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Abstract

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths. In the last decade, the epidermal growth factor receptor (EGFR) signalling pathway has emerged as one of the most important molecular aberrations, representing an attractive therapeutic target in NSCLC. Drugs interfering with the tyrosine kinase domain of the EGFR (EGFR TKIs), such as erlotinib and gefitinib, have demonstrated efficacy in patients with advanced NSCLC irrespective of therapy line and particularly in patients harbouring activating mutations in the EGFR gene (EGFR^mut+). Results of large phase III randomized trials clearly established that EGFR TKIs are superior to chemotherapy as frontline treatment in patients with EGFR^mut+, whereas in the EGFR wild-type (EGFR^WT) or EGFR unknown population, platinum-based chemotherapy remains the standard of care, with no consistent benefit produced by the addition of EGFR TKI. In pretreated NSCLC, EGFR TKIs are considered more effective than standard monotherapy with cytotoxics in the presence of classical EGFR mutations, whereas in the EGFR^WT population, a similar efficacy to docetaxel or pemetrexed in terms of survival has been demonstrated. Unfortunately, patients who initially responded to EGFR TKIs invariably develop acquired resistance. For such patients there is an urgent need for more effective strategies able to delay or possibly overcome resistance. In the present review we analysed the available data on erlotinib in the treatment of advanced NSCLC.

Keywords

erlotinib EGFR non-small cell lung cancer

Introduction

Lung cancer remains the most lethal disease in Western countries, with a case mortality rate of 85% [De Santis et al. 2013]. Non-small cell lung cancer (NSCLC) accounts for 75% of all lung cancers and includes different subtypes, underlying significant biological differences. Disease stage is the most relevant factor influencing mortality. Unfortunately, 70–80% of patients with NSCLC present with locally advanced or metastatic disease and median survival is approximately 12 months with standard chemotherapy [Reck et al. 2014]. In the last decade, a number of trials clearly demonstrated that the pathogenesis of lung cancer involves the accumulation of several molecular abnormalities over time [Govindan et al. 2012; Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004; Soda et al. 2007]. Alterations in gene sequence or expression can occur in critical cell signalling and regulatory pathways involved in cell cycle control, apoptosis and angiogenesis. Most importantly, different molecular events have been identified according to histotype, thus underlining relevant biological rather than morphological differences. Several molecular alterations have been described in adenocarcinomas, especially but not exclusively, in the never/former smoker population [Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004; Soda et al. 2007].

Since its discovery more than 20 years ago, the epidermal growth factor receptor (EGFR) has appeared as a key player in regulating cell proliferation and survival in different types of cancer [Cohen et al. 1996; Grandis and Sok, 2004; Salomon et al. 1995]. EGFR belongs to a family of four different receptors, including EGFR (ErbB-1; Human Epidermal growth factor Receptor HER1), HER2 (c-ErbB-2), HER3 (c-ErbB-3) and HER4 (c-ErbB-4). These proteins are coded by distinct genes that are expressed on chromosomes 7, 17, 12 and 2, respectively. After the ligand binds the receptor, the receptor dimerizes, either as a homodimer or as a heterodimer preferentially with HER2, but also with other members of the EGFR family, and undergoes auto-phosphorylation at specific tyrosine residues within the intracellular domain. These auto-phosphorylation events in turn activate downstream signalling pathways, including the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway, and the phosphatidylinositol 3’-kinase (PI3K)-Akt pathway. Activation of Ras initiates a multistep phosphorylation cascade that leads to the activation of MAPKs. The MAPKs, extracellular signal regulated kinase 1 and 2 ERK1 and ERK2 subsequently regulate gene transcription, cell proliferation and survival (Figure 1) [Lewis et al. 1998].

Figure 1.

EGFR pathway.

As in NSCLC EGFR is often deregulated by overexpression, gene amplification or mutations [Hirsch et al. 2006; Cappuzzo et al. 2005; Suzuki et al. 2005], its inhibition has represented an attractive therapeutic target. Small molecules interfering with the tyrosine kinase activity of the intracellular domain of EGFR, also named EGFR TKIs, have been the most investigated agents in advanced disease. Erlotinib (OSI 774, Tarceva, Genentech, San Francisco, CA, US) and gefitinib (ZD 1839, Iressa, AstraZeneca, Macclesfield, UK) are orally bioavailable synthetic anilinoquinazoline compounds that selectively bind to the adenosine triphosphate (ATP) binding site of the EGFR tyrosine kinase intracellular domain, blocking EGFR auto-phosphorylation. Afatinib (Gilotrif, Boehringer Ingelheim Germany) is a highly selective anilinoquinazoline that irreversibly binds directly to the ATP site in the kinase domain of all HER family members. In European countries, gefitinib and afatinib are approved for patients with EGFR^mut+ only, whereas erlotinib is also approved in second- or third-line treatment for those with EGFR wild type (EGFR^WT). The aim of the present article is to review available data on erlotinib in the treatment of advanced NSCLC.

Erlotinib pharmacokinetics and pharmacodynamics

Erlotinib hydrochloride is an orally disposable synthetic anilinoquinazoline compound that selectively binds to the ATP-binding site of EGFR tyrosine kinase intracellular domain. After oral administration, erlotinib is widely distributed throughout the body with a bioavailability of 60% [Johnson et al. 2005]. It is metabolized in the liver by cytochrome P450s, primarily by CYP3A4 and CYP1A1, and in a minor proportion by CYP3A5 [Johnson et al. 2005]. A population pharmacokinetic study in 591 patients receiving single-agent erlotinib showed a median half life of 36.2 h with a time to reach steady-state plasma concentration of 7–8 days. Patient age, body weight or sex seemed not to affect clearance, while smokers had a 24% higher rate of erlotinib clearance. After a 100 mg oral dose, 91% of the dose was recovered: 83% in faeces and 8% in urine [Johnson et al. 2005]. OSI-420 (desmethyl erlotinib, CP-473420) is the active metabolite. OSI-420 exposure (area under the curve) in plasma is 30% (range 12–59%) of erlotinib, and OSI-420 clearance is more than fivefold higher than erlotinib [Meany et al. 2008].

In an in vitro enzyme analysis [Speake et al. 2006], erlotinib showed comparable binding affinity values against WT and mutant EGFR and no significant differences in activity were found across an enzyme panel of more than 200 isolated targets (predominantly kinases). In the same way, erlotinib showed a high correlation in growth inhibitory activity across a panel of 34 NSCLC cell lines, including three cell lines harbouring activating EGFR mutations [Yuza et al. 2007]. Recently, Kim and colleagues examined the different effects of erlotinib and gefitinib in the inhibition of EGFR and its downstream effectors in cell lines harbouring both WT and oncogenic (L858R) EGFR [Kim et al. 2015]. With respect to key tyrosine residues in mutant EGFR, erlotinib was primary active toward tyrosine Y845 residue in L858R EGFR signalling, which translates into a preferential inhibition of STAT5 phosphorylation. This observation suggested that constitutive activation of L858R EGFR is mediated through phosphorylation of Y845 followed by activation of the STAT5 downstream pathway and erlotinib seems to specifically target these pathways, at least in those NSCLCs harbouring exon 21 mutations. Conversely, gefitinib preferentially acted mainly against Y1045 residue of L858R EGFR, which was closely linked to Cbl downstream effector. These data clearly supported a different antitumor activity of these drugs [Kim et al. 2015].

Studies with erlotinib in combination with chemotherapy as frontline treatment in unselected NSCLC

In 2000, platinum-doublet chemotherapy was the only available treatment for patients with advanced NSCLC with acceptable performance status [Schiller et al. 2002]. However, chemotherapy produced modest survival improvement versus best supportive care with considerable toxic effects. At the same time, preclinical studies identified in EGFR the key regulator of neoplastic growth and survival of NSCLC, as suggested by the fact that EGFR was overexpressed in the vast majority of lung tumours [Cohen et al. 1996; Salomon et al. 1995]. Furthermore, in preclinical lung cancer models the inhibition of EGFR suppressed cancer growth [Cohen et al. 1996; Grandis and Sok, 2004]. As a consequence, the possibility to simultaneously combine chemotherapy and EGFR inhibition with TKIs appeared to be a promising strategy to enhance antitumor activity and possibly improve patient outcome. The potential for combining chemotherapy with erlotinib was investigated in two large randomized trials enrolling more than 2200 patients [Herbst et al. 2005; Gatzemeier et al. 2007]. Both trials started accrual in 2001, had overall survival (OS) as their primary endpoint and, more importantly, allowed patient enrolment irrespective of any EGFR assessment. In TRIBUTE, a study conducted in the USA, erlotinib or placebo was added to carboplatin and paclitaxel for a maximum of six cycles, followed by maintenance therapy with erlotinib or placebo. OS [10.6 versus 10.5 months for erlotinib plus chemotherapy and placebo plus chemotherapy, respectively; hazard ratio (HR) 0.99; p = 0.95], response rate (RR) (21.5% versus 19.3%; p = 0.36) and time to progression (TTP) did not differ between the two arms [Herbst et al. 2005]. Similar results emerged from the other European trial, TALENT, in which erlotinib or placebo was added to cisplatin and gemcitabine with no improvement in OS (43 versus 44.1 weeks, HR 1.06; p = 0.4863) [Gatzmeier et al. 2007]. However, in both trials a trend toward longer progression-free survival (PFS) and OS in the small subgroup of never smokers (TRIBUTE = 72 patients; TALENT = 10 patients) receiving erlotinib contributed to researchers being more selective in their choice of patients for EGFR TKIs. The lack of efficacy of a combination strategy also emerged for gefitinib, the other reversible EGFR TKI, as demonstrated in the INTACT1 and INTACT2 trials [Giaccone et al. 2004; Herbst et al. 2004], leading to the conclusion that a combination of chemotherapy and EGFR TKIs was not effective as a frontline strategy in an unselected population.

Along with the lack of patient selection, the potential antagonism between the two classes of drugs when used in a concomitant fashion can account for the negative results obtained in all these trials. Indeed, EGFR TKIs induce G1 phase cell cycle arrest, whereas the cytotoxic effects of chemotherapy are strictly cell cycle dependent [Piperdi et al. 2004]. Conversely, the sequential or intercalated use of chemotherapy and an EGFR TKI could lead to pharmacodynamic separation determining an optimal therapeutic window for both strategies.

The possibility of sequential use of erlotinib with chemotherapy has been investigated in preclinical models [Davies et al. 2006; Li et al. 2007] and in phase I trials conducted in pretreated population, demonstrating promising activity [Mahaffey et al. 2007; Davies et al. 2007, 2008]. Two trials have explored the efficacy of such a strategy in the frontline setting [Mok et al. 2009b; Wu et al. 2013b]. FASTACT was a proof-of-concept phase II randomized study evaluating the safety and tolerability of sequential administration of erlotinib following standard chemotherapy with the unusual endpoint of nonprogression rate (NPR) at 8 weeks [Mok et al. 2009b]. The study included 154 untreated patients with NSCLC randomly assigned to erlotinib or placebo on days 15–28 of a four-week cycle of gemcitabine and either cisplatin or carboplatin for up six cycles. Notably, treatment with erlotinib or placebo stopped at week 6 with no permission of maintenance treatment. The study failed to meet its primary endpoint, demonstrating no difference in NPR at 8 weeks; however, patients in the erlotinib arm obtained a higher NPR at 16 weeks and a significant reduction in the risk of progression of 53% (PFS 29.4 versus 23.4 weeks, HR 0.47, p = 0.002). In addition, the intermittent schedule of erlotinib did not increase the risk of hematologic toxicities and the incidence of grade 3–4 cutaneous adverse events (AEs) was only 3%. In order to validate the sequential strategy in the frontline setting, the same authors conducted a large phase III trial, also known as FASTACT 2, the results of which were published 4 years later [Wu et al. 2013b]. Unlike FASTACT, patients continued to receive erlotinib or placebo until progression and patients in the placebo arm were crossed over to open-label second-line erlotinib. The primary endpoint was PFS. Overall, 451 patients with NSCLC were included in the study and in the intent-to-treat (ITT) population PFS was significantly prolonged in the erlotinib arm (7.6 versus 6.0 months, HR 0.57, p < 0.0001). Interestingly, the greatest benefit was observed in female patients, never smokers and those with adenocarcinoma histology. Subjects enrolled in the intercalated arm also derived a nonsignificant survival benefit (18.3 versus 15.3 months, HR 0.79, p = 0.0420). Among 301 tumour samples available, 283 were analysed for EGFR mutational status and 53% were positive for classical (exon 19 and exon 21) mutations. In this group of patients, the addition of sequential erlotinib translated into a significant PFS and OS advantage, whereas those with EGFR^WT did not derive any benefit. In addition, patients unsuitable for EGFR analysis (also named EGFR unknown) experienced longer PFS when treated with intercalated erlotinib, thus suggesting that a consistent proportion of these individuals had an EGFR-addicted disease. As FASTACT 2 was not designed to address the question of whether EGFR^mut+ patients could derive additional benefit from intercalated erlotinib, its results confirmed that in the absence of EGFR mutations this strategy was not superior to standard platinum-based chemotherapy.

Studies with erlotinib versus chemotherapy as first-line treatment in an unselected population

For years, oncologists have wanted to replace platinum-based chemotherapy with less toxic drugs, such as EGFR TKIs. The results of a number of phase II trials evaluating erlotinib in the frontline setting in a chemonaïve and unselected NSCLC population suggested that the drugs are less effective than standard platinum-based chemotherapy in the frontline setting in terms of RR and PFS [Giaccone et al. 2006; Hesketh et al. 2008; Arkeley et al. 2009; Lilenbaum et al. 2009; Lee et al. 2011; Pallis et al. 2012; Chen et al. 2012; Stinchcombe et al. 2011; Jackman et al. 2007]. Nevertheless, median survival was similar to that achievable with chemotherapeutics, thus suggesting that an EGFR TKI could be offered as frontline treatment even in the absence of any molecular selection (Table 1).

Table 1.

Phase II trials of first-line erlotinib in unselected patients with NSCLC.

Reference	Phase	No.	Treatment	Primary endpoint	RR/DCR (%)	PFS (months)	OS (months)	EGFR mutant/ tested (n)
Giaccone et al. [2006]	II	53	Erlotinib	PFS	22.7/53	2.7	12.9	7/53
Arkeley et al. [2009]	II	40	Erlotinib	PFS	15/43	1.95	11.5	4/18
Jackman et al. [2007] *	II	80	Erlotinib	OS	10/51	3.5	10.9	9/43
Lilenbaum et al. [2008] ^$	IIR	52	Erlotinib	PFS	4/41	1.9	6.5	0/19
		51	CBDCA + TXL		12/55	3.5	9.7	5/10
Hesketh et al. [2008] ^$	II	81	Erlotinib	OS	8/42	2.1	5	NR
Lee et al. [2011] ^$	II	24	Erlotinib	RR	21/25	1.5	3.2	3/12
Pallis et al. [2012]	II	49	Erlotinib	RR	24.5/NR	6.7	15.5	9/36
Chen et al. [2012] *	IIR	57	Erlotinib	RR	22.8/71.9	4.6	11.7	9/30
		56	Vinorelbine		8.9/57.1	2.5	9.3	15/30
Stinchcombe et al. [2011] *	IIR	44	GEM	PFS	7/NR	3.7	6.8	NR
		51	Erlotinib		0/NR	2.8	5.8
		51	GEM + erlotinib		21/NR	4.1	5.6

Study population with age at least 70 years.

Study population with a performance status of 2 or ineligible for platinum-based chemotherapy.

CBDCA, carboplatin; DCR, disease control rate; EGFR, epidermal growth factor receptor; GEM, gemcitabine; NSCLC, non-small cell lung cancer; NR, not reported; OS, overall survival; PFS, progression free survival; RR, response rate; TXL, paclitaxel.

In a phase III trial, Italian investigators evaluated the possibility of giving erlotinib frontline in an unselected NSCLC population [Gridelli et al. 2012]. In the TORCH study, 760 patients with NSCLC were randomly assigned to a standard platinum regimen followed by erlotinib at the time of progression versus the experimental arm of erlotinib first line followed by chemotherapy at progression. The study was discontinued when an interim analysis revealed that first-line erlotinib was inferior to chemotherapy in terms of PFS and most importantly in terms of OS. In the INNOVATIONS trial, 224 patients who were EGFR unselected were randomized to receive erlotinib plus bevacizumab or cisplatin, gemcitabine and bevacizumab [Thomas et al. 2011]. Similarly to the TORCH trial, in the absence of EGFR selection, the chemotherapy arm was superior to the erlotinib arm in terms of RR, PFS and OS. In the last few years, different studies have been conducted to assess the question of whether an EGFR TKI could be preferable in frail populations unsuitable for chemotherapy, such as patients with poor performance status or older patients. The Tarceva Or Placebo In Clinically Advanced Lung cancer (TOPICAL) study showed that erlotinib did not significantly improve OS when added to best supportive care (compared with best supportive care alone) in biologically unselected patients who were chemonaïve and had a poor performance status (European Cooperative oncology Group ECOG 2/3) or who were unfit for platinum chemotherapy [Lee et al. 2012]. Overall, these data clearly demonstrated that erlotinib is not indicated as frontline therapy in unselected NSCLC, including in patients unsuitable for standard chemotherapy.

Studies with erlotinib as maintenance therapy

An important option for patients not progressing after standard first-line chemotherapy is represented by maintenance therapy. The results of two large randomized phase III trials supported the benefit of erlotinib following platinum-based chemotherapy in unselected patients [Cappuzzo et al. 2010; Johnson et al. 2013]. In the SATURN trial, patients with NSCLC without progressive disease after four cycles of platinum-based chemotherapy were randomized to erlotinib or placebo [Cappuzzo et al. 2010]. The study met its primary and secondary endpoints, showing that patients receiving erlotinib had a significant reduction in the risk of progression (HR 0.71, p < 0.0001) and death (HR 0.81). Importantly, PFS subgroup analysis showed a benefit produced by erlotinib in all patients, irrespective of any clinical or biological characteristic, including in patients with EGFR^WT (HR = 0.78, p = 0.0185). As expected, the highest PFS benefit with erlotinib was observed in patients with EGFR mutations (HR = 0.10, p < 0.0001), with no benefit on survival probably because of the confounding effect of crossover. The ATLAS trial was a phase III study comparing maintenance erlotinib plus bevacizumab versus bevacizumab alone in patients with NSCLC without progressive disease after four cycles of platinum-based chemotherapy plus bevacizumab [Johnson et al. 2013]. Although the study met the primary endpoint of PFS (HR 0.72), the lack of improvement in survival and the high costs of the combination limited the impact of this strategy on clinical practice.

Studies with erlotinib in second-line setting

In the early 2000s, docetaxel was the only drug licensed for second-line therapy in NSCLC, as two trials established its superiority over best supportive care or single agent chemotherapy [Shepherd et al. 2000; Fossella et al. 2000]. However, no options were available for patients with progressive disease after docetaxel treatment or who were unsuitable for this treatment. Given these premises, new treatments were needed for such patients. Early trials of gefitinib and erlotinib reported interesting antitumor activity in a pretreated population [Fukuoka et al. 2003; Kris et al. 2003; Perez-Soler et al. 2004], representing the rationale to further explore these drugs in the second-line setting.

The superiority of erlotinib over placebo as second- or third-line therapy in NSCLC has been demonstrated in the BR21 trial [Shepherd et al. 2005]. In this study, patients with NSCLC whose condition failed to respond to one or more chemotherapy regimens and who were not eligible for further chemotherapy were randomized 2:1 to erlotinib or placebo. The primary endpoint was OS. The study enrolled a total of 731 individuals and met its primary endpoint, showing a survival advantage for patients allocated to the active arm (6.7 versus 4.7 months, HR 0.70; p < 0.001). Treatment with erlotinib was also associated with better PFS (2.2 versus 1.8 months, HR 0.61; p < 0.001) and higher response rate (8.9% versus <1%; p < 0.001). More interestingly, the benefit produced by erlotinib was maintained irrespective of age, histology, performance status, ethnicity and smoking history. The BR21 results not only led to the approval of erlotinib as second- or third-line treatment in NSCLC but it also opened the discussion on whether an EGFR TKI should be preferred to chemotherapy in this setting, even in the absence of any EGFR assessment. Consequently, a number of studies comparing erlotinib with docetaxel or pemetrexed, the other agent approved for second-line treatment [Hanna et al. 2004], were conducted with the aim of identifying the best second-line therapy [Ciuleanu et al. 2012; Garassino et al. 2013; Karampeazis et al. 2013; Kawaguchi et al. 2014]. Four randomized trials directly compared erlotinib with single-agent chemotherapy and their results are reported in Table 2. The TITAN study was designed to demonstrate the superiority of erlotinib over chemotherapy with either docetaxel or pemetrexed. The main inclusion criteria were disease progression during or after four cycles of first-line chemotherapy and availability of tumour tissues for biomarker analyses [Ciuleanu et al. 2012]. The authors did not report any significant difference between the two arms in terms of OS (5.3 versus 5.5 months for erlotinib and chemotherapy, respectively; HR 0.96, p = 0.73), PFS (6.3 versus 8.6 weeks; HR 1.19, p = 0.73) and RR (7.9% versus 6.3%). Although these results appeared inferior to those observed in BR21 [Shepherd et al. 2005] or in the Hanna study [Hanna et al. 2004], the TITAN study population included only patients with rapidly progressive disease during or immediately after chemotherapy, thus explaining their poor prognosis. Moreover, biomarker analyses including EGFR expression level by immunohistochemistry (IHC), gene copy number by fluorescent in situ hybridization (FISH) and mutational status by DNA sequencing did not detect any significant predictor for better survival outcome in any of the subgroups. The HORG trial enrolled only Japanese patients whose condition failed to respond to first- or second-line therapy with erlotinib or pemetrexed with the primary endpoint of TTP [Karampeazis et al. 2013]. In the overall population, erlotinib and pemetrexed had similar outcomes in terms of TTP (3.0 versus 3.9 months, p = 0.195). Similarly, there were no differences in PFS (p = 0.136), RR (p = 0.469) and OS (p = 0.986). Interestingly, patients with squamous cell carcinoma did better with erlotinib (4.1 versus 2.5 months, p = 0.006). Approximately one-third of patients provided tumour tissue for EGFR mutational analysis and no difference in RR, TTP or OS was observed between the two treatment groups irrespective of EGFR status. The DELTA trial aimed to demonstrate the superiority of erlotinib over docetaxel in prolonging PFS in unselected patients with NSCLC. Moreover, the study also explored the impact of treatment according to EGFR status. The study failed to meet its primary endpoint, as in the overall population PFS did not significantly differ between the two arms (2.0 versus 3.2 months for erlotinib and docetaxel, respectively; HR 0.91; p = 0.53). However, patients with EGFR^WT who account for more than 65% of the whole population had a significantly lower risk of progression if exposed to docetaxel (p < 0.01), with no survival advantage. Unlike the other trials, the enrolment in the TAILOR study, a phase III Italian study of erlotinib versus docetaxel, was restricted to patients with proven EGFR^WT tumours [Garassino et al. 2013]. The primary endpoint was OS. Patients in the docetaxel arm lived longer (OS 8.2 versus 5.4 months, HR 0.73; p = 0.05) and had progressive disease later (2·9 versus 2·4 months; HR 0·71, p = 0·02) than those receiving erlotinib. Although these results formally demonstrated the superiority of docetaxel and pointed out the importance of a proper patient selection, the modest efficacy of second-line docetaxel minimizes their clinical impact. Indirect comparison of all the above-mentioned studies showed only minimal difference in terms of efficacy between chemotherapy and erlotinib. In addition, a recent meta-analysis evaluating 3825 patients from 10 randomized trials concluded that chemotherapy and EGFR TKIs are equally effective in an unselected population, with only a PFS improvement favouring chemotherapy in patients with EGFR^WT [Li et al. 2014]. For this reason, medical oncologists generally based their choice on several factors, including personal experience or familiarity with the drug, previous toxicity, patient characteristics and preferences, and costs.

Table 2.

Phase III trials of erlotinib in second or subsequent line of therapy in NSCLC.

Study	No.	Setting	Primary endpoint	Treatment	RR (%)	PFS		OS
			Primary endpoint			PFS (months)	HR p value	OS (months)	HR p value
BR.21 [Shepherd et al. 2005]	488	Second/third line	OS	Erlotinib	8.9	2.2	0.61	6.7	0.70
BR.21 [Shepherd et al. 2005]	243	Second/third line		Placebo	<1.0	1.8	<0.001	4.7	< 0.001
DELTA [Kawaguchi et al. 2014 ]	150	Second/third line	PFS	Erlotinib	17.0	2.0	1.22	14.8	0.91
DELTA [Kawaguchi et al. 2014 ]	151	Second/third line		TXT	17.9	3.2	0.09	12.2	0.53
HORG [Karampeazis et al. 2013]	179	Second/third line	TTP	Erlotinib	9.0	3.6	NR	8.2	0.99
HORG [Karampeazis et al. 2013]	178			PEM	11.4	2.9	0.136	10.1	0.986
TITAN [Ciuleanu et al. 2012]	203	Second line	OS	Erlotinib	7.9	6.3^$	1.19	5.3	0.96
TITAN [Ciuleanu et al. 2012]	221	Second line		TXT or PEM	6.3	8.6^§	0.089	5.5	0.73
TAILOR [Garassino et al. 2013]	112	Second line	OS	Erlotinib	3.0	2.4	0.71	5.4	0.73
TAILOR [Garassino et al. 2013]	110	Second line		TXT	15.5	2.9	0.02	8.2	0.05
WJOG 5108* [Katakami et al. 2014]	280	Second/third line	PFS	Erlotinib	43.9	7.5	1.125	24.5	1.038
WJOG 5108* [Katakami et al. 2014]	279	Second/third line		Gefitinib	46.1	6.5	0.257	22.8	NR
ARCHER 1009 [Ramalingam et al. 2014]	439	Second line	PFS	Erlotinib	8.0	2.6	0.941	8.4	1.079
ARCHER 1009 [Ramalingam et al. 2014]	439	Second line		Dacomitinib	11.0	2.6	0.229	7.9	0.817

66.4% of patients harboured an activating EGFR mutation.

PFS is reported in weeks.

HR, hazard ratio; NSCLC, non-small cell lung cancer; NR, not reported; OS, overall survival; PEM, pemetrexed; PFS, progression-free survival; RR, response rate; TXT, docetaxel.

Finally, two phase III trials compared erlotinib with either gefitinib or dacomitinib head to head, second generation EGFR TKIs, in pretreated patients with NSCLC [Katakami et al. 2014; Ramalingam et al. 2014]. The study by Katakami and colleagues aimed to demonstrate the noninferiority in PFS of gefitinib over erlotinib in Asian patients with progressive disease after first-line chemotherapy. The trial did not show any significant difference in terms of PFS (7.5 versus 6.5 months for erlotinib and gefitinib, respectively, HR = 1.125, p = 0.257) or OS (24.5 versus 22.8 months for erlotinib and gefitinib, respectively, HR = 1.038), even when analyses were restricted to the EGFR^mut+ population [Katakami et al. 2014]. The ARCHER 1009 trials had been designed to confirm the findings of a previous phase II randomized trial in which dacomitinib seemed to be superior to erlotinib in pretreated patients and particularly in those without KRAS mutation [Ramalingam et al. 2014]. Unfortunately, the trial did not show any significant difference in PFS (2.6 months in both arms, HR 0.941, p = 0·229) or OS (7·9 versus 8·4 months for dacomitinib and erlotinib, respectively, HR 1·079, p = 0·817), even when the analyses were restricted to the KRAS^WT subgroup (HRs for PFS and OS 1·022 and 1.095, respectively) [Ramalingam et al. 2014]. For such reasons, dacomitinib did not change the current therapeutic scenario of the second-line setting.

Studies with erlotinib as frontline treatment in EGFR^mut+ NSCLC

A retrospective review of patients responding to EGFR TKIs gefitinib or erlotinib revealed discriminating clinical characteristics, including adenocarcinoma histology, never smoking status, female sex and Asiatic race [Fukuoka et al. 2003; Kris et al. 2003]. During the last 10 years, several investigators conducted studies to find a suitable biomarker within the tumour to predict which patients were likely to respond to EGFR TKIs. It is now clear that EGFR mutations, mainly represented by classical deletion in exon 19 or the L858R substitution in exon 21, are the most relevant predictor for response to EGFR TKIs, including erlotinib, gefitinib and afatinib [Paez et al. 2004; Pao et al. 2004; Lynch et al. 2004] with modest efficacy for such agents in the EGFR^WT population [Thatcher et al. 2005; Shepherd et al. 2005; Miller et al. 2012]. Preclinical models demonstrated that EGFR mutations increased sensitivity to TKI, most likely through induction of critical structural modifications of the ATP-binding site in the TK domain [Lynch et al. 2004; Paez et al. 2004]. In the last 5 years, nine large randomized studies comparing first-line EGFR TKIs, such as gefitinib, erlotinib or afatinib, with standard platinum doublet chemotherapy clearly demonstrated that patients with EGFR^mut+ lung adenocarcinoma had improved responses, PFS and quality of life when treated with the target agent [Mok et al. 2009b; Han et al. 2012; Mitsudomi et al. 2010; Maemondo et al. 2010; Zhou et al. 2011; Rosell et al. 2012; Wu et al. 2013b, 2014; Sequist et al. 2013]. However, no survival improvements have been reported in any of these trials (Table 3).

Table 3.

First-line phase III trials comparing standard chemotherapy with platinum doublet versus EGFR TKIs in an EGFR-mutated population.

Study	No.	Treatment	RR (%)	PFS		OS
				mPFS (months)	HR p value	mOS (months)	HR p value
IPASS* [Mok et al. 2009b]	97	Gefitinib	71.2	9.5	0.48	21.6	1.00
	111	CBDCA + TXL	47.3	6.3	<0.0001	21.9	0.99
First SIGNAL* [Han et al. 2012]	159	Gefitinib	84.6	8.0	0.54	27.2	1.04
	150	CDDP+ GEM	37.5	6.3	0.008	25.6	NR
WJTOG 3405 [Mitsudomi et al. 2010]	88	Gefitinib	62.1	9.2	0.48	36.0	1.18
	89	CDDP + TXT	32.2	6.3	<0.001	39.0	NR
NEJ 002 [Maemondo et al. 2010]	114	Gefitinib	73.7	10.4	0.36	27.7	0.89
	114	CBDCA + TXL	30.7	5.5	<0.001	26.6	0.48
OPTIMAL [Zhou et al. 2011]	82	Erlotinib	83.0	13.1	0.16	22.6	1.06
	72	CBDCA + GEM	36.0	4.6	<0.0001	28.8	0.68
EURTAC [Rosell et al. 2012]	84	Erlotinib	54.5	9.4	0.34	19.3	1.04
	82	Platinum Doublet	10.5	5.2	<0.0001	19.5	0.87
ENSURE [Wu et al. 2013b]	110	Erlotinib	68.2	11.1	0.43	NR	NR
	107	CDDP + GEM	39.3	5.7	<0.0001	NR	NR
LUX Lung 3 [Sequist et al. 2013]	230	Afatinib	56.0	11.1	0.58	16.6	1.12
	115	CDDP + PEM	23.0	6.9	0.0004	14.8	0.60
LUX Lung 6 [Wu et al. 2014]	242	Afatinib	66.9	11.0	0.28	22.1	0.95
	122	CDDP + GEM	23.0	5.6	<0.0001	22.2	0.76

Shown data are restricted to EGFR-mutant population.

CBDCA, carboplatin; CDDP, cisplatin; EGFR, epidermal growth factor receptor; GEM, gemcitabine; HR, hazard ratio; NR, not reported; OS, overall survival; PEM, pemetrexed; PFS, progression-free survival; RR, response rate; TKI, tyrosine kinase inhibitor; TXL, paclitaxel; TXT, docetaxel.

Table 4.

Summary box of clinical results of erlotinib in advanced NSCLC according to EGFR status.

Setting	Results
Locally advanced or metastatic NSCLC with activating EGFR mutations	Erlotinib demonstrated superiority over standard platinum-based chemotherapy as frontline treatment in terms of PFS, ORR and QoL
Locally advanced or metastatic NSCLC without activating EGFR mutations	Erlotinib did not improve OS or RR when added to standard platinum-based chemotherapy in unselected population
	Erlotinib demonstrated superiority over placebo as second- or third-line treatment in patients unsuitable for chemotherapy
	Studies directly and indirectly comparing erlotinib with standard second-line chemotherapy showed no difference in OS with more favourable safety profile

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; QoL, quality of life; PFS, progression-free survival.

Three phase III and two phase II trials have investigated the efficacy and safety of erlotinib as first-line treatment in a EGFR^mut+ population [Zhou et al. 2011; Wu et al. 2013b; Goto et al. 2013; Rosell et al. 2009, 2012]. In 2011, Zhou and colleagues published the results of the OPTIMAL trial, a phase III study comparing erlotinib with carboplatin and gemcitabine in Chinese patients with EGFR^mut+ [Zhou et al. 2011]. A striking HR of 0.16 [95% confidence interval (CI) 0.10–0.26] for PFS was reported for subjects receiving the experimental treatment. In the ENSURE trial a total of 217 Asian patients with EGFR^mut+ NSCLC were randomized 1:1 to erlotinib or cisplatin and gemcitabine [Wu et al. 2013b]. As expected, patients in the erlotinib arm progressed later (11.1 versus 5.7 months, HR 0.43; p < 0.0001) and experienced a higher probability of tumour response (68% versus 39%); moreover, treatment with erlotinib was better tolerated than the platinum doublet, with lower incidence of grade 3–4 AEs, particularly haematologic toxicity. Similarly, in an open-label phase II trial specifically conducted to evaluate the efficacy and safety of frontline erlotinib in a Japanese population of patients with EGFR^mut+ NSCLC, RR and PFS resulted in 78% and 11.8 months, respectively [Goto et al. 2013].

These results have been replicated in a population of white patients. In 2009, Rosell and colleagues published the results of a prospective trial designed with the aim of evaluating the feasibility of a large-scale screening for EGFR mutations in Spanish patients with metastatic NSCLC [Rosell et al. 2009]. According to the trial design, patients with proven activating EGFR mutations were considered for erlotinib, as first or subsequent line of treatment. Overall, 2105 patients with advanced NSCLC from 129 centres were prospectively tested. Mutations were detected in 350 subjects (16%), mostly women, never smokers and with adenocarcinomas; of these patients, 217 received erlotinib treatment as first- (113 patients) or second-/third- line therapy (104 patients). Median PFS was 14 months, quite similar to the results reported in the Asian population. Three years later, the same authors published the final results of the EURTAC trial, the first phase III study comparing erlotinib with standard platinum-based chemotherapy as first-line treatment in European patients with EGFR^mut+ NSCLC [Rosell et al. 2012]. The study, enrolling 173 patients, met its primary endpoint of PFS. Patients treated with erlotinib had a 63% relative reduction in risk of progression compared with those receiving standard chemotherapy (9.7 versus 5.2 months, HR 0.37). Treatment with erlotinib was also associated with higher RR (58% versus 15%, ITT population) and a better toxicity profile. Notably, the subset analyses confirmed a significant PFS benefit in favour of the erlotinib arm independently of age (>65 versus <65 years), sex, performance status (ECOG 0 versus 1 versus 2) and histology (adenocarcinoma versus other histologies).

It is important to remember that deletion in exon 19 and Leu858Arg substitution in exon 21 has been often considered a unique molecular entity (the so-called classical mutations); their clinical and biological significance are not identical. Patients having deletion in exon 19 seemed to derive more benefit from EGFR TKIs. Retrospective data suggested that exon 19 deletions might predict a longer OS or PFS after EGFR TKI therapy than the L858R point mutation [Mitsudomi et al. 2005; Riely et al. 2006; Jackman et al. 2006, 2009]. In a pooled analysis of five studies conducted in the USA, patients with exon 19 deletions had a longer TTP (14.6 versus 9.7 months; p = 0.02) and OS (30.8 versus 14.8 months; p < 0.001) than those with L858R mutations [Jackman et al. 2009]. More recently, in a pooled exploratory analysis of individual patient data from both LUX-Lung 3 and LUX-Lung 6 trials, two phase III trials comparing afatinib with frontline chemotherapy in patients with EGFR^mut+ lung adenocarcinoma, Yang and colleagues showed a statistically significant improvement in OS for afatinib therapy exclusively in individuals carrying del19 (HR 0.81, p = 0.037), with no survival benefit in those harbouring the Leu858Arg mutation [Yang et al. 2015]. A possible explanation is that patients with exon 19 mutant NSCLC are strongly dependent on the EGFR pathway, as demonstrated by the fact that in untreated patients EGFR amplification occurs invariably in patients with exon 19 mutation, whereas in patients with WT or other mutations, it does not [Sholl et al. 2009]. Moreover, preclinical studies have suggested that erlotinib was a much better inhibitor of EGFR in the presence of the exon 19 deletion compared with L858R [Carey et al. 2006]. Clinical data confirmed this hypothesis. Indeed, HRs for PFS in OPTIMAL, EURTAC and ENSURE trials were 0.13, 0.30 and 0.20 for exon 19 and 0.26, 0.55 and 0.54 for exon 21, respectively [Zhou et al. 2011; Rosell et al. 2012; Wu et al. 2013b]. Although this difference may account for different drug sensitivity, patients with exon 21 mutations equally benefited more from erlotinib than from chemotherapy in terms of PFS and RR, confirming that erlotinib is preferable to chemotherapy in the frontline setting irrespective of type of mutation.

Studies with erlotinib in combination with other targeted agents

The occurrence of acquired resistance is the inevitable consequence of a prolonged exposure to EGFR TKIs. Data from randomized trials showed that invariably after a median time of 10 months, patients with EGFR mutant NSCLC progress [Mok et al. 2009b; Han et al. 2012; Mitsudomi et al. 2010; Maemondo et al. 2010; Zhou et al. 2011; Rosell et al. 2012; Wu et al. 2013b; Sequist et al. 2013; Wu et al. 2014]. As EGFR is closely linked to other cell-signalling pathways, such as mesenchymal–epidermal transition (MET) receptor or angiogenesis, their simultaneous inhibition could enhance the antiproliferative activity by acting in a synergistic fashion [Tortora et al. 2008; Dziadziuszko and Jassem, 2012; Engelman et al. 2007]. In addition, preclinical and clinical data demonstrated that the activation of alternate transduction signalling ways represents a mechanism of escape from EGFR inhibition that leads to acquired resistance [Sequist et al. 2011b; Ohashi et al. 2012; Yu et al. 2013]. To further extend PFS, delaying the occurrence of acquired resistance, a number of trials have investigated the combination of erlotinib with other targeted agents, particularly anti-MET agents and antiangiogenic drugs.

In 2013, Spigel and colleagues published the results of a randomized phase II trial exploring the activity of the combination of erlotinib and onartuzumab, a monovalent monoclonal antibody directed against the extracellular domain of the MET receptor, in 137 molecularly unselected patients with NSCLC whose condition failed to respond to at least one prior chemotherapy regimen [Spigel et al. 2013]. Archival tumour tissue was evaluated for MET expression by using IHC and considering as MET positive those samples having at least 50% of tumour cells with moderate (2+) or high (3+) staining intensity (MET diagnostic positive). Coprimary endpoints of the trial were PFS in the ITT population and in the IHC diagnostic positive population. In the ITT population neither PFS (HR 1.09; p = 0.69) nor OS (HR 0.80; p = 0.34) favoured the experimental arm. However, in MET diagnostic positive disease the combination of onartuzumab and erlotinib was superior to erlotinib and placebo in both PFS and OS (HR 0.53; p = 0.04; HR 0.37; p = 0.002, respectively), with a detrimental effect in the MET diagnostic negative subgroup. Moving from these promising findings, the same authors conducted a large, randomized, confirmatory phase III trial aiming to demonstrate a survival improvement for the combination of onartuzumab and erlotinib in MET diagnostic positive NSCLC [Spigel et al. 2014]. The study, enrolling a total of 490 subjects, failed to replicate the results observed in the phase II trial. Particularly, neither OS (6.8 versus 9.1 months, HR 1.27; p = 0.07) nor PFS (2.7 versus 2.6 months, HR 0.99; p = 0.92), the secondary endpoint of the study, differed between the two arms. Similarly, the TKI of the MET receptor tivantinib did not produce any survival benefit when added to erlotinib in pretreated NSCLC, as demonstrated in another phase III study (Scagliotti et al. 2013). The MARQUEE trial was specifically designed to confirm the results of a previous randomized phase II trial in which subgroup analyses revealed a trend towards longer survival for patients with adenocarcinoma histology or KRAS mutation who received the combination of erlotinib and tivantinib [Sequist et al. 2011b]. Unfortunately, a press release from the company announced the early interruption of the trial following a planned interim analysis in the ITT population that showed no survival gain for patients receiving the two drugs [Scagliotti et al. 2013].

Other trials investigated the combination of erlotinib with antiangiogenic drugs, including the monoclonal antibody bevacizumab [Herbst et al. 2007, 2012] or the multitargeted TKIs sunitinib and sorafenib [Scagliotti et al. 2012; Spigel et al. 2011]. In a three-arm, phase II study, patients with relapsed and refractory nonsquamous NSCLC randomly assigned to erlotinib plus bevacizumab, bevacizumab and chemotherapy, or chemotherapy alone, median OS was better in the groups receiving bevacizumab (13·7 months for erlotinib plus bevacizumab and 12·6 months for bevacizumab and chemotherapy) than in the chemotherapy alone arm (8.6 months) [Herbst et al. 2011]. The BeTa trial was subsequently designed to address the question of whether the erlotinib plus bevacizumab combination could prolong OS in NSCLC that has progressed after first-line chemotherapy. The study, enrolling more than 630 patients, failed to demonstrate a survival improvement for patients receiving the dual inhibition of EGFR and vascular endothelial growth factor(VEGF) pathways (9.3 versus 9.2 months, HR 0.97; p = 0.7583); however, PFS was numerically longer in the experimental arm than in th erlotinib plus placebo arm (3.4 versus 1.7 months, HR 0.62). Two additional trials evaluated the combination of erlotinib with sunitinib [Scagliotti et al. 2012] or sorafenib [Spigel et al. 2011], with disappointing results. In a wide cohort of pretreated patients with NSCLC, the addition of sunitinib to erlotinib significantly increased RR (10.6% versus 6.9%; p = 0.0471) and PFS (3.6 versus 2.0 months, HR 0.807; p = 0.0023), with higher incidence in grade 3 and 4 AEs, particularly rash/dermatitis, diarrhoea and asthenia. However, the improvement in PFS did not translate into a survival prolongation, the primary endpoint of this phase III trial [Scagliotti et al. 2012]. In a phase II randomized trial of sorafenib plus erlotinib versus erlotinib plus placebo, no difference in PFS was observed between the two arms in overall population (3.38 versus 1.94 months, for sorafenib plus erlotinib and erlotinib plus placebo, respectively; HR 0.86; p = 0.196); nevertheless, an improvement in both PFS and OS was suggested among the subgroups of patients with EGFR^WT and in the small fraction of patients with FISH EGFR-negative tumours [Spigel et al. 2011].

It is important to underline that in all the above-mentioned trials the declared intent was to prevent resistance to erlotinib. Furthermore, all trials have been conducted in a general population of NSCLC not previously exposed to anti-EGFR agents and not selected for the presence of EGFR mutations. Not surprisingly, the results of combination trials clearly indicated that in the absence of a molecular selection of patients – or in other words, in the absence of a real tumour driver – the efficacy of different pathways inhibition is minimal, if any. Conversely, in EGFR^mut+ NSCLC dual target inhibition seems to be a promising strategy. In a subset analysis of mutation-positive participants in the phase III BeTa study (12 patients treated with erlotinib and bevacizumab and 18 with erlotinib alone) median PFS with erlotinib plus bevacizumab was substantially higher than with erlotinib alone (17·1 versus 9·7 months) [Herbst et al. 2011], supporting the hypothesis to test this combination as frontline treatment in such patients. Recently, Seto and colleagues published the results of the first randomized phase II trial conducted in a Japanese population of 154 patients with EGFR^mut+ NSCLC with the aim of evaluating the impact of the addition of bevacizumab to erlotinib in the first-line treatment of this disease [Seto et al. 2014]. The study met its primary endpoint, demonstrating a PFS advantage for patients receiving erlotinib and bevacizumab (16.0 versus 9.7 months, HR 0.54; p = 0.0015). Interestingly, as reported in other trials [Zhou et al. 2011; Rosell et al. 2012; Wu et al. 2013b], patients harbouring a mutation in exon 19 derived the greatest benefit from the addition to bevacizumab (18.0 versus 10.3 months, HR 0.41; p = 0.0011) compared with those carrying the other classical mutation in exon 21, in which the numerical difference in PFS did not reach statistical significance (13.9 versus 7.1 months, HR 0.67; p = 0.1653). RR did not differ between the two arms (69% versus 64% in experimental and standard arm, respectively), although a greater proportion of patients in the combination arm obtained a disease control rate (99% versus 88%; p = 0.0177), suggesting a potential effect of angiogenesis inhibition in maintaining the tumour suppressor effect of the EGFR pathway blockade. Two additional randomized phase II studies, BELIEF [ClinicalTrials.gov identifier: NCT01562028] and ACCRURC1126 [ClinicalTrials.gov identifier: NCT01532089], with identical designed and conducted in white populations, are currently ongoing and their results will clarify the role of dual EGFR/VEGF inhibition as frontline treatment in patients with EGFR^mut+ NSCLC.

Finally, pivotal studies suggested that new checkpoint inhibitors, particularly nivolumab and pembrolizumab, are showing promising results even in heavily pretreated patients with NSCLC. Rizvi and colleagues presented the preliminary results of a phase I study of biweekly intravenous nivolumab plus a standard daily dose of erlotinib in patients with EGFR^mut+ who were not exposed or resistant to EGFR tyrosine kinase, showing interesting findings [Rizvi et al. 2014]. Indeed, RR was approximately 20% and PFS at 24 weeks was 47%, whereas median duration of response was not reached. Grade 3–4 AEs, including increase in hepatic enzymes, weight loss and diarrhoea, occurred in four patients, leading to treatment interruption in two of them.

Erlotinib safety profile

Data about tolerability of erlotinib mainly derived from the aforementioned trials conducted in a different setting (first and second line) and population (EGFR^mut+ or unselected NSCLC) [Shepherd et al. 2005; Ciuleanu et al. 2012; Garassino et al. 2013; Karampeazis et al. 2013; Kawaguchi et al. 2014; Zhou et al. 2011; Rosell et al. 2012]. Overall, the vast majority of AEs were grade 1 or 2 in severity and the percentage of patients discontinuing treatment due to unresolved toxicity was less than 10%, with a small difference observed across studies. The most common AEs observed during erlotinib therapy and directly related to EGFR inhibition (class effect) were cutaneous and gastrointestinal toxicities. As EGFR is normally involved in processes regulating stimulation of epidermal growth, inhibition of differentiation and tissue reparation, its blockade determines a wide spectrum of cutaneous injuries such as rash, dry skin, pruritus, inflammation, alterations in nail/periungual tissue and hairs. Up to 90% of patients experienced any grade of cutaneous toxicity, with a percentage of individuals displaying severe cutaneous events that rarely exceeded 10%. Diarrhoea is the other most common AE and it is probably related to an excessive chloride secretion, resulting in a secretory type of diarrhoea [Harandi et al. 2009; Yang et al. 2013]. The incidence of diarrhoea of any grade ranged between 50% and 80%, with grade 3 and higher diarrhoea occurring in only less than 5% of subjects. Less common (<20%) AEs included stomatitis, increased transaminases levels, fatigue and nausea. Severe and potential life-threatening (grade 3–4) AEs included pneumonitis and interstitial lung disease, with an overall incidence of less than 2%.

The optimal management of erlotinib-related toxicity consists of supportive care and symptomatic agents together with drug interruptions or modifications. Nonetheless, in order to maximize treatment adherence and benefit, the first measure to manage toxicity should be patient education. It is important to remember that a prompt recognition of an AE is essential to maintain a patient’s quality of life and to avoid the risk of premature discontinuation of treatment. In addition, a temporarily drug interruption of a few days might alone improve the worsening of AEs. However, patient-reported outcomes and patient preference may reveal differences in tolerability that could not be adequately captured from standard AE reporting measures, as well as from physicians. Unlikely chemotherapy, daily assumption of targeted agents such as an EGFR TKI, translates into a low to mild grade chronic toxicity significantly affecting patient morbidity and his or her normal activities. Data from a recently published Italian survey conducted in more than 130 patients with NSCLC treated with targeted agents, including erlotinib, gefitinib, afatinib, crizotinib and bevacizumab, confirmed that toxicities are often underestimated by reference clinicians, suggesting that patient perception should be taken into account with a toxicities grading system to define the real impact of targeted agents on a patient’s quality of life and to refine the optimal management of AEs [Novello et al. 2014].

Conclusion

NSCLC treatment is moving towards individualized therapy and biomarker analysis is becoming the most important element for treatment decisions. In patients with NSCLC, it is now mandatory to evaluate EGFR mutation status before treatment choice. Although in clinical practice EGFR assessment is sometimes difficult for several reasons, including availability of sufficient tumour tissue or facilities, every effort should be made to avoid the risk of precluding a relevant therapeutic option even to a single patient. The results of large randomized trials demonstrated that EGFR TKIs, including erlotinib, are the preferable therapeutic options in patients with EGFR^mut+, irrespective of line of treatment. For patients with EGFR^WT, the addition of concomitant or intercalated erlotinib to standard platinum-based chemotherapy did not produce a significant benefit. In a pretreated population, erlotinib showed comparable results to single-agent chemotherapy, thus remaining an acceptable second-line option even in the absence of EGFR mutations. Unfortunately, even in individuals with EGFR mutations, no patient with metastatic disease is definitively cured due to the occurrence of acquired resistance. Patients with resistance are emerging as a novel and fast-growing clinical entity, for which more effective strategies, including combination EGFR TKIs, with different targeted agents or immunotherapy are under investigations.

Footnotes

Conflict of interest statement

Dr Cappuzzo declares consultancy/advisory role for AstraZeneca, Lilly, Roche, Boehringer Ingelheim, Pfizer and Clovis. Dr Landi declares no potential conflicts of interest.

Funding

This work was supported by the Italian Association for Cancer Research (IG 2012-13157), Fondazione Ricerca Traslazionale and Istituto Toscano Tumori (Project F13/16).

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Experience with erlotinib in the treatment of non-small cell lung cancer

Abstract

Keywords

Introduction

Erlotinib pharmacokinetics and pharmacodynamics

Studies with erlotinib in combination with chemotherapy as frontline treatment in unselected NSCLC

Studies with erlotinib versus chemotherapy as first-line treatment in an unselected population

Studies with erlotinib as maintenance therapy

Studies with erlotinib in second-line setting

Studies with erlotinib as frontline treatment in EGFRmut+ NSCLC

Studies with erlotinib in combination with other targeted agents

Erlotinib safety profile

Conclusion

Footnotes

Conflict of interest statement

Funding

References

Studies with erlotinib as frontline treatment in EGFR^mut+ NSCLC