THEMED ARTICLE y Lung Cancer

Review

Advanced non-small-cell lung cancer with epidermal growth factor receptor mutations: current evidence and future perspectives Expert Rev. Anticancer Ther. 13(10), 1207–1218 (2013)

Raffaele Costanzo1, Agnese Montanino1, Massimo Di Maio2, Maria Carmela Piccirillo2, Claudia Sandomenico1, Pasqualina Giordano2, Gennaro Daniele2, Renato Franco3, Francesco Perrone2, Gaetano Rocco4, Nicola Normanno5,6 and Alessandro Morabito*1

The identification of activating mutations in the tyrosine kinase domain of the EGF receptor (EGFR) predictive of response to tyrosine kinase inhibitors (TKIs) led to a therapeutic revolution in the treatment of patients with metastatic non-small-cell lung cancer (NSCLC). To date, eight randomized clinical trials have demonstrated that first-line treatment with TKIs in advanced NSCLC patients harboring activating EGFR mutations is associated with significant improvement in response rate, progression-free survival, quality of life and tolerability, compared with platinum-based chemotherapy. These results prompted the EGFR TKIs as the current standard first-line treatment of patients with advanced NSCLC harboring activating EGFR mutations. However, there are several questions that need to be addressed, including the best choice among different EGFR TKIs, the treatment of resistant disease and of patients with specific clinical conditions. Ongoing and future, well-designed trials should answer all these questions.

1 Thoraco-Pulmonary Department, Medical Oncology Unit, Istituto Nazionale Tumori “Fondazione G.Pascale” – IRCCS Napoli, Italy 2 Research Department, Clinical Trials Unit, Istituto Nazionale Tumori “Fondazione G.Pascale” – IRCCS Napoli, Italy 3 Pathology and Laboratory Department, Pathology Unit, Istituto Nazionale Tumori “Fondazione G.Pascale” – IRCCS Napoli, Italy 4 Thoraco-Pulmonary Department, Thoracic Surgery, Istituto Nazionale Tumori “Fondazione G.Pascale” – IRCCS Napoli, Italy 5 Research Department, Cellular Biology and Biotherapy, Istituto Nazionale Tumori “Fondazione G.Pascale” – IRCCS Napoli, Italy 6 Centro di Ricerche Oncologiche di Mercogliano (CROM), Mercogliano (AV), Italy *Author for correspondence: Tel.: +39 081 590 3522 Fax: +39 081 770 2938 [email protected]; [email protected]

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Platinum-based chemotherapy has been for many years the standard treatment for all fit patients with metastatic disease, but it is associated with a small survival benefit and substantial toxicity. In the last few years, the identification in a subgroup of NSCLC patients of mutations in the tyrosine kinase domain of the EGF receptor (EGFR), that are highly predictive of response to EGFR tyrosine kinase inhibitors (TKIs), has profoundly changed this scenario, leading to a substantial diagnostic and therapeutic change for patients with metastatic NSCLC [1–3]. EGFR is a 170-kDa plasma membrane glycoprotein, composed of an extracellular ligand binding domain, a transmembrane domain and an intracellular tyrosine kinase domain and belongs to a family of four different tyrosine kinase receptors (EGFR (ErbB1), HER2/neu (ErbB2), HER3 (ErbB3), HER4 (ErbB4)) [4].

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10.1586/14737140.2013.845092

KEYWORDS: afatinib • clinical trials • dacomitinib • EGFR • erlotinib • gefitinib • neratinib • NSCLC

Dimerization of EGFR occurs after binding of a ligand, such as EGF, with activation of the intrinsic tyrosine kinase activity and tyrosine autophosphorylation, which may result in cancer cell proliferation, apoptosis blocking, invasion, metastasis and tumor-induced neovascularization [5]. Therefore, EGFR plays a central role in the process of cell growth and tumor progression and its overexpression occurs in many human epithelial tumors, including NSCLC [6]. On these bases, EGFR has been considered an attractive target for novel biological anticancer agents and several strategies have been developed to target EGFR, including small-molecule TKIs, such as gefitinib and erlotinib, and monoclonal antibodies, such as cetuximab [7]. EGFR mutant NSCLC was first identified in 2004 as a distinct molecular subset of lung cancer, following sequencing of the EGFR gene from patients with NSCLC responding to gefitinib or erlotinib [1–3]. Interestingly,


2013 Informa UK Ltd

ISSN 1473-7140

1207

Review

Costanzo, Montanino, Di Maio et al.

EGFR mutations were found strongly associated with some clinical and pathological features, being more frequent in female patients, adenocarcinoma subtype, non-smokers or former smokers and patients from Eastern Asia [8,9]. The most frequent EGFR mutations are small in-frame deletions in exon 19 (nearly 50%) that affect the conserved sequence LREA (delE746-A750) and a single point mutation in exon 21 (nearly 40%) that substitutes an arginine for a leucine at codon 858 (L858R) [10,11]. These mutations are responsible of constitutive activation of the tyrosine kinase domain of the EGFR, which is normally maintained, in the absence of ligand stimulation, in an auto-inhibited conformation [12]. Therefore, kinase domain mutations of EGFR, referred as ‘activating mutations’, identify a specific subtype of lung cancer, whose growth is dependent on EGFR pathway activation, which represents the leading pathway in inducing cellular transformation in these selected patients (‘oncogenic addiction’) [13]. It has been also demonstrated that activating EGFR mutations may led to increased affinity of TKIs for the mutant receptor compared with the wild-type one. To date, eight randomized clinical trials in selected patients (two including clinically selected patients and six prospectively dedicated to EGFR-mutant patients) have consistently demonstrated the efficacy of TKIs as first-line therapy of EGFR mutated NSCLC (TABLE 1). This review summarizes the available evidences coming from the randomized trials that support the use of TKIs as the standard first-line treatment of patients with advanced NSCLC harboring EGFR mutations. Moreover, it discusses several issues associated with the use of first-generation (gefitinib, erlotinib) and second-generation (afatinib, dacomitinib) TKIs and with the treatment of resistant disease. First-generation, reversible EGFR TKIs

First-generation EGFR TKIs (including gefitinib and erlotinib) selectively target the receptor, through a competitive, reversible binding at the tyrosine kinase domain. Both agents are orally available, small molecules that inhibit ATP binding and subsequent signal transduction and downstream effect or functions, blocking several cellular processes including growth, proliferation, differentiation and migration. Gefitinib

Several Phase II studies showed a high response rate (55–90%) and a progression-free survival (PFS) longer than usually obtained with chemotherapy (approximately 9 months) with first-line gefitinib in Asiatic patients selected for the presence of activating EGFR mutations [14]. Similar results were observed in a Phase II study from the USA, where median PFS for patients with confirmed EGFR mutations treated with gefitinib was 9.2 months [15]. Four randomized Phase III clinical trials have compared gefitinib and platinum-based chemotherapy as first-line therapy in patients with advanced NSCLC, selected on the basis of clinical or molecular criteria [16–19]. The largest trial, the Iressa PanAsia Study (IPASS), randomized 1217 Asian patients with 1208

advanced NSCLC and adenocarcinoma histotype, non-smokers or former light smokers, to receive gefitinib or carboplatinpaclitaxel [16]. The study formally met the primary end point (non-inferiority of gefitinib in this clinically selected population) and also demonstrated the superiority of gefitinib in terms of PFS in the intention-to-treat analysis (hazard ratio [HR]: 0.74, 95% CI: 0.65–0.85; p < 0.001), although the shape of the PFS curves clearly suggested heterogeneity in the efficacy of the two treatments. Actually, a strong interaction between the presence of EGFR mutations and treatment efficacy was demonstrated, with the superiority of gefitinib on PFS limited to patients with EGFR mutations. In detail, 261 out of 437 patients available for molecular analysis (59.7%) had EGFR mutations (mostly exon 19 deletions and L858 mutations). In this subgroup, PFS was significantly longer (HR: 0.48; 95% CI: 0.36–0.64; p < 0.001), and response rate was significantly higher (71.2 vs 47.3%; p < 0.001) with gefitinib than with carboplatin-paclitaxel. On the contrary, gefitinib treatment was associated with a significantly shorter PFS among patients with wild-type EGFR (HR: 2.85; 95% CI: 2.05–3.98; p < 0.001). There was no difference in overall survival (OS) between the two treatment arms in the whole study population and in the subgroups identified according to EGFR mutational status: the OS results, however, were likely confounded by the high proportion (64%) of patients treated with EGFR TKIs after disease progression in the chemotherapy arm [20]. The health-related quality-of-life (HRQoL) analysis showed that significantly more patients improved in HRQoL and symptoms with gefitinib in the EGFR mutation-positive subgroup and with carboplatin/paclitaxel in the EGFR mutation-negative subgroup [21]. Similar findings were observed in the smaller First SIGNAL study, a randomized Phase III trial that compared gefitinib with cisplatin/gemcitabine as first-line treatment in 309 Asian, nonsmokers patients, with advanced adenocarcinoma [17]. In this trial, gefitinib failed to show an OS benefit (primary end point) compared with chemotherapy (22.3 vs 22.9 months, respectively; HR: 0.932; 95% CI: 0.716–1.213; p = 0.604). However, in the subgroup of EGFR mutation-positive patients (42 cases) gefitinib produced a higher statistically significant response rate (84.6 vs 37.5%; p = 0.002) and a longer PFS (HR: 0.544; 95% CI: 0.269–1.100; p = 0.086) compared with cisplatin/ gemcitabine. As expected, among the patients who received gefitinib, the presence of EGFR mutation was significantly predictive for higher response rate (84.6 vs 25.9%, respectively; p < 0.001) and longer PFS (HR: 0.377; 95% CI: 0.210–0.674; p < 0.001), compared with the absence of EGFR mutation. The West Japan Thoracic Oncology Group (WJTOG 3405) trial compared gefitinib versus cisplatin/docetaxel in 172 Japanese patients with lung adenocarcinomas and exon 19 or L858R EGFR mutations [18]. Patients assigned to gefitinib had significantly longer PFS compared with those assigned to chemotherapy, with a median PFS of 9.2 versus 6.3 months (HR: 0.489; 95% CI: 0.336–0.710; p < 0.0001). The objective response rate was 62.1% in the gefitinib arm and 32.2% in the Expert Rev. Anticancer Ther. 13(10), (2013)

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Mok et al. (2009)

Han et al. (2012)

Mitsudomi et al. (2010)

Maemondo et al. (2010)

Zhou et al. (2011)

Rosell et al. (2012)

Yang et al. (2012)

Wu et al. (2013)

IPASS

First SIGNAL

WJTOG 3405

NEJ002

OPTIMAL

EURTAC

LUX-LUNG 3

LUX-LUNG 6

First line, Asian EGFR mutated

First line, worldwide EGFR mutated

First line, Caucasic EGFR mutated

First line, Asian EGFR mutated

First line, Asian EGFR mutated

First line, Asian EGFR mutated

0–1

345

0–1

0–2

174

364

0–2

0–2

0–1

165

230

172

Afatinib versus cisplatin + gemcitabine

Afatinib versus cisplatin + pemetrexed

Erlotinib versus platinum-based doublet

Erlotinib versus gemcitabine + carboplatin

Gefitinib versus carboplatin + paclitaxel

Gefitinib versus cisplatin + docetaxel

8.0 vs 6.3, HR: 0.544, p = 0.086 9.2 vs 6.3, HR: 0.489, p < 0.0001 10.8 vs 5.4, HR: 0.30, p < 0.001 13.1 vs 4.6, HR: 0.16, p < 0.0001 9.7 vs 5.2, HR: 0.37, p < 0.0001 11.1 vs 6.9, HR: 0.58, p = 0.0004 11.0 vs 5.6, HR: 0.28, p < 0.0001

62.1 vs 32.2 (p < 0.0001) 73.7 vs 30.7 (p < 0.001) 83 vs 36 (p < 0.0001) 58 vs 15

69.1 vs 44.3 p < 0.001 66.9 vs 23.0 p < 0.0001

42

Subgroup of EGFR mutated

Gefitinib versus cisplatin + gemcitabine 84.6 vs 37.5 (p = 0.002)

5.8 vs 6.4, HR: 1.198, p = 0.138

55.4 vs 46.3 (p = 0.101)

309

First line, Asian clinically selected

0–2

9.5 vs 6.3, HR: 0.48, p < 0.001

71.2 vs 47.3 (p < 0.001)

261

5.7 vs 5.8, HR: 0.74, p < 0.001

43 vs 32.3 (p < 0.001)

Subgroup of EGFR mutated

Gefitinib versus carboplatin + paclitaxel

0–2

1217

PFS (months)

RR (%)

First line, Asian clinically selected

Treatment

ECOG PS

Pts

Setting

HR: Hazard ratio; NSCLC: Non-small-cell lung cancer: n.r.: Not reported; OS: Overall survival; PFS: Progression-free survival; RR: Response rate; TKI: Tyrosine kinase inhibitor.

Author (year)

Study

Table 1. Randomized Phase III clinical trials with TKIs in clinically or molecularly selected mutated NSCLC.

[18]

[19]

[24]

[25]

[32]

[34]

30.5 vs 23.6 p = 0.31 22.6 vs 28.8 HR: 1.065, p = 0.69 19.3 vs 19.5 HR: 1.04, p = 0.87 n.r.

n.r.

[17]

[16]

Ref.

30.9 vs n.r. HR: 1.638, p = 0.211

27.2 vs 25.6 HR: 1.043, p = n.r.

22.3 vs 22.9 HR: 0.932, p = 0.604

HR: 0.78, 95% CI: 0.50–1.20

18.6 vs 17.3 HR: 0.91, 95% CI: 0.76–1.10

OS (months)

Advanced non-small-cell lung cancer with EGF receptor mutations

Review

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Costanzo, Montanino, Di Maio et al.

chemotherapy arm (p < 0.0001). Also in this trial, no significant difference in OS was observed. The North-East Japan Study Group (NEJ002 study) compared gefitinib with carboplatin/paclitaxel as first-line treatment of advanced NSCLC patients with activating EGFR mutation [19]. The study was stopped by the Independent Data and Safety Monitoring Committee after a pre-planned interim analysis that showed a significant difference in PFS favoring gefitinib (10.4 vs 5.5 months; HR: 0.36). The final analysis confirmed this significant difference (median PFS 10.8 vs 5.4 months; HR: 0.30; 95% CI: 0.22–0.41; p < 0.001). Therefore, the results of these four prospective randomized clinical trials conducted in first-line setting in Asian patients strongly support the use of first-line gefitinib for patients with EGFR mutation-positive advanced NSCLC. On these bases, gefitinib was the first TKI to be approved for treatment of advanced NSCLC patients with activating EGFR mutations. A Phase IV, open-label, single-arm, study of first-line gefitinib in 107 Caucasian patients with EGFR mutation-positive NSCLC has recently confirmed that gefitinib is effective in this setting, irrespective of the ethnicity, as assessed by response rate (70%), disease control rate (91%), median PFS (9.7 months) and median OS (19 months) [22]. Erlotinib

The activity of erlotinib in advanced NSCLC patients with EGFR mutations was first evaluated in a large Spanish trial, where lung cancers from 2105 patients were screened for EGFR mutations [23]. A high response rate (70.6%) and a PFS of 14 months was observed with erlotinib treatment in the group of 350 patients (16.6%) found positive for EGFR mutations. Two randomized Phase III trials evaluated the efficacy of erlotinib as first-line therapy in patients with EGFR mutations [24,25]. The OPTIMAL trial compared first-line erlotinib versus carboplatin/gemcitabine in 165 Chinese patients with advanced EGFR mutation-positive NSCLC [24]. There was a significant improvement in PFS (primary end point) for patients receiving erlotinib compared with chemotherapy (median 13.1 vs 4.6 months; HR: 0.16; 95% CI: 0.10–0.26; p < 0.0001), and this improvement was observed in all patient subgroups, irrespective of age, gender, performance status and histology. Patients treated with erlotinib had a higher response rate (83 vs 36%; p < 0.0001) and a clinically relevant improvement in quality of life (p < 0.0001 for all scales) compared with chemotherapy group [26]. OS did not significantly differ between the two treatment arms (HR: 1.065; p = 0.6849), possibly due to high rate of crossover to TKI therapy in the chemotherapy arm [27]. The results of the OPTIMAL study were reinforced by the EURTAC (Erlotinib vs standard chemotherapy as first-line Treatment for European patients with advanced EGFR mutation-positive NSCLC) trial, a Phase III study, comparing erlotinib versus standard chemotherapy (cisplatin or carboplatin plus docetaxel or gemcitabine) in a population of Caucasian patients [25]. Median PFS was 9.7 months in the erlotinib group 1210

compared with 5.2 months in the chemotherapy group (HR: 0.37; 95% CI: 0.25–0.54; p < 0.0001). In the intention-to-treat population, response rate was 58% in the erlotinib group compared with 15% in the chemotherapy group. OS did not significantly differ between the two groups: median survival was 19.3 months in the erlotinib arm versus 19.5 months in the control group (HR: 1.04; 95% CI: 0.65–1.68; p = 0.87). The frequent crossover to erlotinib at progression in the chemotherapy arm might have confounded the OS comparison. To date, no direct comparison between erlotinib and gefitinib in patients with EGFR mutation-positive NSCLC exists. A randomized, non-comparative, Phase II study evaluated the activity and safety of gefitinib and erlotinib as second-line therapy for 96 patients with advanced NSCLC without molecular selection [28]. Response rate was 47.9% in the gefitinib arm and 39.6% in the erlotinib arm. Median PFS was 4.9 months in the gefitinib arm and 3.1 months in the erlotinib arm. Only 49 patients (51%) had adequate tissue samples for EGFR mutation test: overall, 17 patients had activating EGFR mutations, 9 in the gefitinib arm and 8 in the erlotinib arm. The response rate in these patients was 66.7% in gefitinib arm and 62.5% in erlotinib arm. The median PFS for all EGFR mutation-positive patients was 11.9 months compared with only 2.8 months for wild-type (p = 0.086). However, the authors concluded that, given the small number of patients analyzed for molecular study for each arm, caution should be exercised and prospective studies are needed. The question whether erlotinib is better than gefitinib should be answered by a randomized Phase IIb study (the CTONG 0901 study), conducted in China. In this trial, 70 patients with advanced NSCLC harboring EGFR exon 21 mutation will be randomized to first-line gefitinib or erlotinib: primary end point of the study is response rate (ClinicalTrials.gov identifier: NCT01024413). Second-generation, irreversible EGFR TKIs

The second-generation of EGFR TKIs have the advantage of forming covalent, irreversible bonds with the target, which should increase their effectiveness through a prolonged inhibition of EGFR signaling. It is hypothesized that the prolonged and irreversible inhibition of the receptor has the potential for further improvement in response to treatment over the firstgeneration TKIs such as erlotinib and gefitinib [29,30]. In particular, in preclinical studies irreversible TKIs effectively killed cells with acquired resistance to first-generation TKIs [31]. Several irreversible oral TKIs that target simultaneously multiple members of the EGFR family are currently in clinical development for NSCLC, including afatinib, dacomitinib and neratinib. Afatinib

The activity of afatinib as first- or second-line therapy for NSCLC patients with tumors harboring EGFR mutations was evaluated in a Phase II single-arm study (LUX-LUNG 2) [32]. Response rate was 61%, with a disease control rate of 82%. Median PFS was 10.1 months. The LUX-LUNG 3 trial was Expert Rev. Anticancer Ther. 13(10), (2013)

Advanced non-small-cell lung cancer with EGF receptor mutations

an open-label, randomized, Phase III trial comparing afatinib versus cisplatin/pemetrexed as first-line therapy for 345 patients (from North and South America, Europe, Asia and Australia) with advanced adenocarcinoma of the lung harboring EGFR mutations [33]. Afatinib significantly prolonged PFS as compared with chemotherapy (11.1 vs 6.9 months; HR: 0.58; 95% CI: 0.43–0.78; p = 0.001). In 308 patients with common mutations (Del19/L858R), PFS with afatinib was 13.6 months (HR: 0.47; 95% CI: 0.34–0.65; p = 0.001). Moreover, treatment with afatinib was associated with a delay in worsening of lung cancer-related symptoms and improvement in quality of life. These findings were confirmed by the LUX-LUNG 6 study that compared afatinib with cisplatin/gemcitabine in 364 Asian patients with advanced adenocarcinoma of the lung and EGFR mutation [34]. Afatinib significantly improved PFS (11 vs 5.6 months; HR: 0.28; p < 0.0001), response rate (66.9 vs 23.0%; p < 0.0001) and disease control rate (92.6 vs 76.2%; p < 0.0001) as compared with chemotherapy. Moreover, significantly higher number of patients had improvement of cough (p < 0.0003), dyspnea (p < 0.0001) and pain (p = 0.003) with afatinib than with chemotherapy [35]. Finally, a randomized Phase IIb clinical study (the LUX-LUNG 7 study) is evaluating in a head-to-head comparison whether afatinib is better than gefitinib in terms of PFS as first-line therapy of 264 patients with EGFR mutation: the study will have the power to detect a 0.73 HR (corresponding to an improvement in PFS from 10 to 13.7 months) (ClinicalTrials.gov identifier: NCT01466660). Dacomitinib

Dacomitinib showed antitumor activity in patients with progressive NSCLC after treatment with an EGFR TKI and one or more chemotherapy regimens, and this represented the background to test its potential utility in earlier lines of therapy [36]. A randomized Phase II study compared dacomitinib with erlotinib in 188 patients with advanced NSCLC (30 of whom EGFR mutation positive) pre-treated with one or two prior chemotherapy regimens [37]. PFS (primary end point) was 2.86 months for patients treated with dacominitib and 1.91 months in the erlotinib arm (HR: 0.66; 95% CI: 0.47–0.91; p = 0.012). Median OS was longer for patients treated with dacomitinib than erlotinib, although this difference was not statistically significant (9.53 vs 7.44 months; HR: 0.80; 95% CI: 0.56–1.13; p = 0.205). However, in the small subgroup of patients harboring EGFR mutation, median PFS was 7.44 months for both dacomitinib and erlotinib (HR: 0.46; 95% CI: 0.18–1.18; p = 0.098). A large randomized Phase III clinical study (the ARCHER 1050 study) is comparing dacomitinib and gefitinib in 440 patients with advanced NSCLC and EGFR exon 19/21 mutations. Primary end point is PFS (ClinicalTrials. gov identifier: NCT01774721). Neratinib

Neratinib has been studied in a Phase II trial to assess the response rate in specific groups of NSCLC patients thought www.expert-reviews.com

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likely to benefit from an irreversible EGFR TKI: patients previously benefiting from first-generation TKI therapy who developed acquired resistance after at least 12 weeks of treatment (arm A if they were EGFR mutation positive or arm B if they were wild-type) and TKI-naı¨ve patients (arm C) with clinical characteristics predicting TKI response (adenocarcinoma and light smoking histories) [38]. The response rate was 3% in arm A and 0% in arms B and C. No patients with known T790M responded. Of note, three of four patients with an exon 18 G719X EGFR mutation had a partial response and the fourth had stable disease lasting 40 weeks. The authors supposed that the low activity of neratinib was probably due to insufficient bioavailability related to diarrhea-imposed dose limitation. Safety & tolerability

The adverse events reported in randomized Phase III clinical trials with EGFR TKIs as first-line treatment of patients with advanced NSCLC harboring EGFR mutations are summarized in TABLE 2 [16–19,24,25,33,34]. Rash was the most common adverse event with all TKIs, and it was observed in 71–76% patients treated with gefitinib in the two Japanese studies dedicated to mutated patients, in 73–80% patients treated with erlotinib and in 81–89% patients treated with afatinib. Overall, grade ‡3 rash was uncommon in the studies with gefitinib (2–5.3%), it was 2–13% with erlotinib, in Asian and Caucasian population, respectively, and it was observed in 14.6–16.2% patients treated with afatinib. Diarrhea was common with gefitinib (34.2–48%) and erlotinib (25–57%), but it was reported by almost all patients treated with afatinib (88.3–95.2%). Moreover, grade ‡3 diarrhea was rare with gefitinib (1% of patients), while it was observed in 5% Caucasian patients treated with erlotinib and in 5.4–14.4% patients treated with afatinib. Mucositis was reported in less than 20% patients treated with gefitinib and erlotinib, while it was observed in 51.9–72.1% patients treated with afatinib (grade ‡3 in 5.4–8.7%). Severe nausea, vomiting or bone marrow toxicity were infrequent with all TKIs. Elevated levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were observed in 55.3–75% patients treated with gefitinib (grade ‡3 in 14–26.3% cases) and in 6–37% patients treated with erlotinib (grade ‡3 in 2–4% cases): however, one patient in the erlotinib group of the EURTAC trial had a fatal hepatotoxicity. No liver dysfunction was reported with afatinib in LUX-LUNG 3 trial, while ALT increase was observed in 20.1% patients treated with afatinib in LUX-LUNG 6 trial. The most serious adverse event associated with gefitinib therapy was interstitial lung disease (ILD), that was reported in 5.3 and 2.3% patients treated with gefitinib in NEJ002 and in WJTOG3405 trial, with one treatment-related death in both trials, respectively, while no fatal ILD-like events were observed in the two trials with erlotinib. Three cases of ILD-like events (grade 5 in one case) were reported with afatinib in the LUX-LUNG 3 trial, while no one was reported in the LUX-LUNG 6. 1211

1212

21.9%

17.0%

16.6%

12.9%

16.8%

Anorexia

Mucositis

Nausea

Vomiting

Asthenia

-

n.r.

2.6%

n.r.

n.r.

2.2%

3.7%

0.3%

0.2%

0.3%

0.2%

1.5%

0.3%

-

0%

3.8%

0.3%

3.1%

Grade 3–5

-

30.2%

6.3%

20.1%

9.5%

28.3%

18.9%

24.5%

40.2%

44.6%

6.3%

11.3%

20.1%

49.7%

n.r.

72.4%

All

1.3%

11.3%

1.3%

1.9%

1.9%

10%

0%

0%

1.9%

13.8%

0%

-

0%

2.5%

n.r.

29.3%

Grade 3–5

Gefitinib (First SIGNAL)

-

75%

12%

33%

7%

36%

n.r.

16%

19%

n.r.

8%

8%

14%

48%

29%

76%

All

2.3%

14%

0%

0%

0%

2%

n.r.

1%

0%

n.r

1%

-

0%

1%

1%

2%

Grade 3–5

Gefitinib (WJTOG 3405)

NSCLC: Non-small-cell lung cancer; n.r.: Not reported; TKI: Tyrosine kinase inhibitor.

Interstitial lung disease

AST/ALT elevation

n.r.

10.9%

Neuropathy

Thrombocitopenia

11%

Alopecia

n.r.

12.0%

Constipation

Anemia

46.6%

Diarrhea

n.r.

13.5%

Paronychia

Neutropenia

66.2%

All

Gefitinib (IPASS)

Rash or acne

Adverse events

-

55.3%

7.0%

18.4%

6.1%

10.5%

n.r.

n.r.

n.r.

14.9%

0.8%

n.r.

n.r.

34.2%

n.r.

71%

All

5.3%

26.3%

0%

0%

0.9%

2.6%

n.r.

n.r.

n.r.

5.3%

0%

n.r.

n.r.

0.9%

n.r.

5.3%

Grade 3–5

Gefitinib (NEJ002)

-

37%

4%

5%

6%

5%

1%

1%

13%

n.r.

n.r.

n.r.

0%

25%

4%

73%

All

0%

4%

0%

0%

0%

0%

0%

0%

1%

n.r.

n.r.

n.r.

0%

1%

0%

2%

Grade 3–5

Erlotinib (OPTIMAL)

Tyrosine kinase inhibitors

Table 2. Adverse events with TKIs as first-line therapy of EGFR mutated NSCLC.

-

6.0%

1%

12%

0

57%

n.r.

n.r.

n.r.

31%

9%

14%

n.r.

57%

n.r.

80%

All

1%

2.0%

0%

1%

0

6%

n.r.

n.r.

n.r.

0%

1%

-

n.r.

5%

n.r.

13%

Grade 3–5

Erlotinib (EURTAC)

0.4%

n.r.

n.r.

3.1%

0.9%

17.5%

17.0%

17.9%

72.1%

20.5%

n.r

n.r.

n.r.

95.2%

56.8%

89.1%

All

0.9%

n.r.

n.r.

0.4%

0.4%

1.3%

3.1%

0.9%

8.7%

3.1%

n.r.

-

n.r.

14.4%

11.4%

16.2%

Grade 3–5

Afatinib (LUX-LUNG 3)

n.r.

20.1%

n.r.

5.4%

2.1%

10.0%

9.6%

n.r.

51.9%

10.0%

n.r.

n.r.

n.r.

88.3%

n.r.

80.8%

All

n.r.

1.7%

n.r.

0.4%

0.4%

0.4%

0.8%

n.r.

5.4%

1.3%

n.r.

n.r.

n.r.

5.4%

n.r.

14.6%

Grade 3–5

Afatinib (LUX-LUNG 6)

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The only direct comparison between gefitinib and erlotinib came from the small Korean randomized Phase II study in patients with advanced NSCLC who failed previous chemotherapy [28]. In this study, more treatment-related grade 3– 4 adverse events were observed with erlotinib than gefitinib (12.5 vs 4.2%, respectively). Overall, skin rash was the most common adverse event (62.5% in gefitinib arm vs 72.9% in erlotinib arm): grade 2–3 skin rash was observed in 10.4% patients in gefitinib arm and in 43.7% patients in erlotinib arm. Moreover, more patients in the erlotinib group suffered from fatigue (16.7 vs 0%). Finally, two patients of gefitinib group and one patient of erlotinib group died due to pneumonia, but there was no confirmed ILD.

Review

Table 3. Mechanisms of resistance to tyrosine kinase inhibitors. Resistance

Mechanisms

Primary

Low BIM expression Low IkB expression with increased NF-kB activation High levels of BRCA1 mRNA expression

Secondary

TKI-resistant EGFR mutations (T790M) MET amplification HER2 amplification PIK3CA mutations BRAF mutations

Resistant disease

The efficacy of current EGFR-TKIs in patients with activating mutations is limited by the development of acquired resistance, generally after a period of treatment of 6–12 months. Moreover, approximately 30% of patients do not respond at all to TKIs despite the presence of activating EGFR mutations. Different mechanisms have been proposed to cause intrinsic resistance of EGFR mutant NSCLC to TKI, including the proapoptotic BH-3-only molecule (BIM) [39], the DNA repair protein BRCA1 [40] and the NF-kB regulator IkB [41]. However, the majority of available information is related to acquired resistance (TABLE 3). Clinical criteria for acquired resistance include: i) previous treatment with a single-agent EGFR TKI; ii) confirmed activating EGFR mutations or objective clinical benefit from treatment with an EGFR TKI (defined as documented objective response or durable clinical benefit after initiation of gefitinib or erlotinib); iii) systemic progression of disease within 30 days of continuous EGFR TKI therapy; iv) no intervening systemic treatment between cessation of EGFR TKIs and initiation of new therapy [42]. The first major mechanism of acquired resistance is the development of second-site EGFR mutations. In particular, the substitution of the amino acid threonine by methionine in amino acid position 790 (T790M) on exon 20 is the most common secondary resistance mutation, accounting for about 50% of tumors relapsed from prior TKI therapy [43,44]. The T790M mutation results in alteration of the topology of the ATP-binding pocket, interrupting the physicochemical binding of gefitinib/erlotinib, but also leading to much increased affinity of the EGFR protein to ATP, resulting in resistance to EGFR TKIs [45]. It has been also demonstrated with highly sensitive techniques that a number of NSCLC patients (up to 35%) with an activating EGFR mutation may also carry clones of tumor cells with the T790M mutation before exposure to TKIs, which are not detectable by using routine diagnostic tests [40]. Patients harboring the exon 20 T790M mutation are generally considered to be resistant to reversible TKIs (gefitinib or erlotinib) [46]. However, it is important in these cases the relative quantification of mutant alleles that might provide information useful for treatment decision. Indeed, patients www.expert-reviews.com

Activation of AXL kinase MAPK1 amplification Epithelial to mesenchymal transformation Histologic transformation into small-cell lung cancer Suboptimal drug exposure in the brain

who co-express the T790M and a sensitizing mutation before exposure to TKI might benefit of treatment with these drugs [47]. Other important mechanisms of acquired resistance to TKIs include the activation of EGFR signaling through different aberrant pathways. The amplification of the MET oncogene or the overexpression of MET protein, that activates ERBB3/PI3K/AKT signaling, are rare in baseline tumor samples from EGFR TKI-naı¨ve patients, but they are observed in 5–20% of tumor samples after EGFR TKIs treatment [48]. Furthermore, studies on patients with acquired resistance to TKIs revealed the presence of HER2 amplification in 12% of cases, PIK3CA mutations up to 5% of cases, BRAF mutations in 1% of cases [49–51]. Activation of AXL kinase and amplification of MAPK1 have also been suggested to be involved in acquired resistance to EGFR TKIs [52,53]. Other mechanisms of acquired TKIs resistance include epithelial to mesenchymal transformation and histologic transformation into small-cell lung cancer [54]. Finally, another mechanism potentially involved in secondary resistance may be a suboptimal drug exposure in the brain [54]. Several studies showed that drug concentration of TKIs in the brain is only 1–5% of the levels found in plasma, and this condition can explain the high percentage of disease progression in central nervous system (in about 30% of patients) observed during treatment with TKIs [55,56]. Recently, a retrospective study aimed to classify the diversity of EGFR-TKI failure, and to investigate the usefulness of clinical modes in subsequent management and prognosis [57]. Onehundred and twenty consecutive clinical trial patients with EGFR-TKI failure were enrolled as the training set to establish a clinical model based on clinical factors, while another 1213

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107 routine patients were enrolled as the validating set according to a Bayes discriminant analysis. The study showed that the duration of disease control, the evolution of tumor burden and the clinical symptom were verified as feasible grouping variables, leading to classify the cohort of patients into three groups, including dramatic progression, gradual progression and local progression. PFS for the dramatic progression, gradual progression and local progression groups were 9.3, 12.9 and 9.2 months, respectively (p = 0.007). OS for the three groups was 17.1, 39.4 and 23.1 months, respectively (p < 0.001). Moreover, the study suggested that TKI continuation was superior to switching chemotherapy in patients with gradual progression (39.4 vs 17.8 months; p = 0.02). On the contrary, patients in dramatic progression group demonstrated a better survival with switching to chemotherapeutic regimens instead of continued TKI therapy (23.9 vs 18.6 months; p = 0.07). In such patients, a repeat biopsy may reveal clinically relevant findings of changes in histology or new mutations that may potentially lead to histologically and molecularly informed treatment decisions [58]. Discussion & conclusions

The increased understanding of the EGFR pathway in NSCLC with the identification of activating mutations in the tyrosine kinase domain of EGFR and the impressive clinical results observed with TKIs in EGFR mutant patients have completely changed in the last few years the diagnostic and therapeutic algorithm of patients with advanced NSCLC. Several randomized trials have demonstrated that first-line treatment with TKIs in advanced NSCLC patients harboring activating EGFR mutations is associated with clinically relevant and statistically significant improvement in response rate and in the PFS compared with platinum-based chemotherapy, although no improvement in OS have been observed, probably due to the high proportion of patients (59–98%) from first-line chemotherapy crossing over to second-line therapy with EGFR TKIs. Moreover, first-line treatment with TKIs is associated with improvement in quality of life and better toxicity profile than chemotherapy. A large meta-analysis exploring the impact of EGFR TKIs in NSCLC, including 23 randomized clinical trials with 14,570 patients, have recently confirmed that front-line treatment with TKIs prolonged PFS in EGFR mutantpositive patients with a HR 0.43 (95% CI: 0.38–0.49; p < 0.001), strongly supporting the use of TKIs as front-line therapy for EGFR mutant-positive patients with advanced NSCLC [59]. However, none of the randomized clinical trials demonstrated a benefit in OS with first-line EGFR TKIs and there are no prospective studies comparing first- and second-line therapy with EGFR TKIs in patients with advanced NSCLC. There are consistent arguments supporting the use of first-line EGFR TKI, including the relevant advantage in PFS (almost doubled with TKIs) and in response rate, the better tolerance, the improvement in quality of life and the assurance of drug exposure, considering 1214

that 30–41% of patients with EGFR mutations randomly assigned to first-line chemotherapy in randomized clinical trials, actually did not receive EGFR TKIs as second-line therapy, missing definitely the opportunity to receive the most effective treatment [60]. The only concern regarding the use of TKI as first-line therapy of patients with NSCLC harboring EGFR mutations can be the turnaround time of the EGFR mutation test. In clinical practice, it takes several days or weeks to wait for the result of EGFR mutation test. Patients with huge tumor burden are at risk of rapid deterioration of clinical conditions and they could be not suitable for waiting for EGFR mutation results. In these cases, where the promptness of therapy is necessary, a comprehensive evaluation of the patient based also on clinical characteristics associated with the presence of EGFR mutation is needed and a possible approach is to start systemic chemotherapy while waiting for the results of the EGFR mutation analysis. A solution to reduce the timing for EGFR mutation testing is to include this analysis in the initial pathology workout for patients with advanced NSCLC without waiting for the request of the oncologist. On the contrary, a treatment strategy based on TKIs as firstline therapy in unselected patients with advanced NSCLC followed at progression by chemotherapy is inferior in terms of OS to standard chemotherapy followed at progression by TKIs and cannot be recommended in clinical practice [61]. However, there are several clinical and methodological issues that need to be addressed, including: the best choice among different EGFR TKIs; the treatment of resistant disease; and the treatment of patients with specific clinical conditions, such as poor performance status, brain metastasis or leptomeningeal carcinomatosis. Currently, there are no direct comparisons between different TKIs: actually, gefitinib was the first EGFR TKI with demonstrated efficacy in the treatment of patients with advanced NSCLC harboring activating EGFR mutations and therefore it has been considered as control arm in all the ongoing randomized prospective clinical trials that are comparing the different TKIs (the CTONG 0901 study, comparing erlotinib with gefitinib; the LUX-LUNG 7 study, comparing afatinib with gefitinib; the ARCHER 1050 study, comparing dacomitinib with gefitinib). The only direct comparison between gefitinib and erlotinib, coming from a small randomized Phase II study conducted without molecular selection, suggest a better toxicity profile with gefitinib, in terms of rash and fatigue [28]. Several strategies are being explored to overcome resistance to TKIs, including: treatment beyond progression; rechallenge with a TKI after a chemotherapy treatment; use of second- or third-generation EGFR TKI; and drug combinations [54]. Factors to consider in presence of disease progression during treatment with TKIs in patients with EGFR mutant, advanced NSCLC are the risk of tumor flare, the tumor growth rate and the opportunity of additional treatments, on the basis of age, performance status and Expert Rev. Anticancer Ther. 13(10), (2013)

Advanced non-small-cell lung cancer with EGF receptor mutations

comorbidities. RECIST criteria are usually considered not optimal in this clinical setting and patients with slow progression could benefit of continuing therapy with TKIs beyond progression [62]. Few studies have assessed the activity of chemotherapy after TKIs in EGFR mutant NSCLC: preclinical data on cell lines with acquired resistance to EGFR TKIs have found increased effect of chemotherapy when combined with TKIs [63]. On these bases, a randomized Phase III clinical trial (IMPRESS study) is assessing the efficacy of continuing gefitinib in addition to chemotherapy versus chemotherapy alone in patients who have EGFR mutation-positive advanced NSCLC in progression after first-line gefitinib (ClinicalTrials.gov identifier: NCT01544179). There are emerging evidence suggesting the possibility of a successful re-administration of gefitinib or erlotinib following a drug holiday [64,65]. This hypothesis will be prospectively tested in a Phase II, single-arm clinical trial (the ICARUS study), that will evaluate the activity of gefitinib as treatment re-challenge in patients with advanced, EGFR mutation-positive NSCLC who previously responded to gefitinib and received subsequent chemotherapy (ClinicalTrials.gov identifier: NCT01530334). Second-generation TKIs are more potent than first-generation EGFR TKIs, but they still inhibit EGFR activating mutations, although at lower concentrations [66]. Third-generation EGFR TKIs, including WZ4002, CO1686 and AP26113, specifically inhibit EGFR mutants, including EGFR T790M [67–69]. On these bases, two Phase I/II trials are ongoing with CO1686 and AP26113 in patients with EGFR mutated NSCLC resistant to reversible EGFR inhibitors (ClinicalTrials.gov identifiers: NCT01526928 and NCT01449461, respectively). Drug combinations have been explored by several studies. Negative results have been reported with the combination of erlotinib and cetuximab and with the combination of EGFR TKIs with other biologic agents, including SRC inhibitors, HSP90 inhibitors, mTOR inhibitors [70]. Encouraging data were presented on the association of afatinib and cetuximab in patients with non-squamous NSCLC harboring EGFR sensitizing mutations, previously treated with erlotinib or gefitinib for a median time period of 2.4 years. Partial responses were observed in 51% of cases, although 35 out of 55 evaluable patients had T790M mutation. Stable disease was obtained in 44% of patients, leading to a clinical benefit of 95% [71]. Treatment of patients with advanced NSCLC and poor performance status (ECOG PS 3–4) is a major challenge in oncology: currently, there is no standard therapy, except supportive care, and median OS is shorter than 2–3 months. However, some reports have recently showed that patients with EGFR mutant advanced NSCLC can be dramatically responsive to gefitinib (showing a ‘Lazarus’ response), even when the performance status is extremely poor [72,73]. Therefore, analysis for EGFR mutations should be always considered for those patients who are unfit for chemotherapy, due to age, comorbidities or poor performance status, but who

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Review

present clinical characteristics associated with a high incidence of EGFR mutations (never or former or light smokers), given the possibility to successfully treat with TKIs. Finally, retrospective analysis and small prospective studies have shown the activity of EGFR TKIs on brain metastases, with high intracranial response rates and prolonged disease control, also without the addition of brain radiotherapy [74,75]. On these bases, the use of whole brain radiotherapy could be deferred until the occurrence of tumor resistance: however, this evidence should be confirmed by prospective randomized clinical trials. In conclusion, TKIs of EGFR are currently the standard first-line treatment of patients with advanced NSCLC harboring activating EGFR mutations. Ongoing and new, welldesigned trials should better define which is the best TKI in first-line setting, the role of EGFR TKIs in other clinical setting, such as adjuvant or neoadjuvant or in combination with radiotherapy in patients with locally advanced NSCLC and EGFR mutations, the role of irreversible inhibitors of EGFR tyrosine kinases and of new drugs combinations in overcoming the resistance to TKIs. Expert commentary & five-year view

The impressive clinical results observed with TKIs in EGFR mutant patients have completely changed in the last years the diagnostic and therapeutic algorithm of patients with advanced NSCLC. TKIs of EGFR are the current standard first-line treatment of patients with advanced NSCLC harboring activating EGFR mutations. However, there are several questions that need to be addressed, including the choice among different EGFR TKIs, the treatment of resistant disease and of patients with specific clinical conditions, such as poor performance status or brain metastases. In particular, the resistance to TKIs is a major problem, affecting about one-third of patients since the beginning and almost all patients in the course of the treatment. Several strategies are being explored to overcome resistance to TKIs, including treatment beyond progression, rechallenge with a TKI after a chemotherapy treatment, use of second- or thirdgeneration EGFR TKI, drug combinations. The results of ongoing and new, well-designed trials should answer these questions. Financial & competing interests disclosure

Honoraria: A Morabito, Roche, Astra Zeneca; R Costanzo, Astra Zeneca; M Di Maio, Roche; F Perrone, Roche, Boehringer-Ingelheim. Consultant: N Normanno, Astra Zeneca; M Di Maio, Boehringer-Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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Key issues • EGF receptor (EGFR) plays a central role in the process of cell growth and tumor progression and its overexpression occurs in many human epithelial tumors, including non-small-cell lung cancer (NSCLC). • Activating mutations of EGFR identify a specific subtype of lung cancer, whose growth is dependent on EGFR pathway activation, which represents the leading pathway in inducing cellular transformation in these selected patients. • It has been demonstrated that activating EGFR mutations lead to increased affinity of tyrosine kinase inhibitors (TKIs) for the mutant receptor compared with the wild-type one. • Several randomized clinical trials have consistently demonstrated the superiority of TKIs over chemotherapy as first-line therapy of EGFR mutated NSCLC, in terms of response rate, progression-free survival (PFS), quality of life and tolerability. • However, no improvement in overall survival has been observed, probably in consideration to the high proportion of patients crossing over from first-line chemotherapy to second-line therapy with EGFR TKIs. • These results prompted the TKIs of EGFR as the current standard first-line treatment of patients with advanced NSCLC harboring activating EGFR mutations. • Currently, there are no direct comparisons between different TKIs: gefitinib was the first EGFR TKI with demonstrated efficacy in the treatment of NSCLC patients with activating mutations of EGFR and it has been considered as the control arm in the ongoing randomized clinical trials that are evaluating the efficacy of different TKIs.

cancer. J. Thorac. Dis. 2(3), 144–153 (2010).

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