REVIEW ARTICLE

Maciej Krzakowski

Klinika Nowotworów Płuca i Klatki Piersiowej, Centrum Onkologii — Instytut im. Marii Skłodowskiej-Curie w Warszawie

Afatinib — current applications and perspectives

ABSTRACT

The use of epidermal growth factor receptor tyrosine kinase inhibitors resulted in significantly improved quality of life and survival prolongation in patients with advanced lung adenocarcinoma harbouring activating EGFR mutations. Tyrosine kinase inhibitors — compared with chemotherapy — produce less treatment-related adverse effects. Tyrosine kinase inhibitors may have either reversible or irreversible activity, which may be important for their use in clinical practice. This paper presents current knowledge and potential use of afatinib in non-small cell lung cancer patients.

Key words: non-small-cell lung cancer, epidermal growth factor receptor, irreversible tyrosine kinase inhibitor, afatinib

Oncol Clin Pract 2016; 12, 1: 12–17

Introduction

Unsatisfactory results of palliative chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) caused efforts to find more efficient modes of treatment. The identification of human epidermal receptor (HER) and its downstream signalling pathway was very important for understanding the nature of NSCLC and the evolution of its therapy. The receptors from the HER (ErbB) family — HER1 (EGFR, epidermal growth factor receptor), HER2, HER3, and HER4 are superficial proteins, built from extracellular, transmembrane, and intracellular domains. Except HER2, all the receptors are activated by corresponding ligands. Epidermal growth factor (EGF) is one of the ligands for EGFR (HER1). Activation of receptors from the HER family leads to homodimerisation or heterodimerisation as well as autophosphorylation of the intracellular part of receptor protein, mediated by tyrosine kinase (TK), ultimately resulting in activation of downstream signalling pathway, enhancing proliferation, migration, and other processes connected to cancer progression [1]. High concentration of EGF and other ligands, EGFR protein overexpression, as well as mutation or amplification of EGFR gene, responsible for coding EGFR protein, lead to activation of EGFR signalling pathway [1, 2].

The first compounds inhibiting EGFR pathway were synthesised in the 1980s [3]. Currently anti-EGFR drugs, used in clinical practice to treat patients with NSCLC include small-molecule tyrosine kinase inhibitors (TKIs) of EGFR tyrosine kinase, with a mechanism of action based on autophosphorylation inhibition (erlotinib, gefitinib, afatinib) and monoclonal antibodies (cetuximab, necitumumab), blocking ligand from binding to the receptor [4].

The first randomised clinical trials, aiming to assess the clinical value of EGFR TKIs, were performed in a second-line setting (after failure of first-line platinum-based chemotherapy) and assumed a comparison of gefitinib or erlotinib with placebo [5, 6]. The results were contradictory — the study with erlotinib (BR-21) [5] showed a statistically significant overall survival benefit of approximately 2 months, whereas significant prolongation was not seen in the gefitinib study (ISEL) [6]. Of note, interpretation of the presented data should consider the fact that the eligible patients were enrolled to both trials independently of EGFR mutation status.

The use of EGFR TKIs as well as the results of treatment of patients with NSCLC have been basically changed after discovery of predictive value of EGFR activating mutations based on in vitro studies [7], which was subsequently confirmed in many clinical trials [8]. Deletions in exon 19 and substitutions in exon 21 account for approximately 85% of all activating EGFR mutations and are detected in approximately 10–12% of Caucasian patients and 40–50% of Asian patients [9]. Compared to chemotherapy, patients with the previously mentioned activating EGFR mutations achieve better results of treatment with EGFR TKIs either in first-line or in second-line, together with less expressed adverse events and better quality of life (QoL).

Pharmacological characteristics of afatinib

Afatinib irreversibly binds to EGFR (HER1) as well as HER2 and HER4 (e.g. “pan-HER inhibitor”). The results of preclinical studies showed that the affinity of afatinib to EGFR is higher with the presence of exon 19 deletion in the EGFR gene. Another feature, potentially playing a role in clinical practice, is increased activity in the presence of T790M mutation, responsible for resistance to anti-EGFR targeted therapy, as compared with erlotinib and gefitinib [10].

Afatinib could be administered with the same effectiveness in a total daily dose of either 40 mg or 50 mg. Serum peak concentration of the drug is reached after 2–6 hours, and afatinib shows decreased transformation into conjugated forms and improved tissue distribution compared to reversible EGFR TKIs. The half-life of afatinib is 34–37 hours [11].

Clinical trials with afatinib

The program of clinical trials evaluating the potential use of afatinib in patients with NSCLC (LUX-Lung — Table 1) contained prospective studies in first- and second-line settings [12–19]. Although the majority of randomised LUX-Lung studies assumed a comparison with chemotherapy, in two trials afatinib was compared head-to-head with other anti-EGFR agents (erlotinib and gefitinib). The studies were conducted in patients with diagnosis of adenocarcinoma, because EGFR mutations are more often found in this type of NSCLC. Additionally, one trial enrolled patients with squamous-cell lung cancer.

Table 1. LUX-Lung (LL) clinical trials program in non-small cell lung cancer

LL — LUX-Lung; OS — overall survival; PFS — progression-free survival; ORR — objective response rate; HR — hazard ratio; NSCLC — non-smallcell lung cancer; mEGFR — mutated EGFR; DDP — cisplatin; PXD — pemetrexed; GCB — gemcitabine; d1 — day 1 of cycle; d8 — day 8 of cycle; TTF — time to treatment failure

Studies without consideration of EGFR mutation status

Studies with unselected patients (qualified regardless of EGFR mutation status) [12–14] showed overall survival ranging between 11 and 19 months and other important benefits in terms of clinical symptoms control as well as QoL improvement.

The LUX-Lung 5 [14] clinical study enrolled patients with NSCLC progression during therapy with reversible EGFR TKIs and chemotherapy, who received afatinib in combination with paclitaxel; statistically important prolongation of progression-free survival (PFS) (5.6 versus 2.8 months) in patients treated with combination of afatinib with paclitaxel could support the possibility of clinical benefits of long-lasting inhibition of EGFR pathway after cancer progression compared to chemotherapy alone.

Additional retrospective analysis of the LUX-Lung 1 clinical trial [12] confirmed the relationship between the benefits and mutations in EGFR gene. A further observational British study also indicated the beneficial palliative effect of afatinib [20].

The lack of statistically significant influence of afatinib on overall survival (OS) in LUX-Lung 1 [12] and LUX-Lung 5 [14] clinical trials was explained by the use of afatinib in control groups in both studies after disease progression.

Studies considering EGFR mutation status

Three out of four clinical trials, conducted in EGFR TKIs-naïve patients with activating EGFR mutations [15–18], assumed randomisation (phase III clinical studies) to targeted therapy and either chemotherapy [16, 17] or reversible EGFR TKIs [18]. The forth study was LUX-Lung 2, a phase II clinical trial, which showed very high response rate (RR) (61%) and significant survival indices (median of progression-free survival and overall survival — 10 months and nearly 25 months, respectively). There were no differences according to afatinib daily dose (40 versus 50 mg); however, higher dose led to significantly more intense toxicity [15].

Randomised clinical trials are of the highest value [16–18]. Both LUX-Lung 3 [16] and LUX-Lung 6 [17] had a very similar design, in which afatinib was compared to platinum-based chemotherapy in patients with activating EGFR mutations in a first-line setting, and a primary endpoint analysis indicated a statistically significant difference in progression-free survival. The incidence of mutations in EGFR gene was comparable in both trials and both treatment arms with slightly higher prevalence of deletions in exon 19 than substitutions in exon 21 (other mutations were reported in approximately 11% of patients). The majority of patients in both trials were patients of Eastern Asiatic origin (LUX-Lung 3 — 72%, LUX-Lung 6 — 100%). Both trials met their primary endpoints, showing a statistically significant difference in favour of afatinib, according progression-free survival (median in LUX-Lung 3 and LUX-Lung 6 — 11.1 versus 6.9 months and 11 versus 5.6, respectively). In the LUX-Lung 3 study this significant difference in the afatinib group was also seen when comparing common EGFR mutations (deletion in exon 19 or substitution in exon 21) with other types of mutations (media 13.6 and 11 months, respectively). There was no difference between patients receiving chemotherapy and patients treated with afatinib, according overall survival; however, the median of overall survival in patients with deletions in exon 19 was significantly longer in the afatinib group compared to the chemotherapy group (median in LUX-Lung 3 and LUX-Lung 6 — 33.3 versus 21.1 months and 31.4 versus 18.4, respectively).

Based on similar designs of both trials combined analysis was conducted, which showed statistically significant prolongation of overall survival in patients treated with afatinib (median — 27.3 months in the afatinib group versus 24.3 months in patients receiving chemotherapy). This benefit was mainly driven by significant prolongation of overall survival in patients with deletion in exon 19 (median — 31.7 versus 20.7 months), whilst in patients with substitution in exon 21 of EGFR gene better results were observed after use of chemotherapy (median — afatinib 22.1 months, chemotherapy 26.9 months) [21].

The results of the LUX-Lung 2 as well as the LUX-Lung 3 and 6 study were also analysed retrospectively regarding the efficacy of afatinib in patients with uncommon EGFR mutations, indicating in 12% of treated patients (75/600) [22]. In patients with some uncommon mutations afatinib produced significant activity — progression-free survival and overall survival were longer in patients with point mutations and duplications (Gly719Xaa, Leu861Gln, and Ser768Ile) in exons 18–21 (median — 10.7 and 19.4 months, respectively) as compared to other disorders in EGFR gene. In the case of primary mutations T790M in exon 20 of EGFR gene (only 2% of patients), the results of afatinib treatment were worse in patients with the point mutations and duplications mentioned above (median of progression-free survival and overall survival 2.9 and 14.9 months, respectively) [22].

The results of the LUX-Lung 7 study [18] were presented only as a conference presentation — afatinib and gefitinib were compared in treatment-naïve patients with advanced adenocarcinoma and one of the common EGFR mutations (patients with mutations other than deletion in exon 19 and substitution in exon 21 were considered as ineligible). The sample size was calculated based on one of the primary endpoints, e.g. indicating difference in progression-free survival, which could result in some misinterpretations of the results (remaining primary endpoints included time to treatment failure and overall survival). Caucasian patients accounted for approximately 42% of the studied population, and baseline demographic and clinical characteristics were well-balanced. After approximately 27 months of follow-up the risks of disease progression and treatment failure were significantly decreased (by 27%, medians are presented in Table 1). Again,after 18 and 24 months of observation, the analysis of progression-free survival curves showed consistent differences in favour of afatinib. The response rate was higher in patients treated with afatinib (Table 1), and the responses in this group of patients were more prolonged (2 months difference). The results according to the influence of both drugs on overall survival are still awaited. Adverse events were typical for this class of drugs and did not lead to treatment discontinuation.

Study conducted in patients with squamous NSCLC

The LUX-Lung 8 [19] study was a phase III trial comparing the efficacy of afatinib and erlotinib in patients with squamous NSCLC in a first-line setting. There were significant but numerically very low differences in favour of afatinib (progression-free survival — 2.6 versus 1.9 months, overall survival — 7.9 versus 6.8 months, respectively); however, the disease control rate [DCR, which comprises atotal proportion of patients who demonstrate a response to treatment, e.g. the sum of complete responses (CR) + partial responses (PR) + stable disease (SD)] was two-fold higher in afatinib-treated patients. Grade 3 diarrhoea was more frequent after afatinib treatment, whilst grade 3 rash was more frequent in the erlotinib-treated group. A comparison of activity according to symptoms relief showed that afatinib significantly more frequently allowedcontrol of cough and dyspnoea.

Efficacy in patients with metastases in the central nervous system

According to inclusion criteria, patients with metastases to the central nervous system (CNS) were also allowed to participate in the LUX-Lung clinical trials program, provided they had a stable neurological state. Observations from the LUX-Lung 3 study support the efficacy of afatinib in this group of patients in cases of patients harbouring activating EGFR mutations [16]. Combined analysis of the results ofthe LUX-Lung 3 [16] and LUX-Lung 6 [17] studies included evaluation of the effect of afatinib treatment in patients with “asymptomatic” metastases in CNS at the time of treatment initiation (a total of 81 patients). Progression-free survival time in patients treated with afatinib was significantly longer compared to those receiving chemotherapy (median — 8.2 and 5.4 months, respectively) [23].

The results from patients treated in Germany as part of an expanded access program [24] confirmed the efficacy of this drug in patients with metastases in CNS; however, this type of evidence is usually not classified as “high quality”. The presented program compared the efficacy of afatinib in patients with or without metastases in CNS, previously treated with chemotherapy, reversible EGFR TKI, and radiotherapy. Both groups were well-balanced according to the most important clinical characteristics, and the majority of them harboured one of the common EGFR mutations. It was revealed that progression-free survival time was comparable in patients with or without metastases in CNS.

Adverse events

The most common treatment-emergent adverse events (AEs) of afatinib include skin rash and paronychia, mucositis, as well as diarrhoea and asthenia (Table 2). The incidence of the mentioned AEs in higher grades did not exceed a few percent.

Table 2. Incidence of adverse events with high intensity (grade 3–5) during afatinib treatment in randomised clinical trials (studies conducted in patients with adenocarcinoma treated solely with afatinib)

/—/ — lack of data; # — data for afatinib in daily dose of 40 mg

The clinical picture of skin and mucosal changes results from the presence of EGFR protein in epidermal cells and mucosal cells in the gastrointestinal track, and is characteristic for all drugs targeting EGFR. Direct head-to-head comparisons of reversible EGFR TKIs and afatinib in the LUX-Lung 7 [18] and LUX-Lung 8 [19] studies showed similar incidences of AEs grade 3 and 4; however, diarrhoea was more frequent in patients treated with afatinib, whilst skin rash was more frequent after reversible EGFR TKIs. Of note, serious adverse events (SAEs) were more commonly observed during older clinical trials conducted within the LUX-Lung program; appropriate and early diagnosis of complications as well as proper management could significantly decrease the incidence of SAEs. Furthermore, use of afatinib in a daily dose of 40 mg also decreases the risk of AEs [11]. Appropriate preventive and therapeutic management as well as reduction of afatinib dose to either 30 or 20 mg could limit treatment discontinuation rate to approximately 2–3% [25]. Patients treated with afatinib and reversible EGFR TKIs should have the possibility of continuous contact with treating physicians because early reporting of side effects allowsthe use of appropriate management, which could prevent serious complications in the majority of patients (e.g. early administration of loperamide in patients with loose stools, together with afatinib dose reduction, could effectively prevent more intense diarrhoea). Supportive care is of high importance (e.g. correcting electrolyte imbalances resulting from diarrhoea).

Adverse events connected with afatinib treatment do not negatively affect quality of life. Compared to chemotherapy, the objective benefits regarding response rate and survival are accompanied with an improvement in QoL, as was observed in the LUX-Lung 3 study [26]. In this trial treatment with afatinib led to significantly better control of cough and dyspnoea, compared to chemotherapy, and all QoL parameters (general state and physical, cognitive, and social functioning) were significantly improved in patients treated with afatinib, regardless of the significantly more frequent diarrhoea, mucositis, and asthenia.

Discussion and conclusions

The results of the presented studies [12–19] support the use of afatinib in patients with advanced lung adeno­carcinoma harbouring activating mutations of EGFR gene (deletion in exon 19 and substitution in exon 21). In this group of patients EGFR TKIs are definitely more beneficial treatment option, compared to chemotherapy. TKIs produced statistically significant and numerically important prolongation of progression-free survival time. Currently afatinib is the only drug targeting EGFR, which leads to a significant difference in overall survival compared to platinum-based first-line chemotherapy [21]. Afatinib is especially indicated in patients with deletion in exon 19 of EGFR gene, that may be explained by the pharmacological features of the drug. Although the value of afatinib in the treatment of patients with NSCLC and other EGFR mutations seems to be significant, it needs to be confirmed in prospective trials. Clinical benefits during first-line treatment with afatinib are also seen in patients with baseline metastases in the central nervous system. Similarly to other EGFR TKIs, treatment with afatinib leads to characteristic adverse events, the intensity of which could be limited by appropriate supportive care without a risk of treatment discontinuation in a reasonable number of patients. An important feature of afatinib is the possibility of dose adjustment, which additionally makes the use more easy in clinical practice.

Currently the additional benefits according to survival rates in patients with lung adenocarcinoma harbouring EGFR mutations are the subject of prospective clinical trials [27]. The synergistic action of EGFR TKIs and cetuximab (monoclonal antibody targeting EGFR and thus inhibiting ligand binding) is theoretically proven, which is preliminarily confirmed in clinical trials evaluating concomitant treatment with afatinib and cetuximab, e.g. double inhibition of EGFR pathway [28].

Address for correspondence:

Prof. dr hab. n. med. Maciej Krzakowski

Klinika Nowotworów Płuca i Klatki Piersiowej

Centrum Onkologii — Instytut

im. Marii Skłodowskiej-Curie

ul. Rentgena 5, 02–781 Warszawa

Oncology in Clinical Practice

2016, Vol. 12, No. 1, 12–17

Translation: dr n. med. Dariusz Stencel

Copyright © 2016 Via Medica

ISSN 2450–1654

References

1. Solomon DS, Brandt R, Ciardello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183–232.

2. Citri A, Yarden Y. EGF-ERRB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006; 7: 505–516.

3. Masui H, Kawamoto T, Sato JD et al. Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 1984; 44: 1002–1007.

4. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003; 21: 2787–2799.

5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–132.

6. Thatcher N, Chang A, Parikh P et al. Gefitinib plus best supportive care in previously treated patients with refreactory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study. Lancet 2005; 366: 1527–1537.

7. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129–2139.

8. Haaland B, Tan PS, de Castro G, Lopes G. Meta-analysis of first-line therapies in advanced non-small-cell lung cancer harbouring EGFR-activating mutations. J Thorac Oncol 2014; 9: 805–811.

9. Rosell R, Moran T, Queralt C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361: 958–967.

10. Solca F, Dahl G, Zoephel A et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 2012; 343: 342–350.

11. Stopfer P, Marzin K, Narjes J et al. Afatinib pharmacokinetics and metabolism after oral administration to health male volunteers. Cancer Chemother Pharmacol 2012; 69: 1051–1061.

12. Miller VA, Hirsh V, Cadranel J et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012; 13: 528–538.

13. Katakami N, Atagi S, Goto K et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressedduring prior treatment with erlotinib, gefitinib, or both. J Clin Oncol 2013; 31: 3335–3341.

14. Schuler MH, Yang CH, Park K et al. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. Ann Oncol 2016; 27: 417–423.

15. Yang JC, Shih JY, Su WC et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol 2012; 13: 539–548.

16. Sequist LV, Yang IC, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327–3334.

17. Wu YL, Zhou C, Hu CP et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15: 213–222.

18. Park K, Tan EH, Zhang L et al. Afatinib versus gefitinib as first-line treatment for patients with advanced non-small-cell lung cancer harboring activating EGFR mutations: LUX-Lung 7. Ann Oncol 2015: 26 (suppl 9): ix161–ix162.

19. Soria JC, Felip E, Cobo M et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label, randosed, controlled phase 3 trial. Lancet Oncol 2015; 33: dx.doi.org/10.1016/s1470-2045(15)00126-6.

20. Khan F, Ottensmeier C, Popat S et al. Afatinib use in non-small-cell lung cancer previously sensitive to epidermal growth factor receptor inhibitors: the United Kingdom Named Patient Programme. Eur J Cancer 2014; 50: 1717–1721.

21. Yang JC, Wu JL, Schuler M et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015; 16: 141–151.

22. Yang JC, Sequist LV, Geater SL et al. Activity of afatinib in uncommon epidermal growth factor receptor (EGFR) mutations: findings from three trials of afatinib in EGFR mutation-positive lung cancer. Lancet Oncol 2015;16: 830–838.

23. Schuler M, Wu YL, Hirsh V et al. First-line afatinib versus chemotherapy in patients with non-small-cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastatses. J Thorac Oncol 2016; 11: 380–390.

24. Hoffknecht P, Tufman A, Wehler T et al. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol 2015; 10: 156–163.

25. Arriola E, Requart N, Artal A et al. Management of adverse events of afatinib: a consensus of the recommendations of the Spanish expert panel. Future Oncol 2015; 11: 267–277.

26. Yang JC, Hirsh V, Schuler M et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3342–3350.

27. Zhou C, Yao LD. Strategies to improve outcomes of patients with EGFR-mutant non-small-cell lung cancer: review of the literature. J Thorac Oncol 2015; 11: 174–186.

28. Janjigian YY, Smit EF, Groen HJ et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov 2014; 4: 1036–1045.