subgroups.1 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).1 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).26 Median OS for osimertinib-treated patients is not yet evaluable.
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.27, 28 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.5 In this study, ORR in all patients was 90% and the median duration of response was 12.5 months (95% CI: 9–14).5 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%.5 These 27 patients were then treated with osimertinib, with an ORR of 81%.5 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).5
Emergence of the EGFR T790M mutation did not appear to correlate with any baseline characteristics.31
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*Afatinib is approved in more than 70 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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