Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Cancers

EGFR mutations identify patients who are more likely to respond to treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) than cytotoxic chemotherapy. The distinct success of the first-generation EGFR TKIs erlotinib and gefitinib has been accompanied by the observation that acquired resistance to these treatments develops after a median of 1 year of treatment. Newer, second-generation EGFR TKIs have been developed with the intent to delay or overcome acquired resistance by the broader inhibition of kinases (eg, HER2 and vascular endothelial growth factor receptor) and/or altering the interactions with EGFR through irreversibly binding to the kinase domain. This article discusses many of these agents (including afatinib, dacomitinib, XL647, AP26113, and CO-1686) which have the potential for greater efficacy compared with first-generation EGFR TKIs, and may also have clinical activity against other oncogenic mutations within the EGFR family, including HER2.

Epidermal Growth Factor Receptors

The epidermal growth factor receptor (EGFR) family includes 4 receptor tyrosine kinases: EGFR (HER1), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). The EGFR is composed of an extracellular ligand binding region, a transmembrane region, and an intracellular tyrosine kinase domain. Ligand binding to the extracellular region of EGFR induces a conformational change in the receptor that promotes dimerization. Dimerization of the receptor results in autophosphorylation of the intracellular domain, which in turn recruits proteins involved in downstream signaling. The resultant signal transduction cascade activates pathways, including the RAS/RAF/MEK and PI3K/AKT pathways, leading to cell proliferation and survival.1

Activating mutations in EGFR were discovered to be oncogenic in a subset of lung cancers in 2004.2,3 Somatic EGFR mutations increase the activity of the receptor through allowing activation of the kinase receptor in the absence of ligand binding, thereby inducing a constitutively active state that leads to sustained downstream signaling. EGFR-mutated tumors seem to be dependent on EGFR signaling for growth and survival, making inhibition of EGFR an attractive therapeutic target.

First-Generation EGFR Tyrosine Kinase Inhibitors

Gefitinib and erlotinib were the first EGFR tyrosine kinase inhibitors (TKIs) that were approved for the treatment of patients with non–small cell lung cancer (NSCLC). These drugs inhibit kinase activity through competitively interacting with the ATP-binding site of EGFR, preventing autophosphorylation and consequently inhibiting downstream signaling. This inhibition leads to apoptosis in cells dependent on EGFR signaling, such as those with EGFR mutations.

Gefitinib efficacy was first evaluated in 2 single-arm phase II studies in patients with NSCLC who had received prior chemotherapy. The success of these trials led to the accelerated approval of gefitinib in 20034,5 and initiation of a phase III trial6 (ISEL), which randomized patients to gefitinib versus placebo and found no difference in median survival (5.6 vs. 5.1 months, respectively). The lack of an overall survival benefit in ISEL prompted the FDA to restrict gefitinib use. Notably, these early studies did not select or evaluate patients based on EGFR mutation status.

Subsequent trials of gefitinib focused on subsets of patients more likely to respond to gefitinib. The IPASS trial randomized East Asian patients with adenocarcinoma who were former light or never smokers (the key clinical characteristics associated with response to EGFR TKI and presence of EGFR mutations) to receive either gefitinib or the combination of carboplatin and paclitaxel as first-line treatment.7 Gefitinib prolonged progression-free survival (PFS; 9.5 vs. 6.3 months for gefitinib vs. chemotherapy, respectively), with the positive study results largely driven by the predominance of EGFR mutations in the study population (60% of patients had tumors with EGFR mutations). Notably, patients with these clinical characteristics who did not have EGFR mutations and received initial gefitinib had a median PFS of less than 2 months and a response rate of 1%. Based on IPASS and other studies, the EMEA approved gefitinib for use in patients with EGFR-mutant advanced NSCLC. Gefitinib has also been studied specifically in patients with EGFR-mutant lung cancers. In both the WJOTG 34058 and NEJ20029 studies, patients were randomized to gefitinib or platinum-based chemotherapy, and gefitinib led to improved PFS and objective response rates compared with cytotoxic chemotherapy in patients with EGFR mutations.

Similar to gefitinib, erlotinib was also compared with placebo in patients with advanced, previously treated NSCLC without determination of EGFR mutation status.10 Median overall survival (OS) in these unselected patents was longer in those treated with erlotinib than placebo (6.7 vs. 4.7 months), with a radiographic response rate (RR) of 9% versus less than 1% with placebo. These results led to the FDA approval of erlotinib in advanced NSCLC. Subsequent studies, including OPTIMAL and EURTAC,11,12 evaluated erlotinib in the first-line setting compared with chemotherapy in patients with EGFR-mutant NSCLC. Both OPTIMAL and EURTAC showed improved PFS and RR with the use of erlotinib compared with cytotoxic chemotherapy, with results very similar to those in trials that compared gefitinib versus chemotherapy. Taken together, the data indicate that the benefits of first-generation EGFR TKIs are dramatic, particularly in patients with somatic EGFR mutations.

Acquired Resistance to First-Generation EGFR TKIs

Patients harboring EGFR mutations with lung adenocarcinomas respond to treatment with erlotinib and gefitinib, but eventually experience disease progression, developing acquired resistance after a median of 12 to 16 months.7,9,13 The study of tumor samples of patients with acquired resistance to EGFR TKI therapy has elucidated various mechanisms of resistance, with a specific mechanism identified approximately 70% of the time.14,15 The most common cause of resistance is the acquisition of the T790M missense mutation encoded by exon 20 of EGFR, which is found in more than 60% of patients with clinical acquired resistance.16,17 Other secondary mutations within EGFR have been described, including EGFR D761Y and T854A, that are associated with the development of acquired resistance to EGFR TKIs.18,19 Amplification of MET is another finding observed at the time of acquired resistance.20,21 Small cell histologic transformation has also been associated with the development of acquired resistance.22 More recent work has identified HER2 amplification and acquired BRAF mutations as potential mechanisms of resistance, both of which have potential therapeutic implications that will require further study.23,24

Second-Generation EGFR TKIs

Acquired resistance to first-generation EGFR TKIs has prompted the clinical development of second-generation EGFR TKIs (Table 1). Second-generation EGFR TKIs may be able to overcome some of the mechanisms of resistance to first-generation EGFR TKIs and have the potential to be more effective than erlotinib or gefitinib as first-generation EGFR TKIs. Most of the second-generation TKIs form irreversible, covalent attachments to the EGFR kinase domain, and may have additional activity against other receptors in the EGFR family or structurally similar receptors, such as vascular endothelial growth factor (VEGF; Table 1). In addition, because of their covalent binding, they may have more activity against T790M or other secondary mutations against which first-generation TKIs are relatively ineffective. Several ongoing trials are also evaluating EGFR TKIs in combination with other agents that target parallel signaling pathways, or target the EGFR in a different manner to circumvent resistance to first-generation EGFR TKIs.

Neratinib (HKI-272)

Neratinib is an oral, irreversible inhibitor of both EGFR and HER2, with preclinical studies suggesting it is active against EGFR T790M25 and also against cells with HER2 mutations.26,27 A phase I study28 conducted among patients with advanced solid tumors established the maximum tolerated dose (MTD) of neratinib at 320 mg daily because of a dose-limiting toxicity of grade 3 diarrhea. Neratinib was studied further in a multicenter phase II study29 in patients with advanced NSCLC. During the study, the dose of neratinib needed to be decreased to 240 mg daily orally because of the development of grade 3 diarrhea in more than 50% of patients at the higher dose. The response rate was 2%, with no responses seen in patients with clinical acquired resistance whose tumors harbored EGFR T790M or in patients who did not have a sensitizing EGFR mutation. The lack of efficacy may be related to the high concentrations of neratinib required in preclinical studies to inhibit EGFR T790M and the limitations of clinical dosing of neratinib that resulted from excessive toxicity.30 No studies of neratinib in NSCLC are currently ongoing.

Dacomitinib (PF-00299804)

Dacomitinib is an irreversible pan-HER TKI with activity against EGFR, HER2, and HER4. Preclinical studies and xenograft models showed activity against EGFR T790M– and HER2-mutated cell lines.31,32 Results from a phase I study33 of dacomitinib in patients with NSCLC established the safety of 45 mg daily orally in a population enriched for

Table 1

EGFR Tyrosine Kinase Inhibitors and Their Receptor Targets

Table 1
HER gene amplifications, EGFR/HER2 mutations, and KRAS wild-type patients. A phase II study was then performed in patients with NSCLC whose disease had progressed on chemotherapy and erlotinib.34 At the time of study presentation, 62 patients were evaluable, with 3 confirmed partial responses and 35 patients with stable disease for more than 6 weeks. Because of relative safety and potential signals of efficacy, a phase II study randomizing patients to either erlotinib or dacomitinib was undertaken in 188 patients with advanced NSCLC after disease progression on cytotoxic chemotherapy35 (Table 2). Dacomitinib led to a longer median PFS (12.4 vs. 8.3 weeks) than erlotinib, and a randomized phase III trial (ARCHER) in this same population is ongoing. Dacomitinib is also being evaluated in the first-line setting in a phase II study of patients with light smoking histories or adenocarcinoma with a sensitizing EGFR mutation.36 Of 46 evaluable patients, 34 had a partial response to dacomitinib therapy, and the preliminary median PFS was 17 months. This study is ongoing, along with a specific cohort evaluating patients with HER2 mutations.

Afatinib (BIBW 2992)

Afatinib, an irreversible inhibitor of both the EGFR and HER2 kinase, is the most extensively studied second-generation EGFR TKI. In preclinical studies, afatinib inhibits both the wild-type and mutant forms of EGFR and is active against EGFR T790M.37 In a phase I trial that established the MTD of 50 mg daily orally, the dose-limiting toxicities were rash and

Table 2

First-Line Clinical Trials of Second-Generation Tyrosine Kinase Inhibitors: Unselected Patients

Table 2
dyspnea secondary to pneumonitis.38 Common side effects of afatinib include nausea, vomiting, fatigue, and rash. Extensive clinical studies of afatinib have been completed and other studies are in progress both in the first-line setting in patients with EGFR mutant tumors and in the setting of acquired resistance to first-generation EGFR TKIs (Tables 3 and 4).

In patients with advanced lung adenocarcinoma who have EGFR mutations and have not received a prior EGFR TKI, 3 studies with afatinib were performed or are in progress, including a single-arm phase II study.39 The objective response rate was 66%, with median overall survival and PFS of 24 and 14 months, respectively. To validate these findings and compare the efficacy of afatinib with that of cytotoxic chemotherapy in this population, 2 randomized phase III trials were performed. The trial of cisplatin/gemcitabine versus afatinib is ongoing, with no preliminary results available. The preliminary results of the trial randomizing patients with previously untreated lung adenocarcinoma to afatinib or cisplatin/pemetrexed chemotherapy (LUX-Lung 3) were recently presented. In the overall population, the median PFS was 11 months for those treated with afatinib compared with 7 months in those treated with cisplatin and pemetrexed chemotherapy.40 When only patients with the most common EGFR-sensitizing mutations were included, the median PFS for afatinib treatment was 14 months versus 7 months for cisplatin and pemetrexed.

Three prospective studies of afatinib have been conducted in patients with advanced NSCLC whose disease progressed on first-generation EGFR TKIs. The first reported trial (LUX-Lung 1) was a phase III study that randomized 585 patients with advanced lung adenocarcinoma who had disease progression after platinum-based chemotherapy and at least 3 months of gefitinib or erlotinib 2:1 to afatinib or placebo.41 PFS (3 vs. 1 month) and response rate (7% vs. 0%) were increased with afatinib, but the primary end point of overall survival was not different. Only 37% of patients met the standard criteria for acquired resistance, which includes previous treatment with a single-agent EGFR TKI, and either a known sensitizing EGFR mutation or prior clinical benefit with an EGFR TKI, and documented systemic progression on EGFR TKI.42 Post hoc subset analysis of

Table 3

First-Line Clinical Trials of Second-Generation TKIs: Patients With EGFR Mutations

Table 3
this subgroup showed no differences from the overall study results.

The hypothesis that continued EGFR inhibition is important after disease progression on EGFR TKI (supported by some prospective and retrospective data43) is being evaluated in a phase III trial comparing continued afatinib plus chemotherapy versus chemotherapy alone (LUX-Lung 5) in patients whose disease progressed on single-agent afatinib. This study is ongoing, with a primary end point of overall survival (ClinicalTrials.gov identifier: NCT01085136).

Preclinical data suggest that dual targeting of EGFR with both a second-generation EGFR TKI and an EGFR monoclonal antibody may be especially effective at inducing shrinkage of EGFR mutant tumors that have developed resistant to erlotinib or gefitinib by way of acquired EGFR T790M.44

An earlier phase I/II study of erlotinib and cetuximab did not show any significant activity in patients with acquired resistance to erlotinib.45 A recently completed study evaluated the combination of afatinib and cetuximab in patients with advanced NSCLC whose disease progressed on erlotinib or gefitinib (ClinicalTrials.gov identifier: NCT0109001). Confirmed partial responses were seen in 35% of patients, including 11 of 35 patients with EGFR T790M+ NSCLC46; 90% of patients had a partial response or stable disease. This is the first targeted therapy in the setting of EGFR TKI acquired resistance that has shown significant activity in EGFR T790M+ tumors.

EGFR T790M–Specific Inhibitors

Another strategy has been the development of pyrimidine-based EGFR T790M inhibitors that have potent selectively for EGFR T790M and other mutant receptors rather than wild-type EGFR, with the goal of improving efficacy and reducing toxicity associated with wild-type EGFR inhibition.47 Although the prototype compound initially reported has not been further developed, another compound is in development. CO-1686 (Clovis Oncology) is a covalent, irreversible small molecule that specifically inhibits mutant EGFR. A phase I/II trial of C0-1686 in patients with EGFR-mutant advanced NSCLC who have received prior EGFR-directed therapy is currently ongoing (ClinicalTrials.gov identifier: NCT01526928).

Dual EGFR/VEGF Inhibitors

XL647, vandetanib, and BMS-690514 are all dual EGFR and VEGF kinase inhibitors that may prevent or overcome acquired resistance to EGFR TKIs through dual inhibition of these parallel signaling pathways. A phase II study of XL647 was performed

Table 4

Clinical Trials After Acquired Resistance: Patients With EGFR Mutations

Table 4
in a patient population enriched for EGFR mutations in the first-line setting and found a 28% partial response rate, with all 8 patients with EGFR mutations experiencing tumor shrinkage (7 partial response/1 stable disease).48 A subsequent phase II study was completed in 41 patients with advanced EGFR-mutated NSCLC whose disease had either progressed on erlotinib or gefitinib, or whose tumor contained a documented EGFR T790M mutation. The objective response rate was 3%, indicating inadequate activity to warrant further study in this population.49

Vandetanib has been extensively studied in advanced NSCLC although no current studies are ongoing. Combining vandetanib with chemotherapy has not led to significant improvements in overall survival, as evidenced by the ZEAL and ZODIAC trials.50,51 The ZEPHYR study evaluated vandetanib versus placebo in patients whose disease progressed on an EGFR TKI and found no difference in the primary end point of overall survival compared with placebo.52

A phase II study evaluated BMS-690514 in patients with advanced NSCLC who were either TKI-naïve or whose disease had progressed on EGFR TKI therapy, with results showing a disease control rate of 39% and 22%, respectively.53 A clinical trial of BMS-690514 versus erlotinib in patients with advanced NSCLC that progressed on platinum therapy is ongoing, with no results yet presented (Clinical-Trials.gov identifier: NCT00743938).

Dual EGFR/Anaplastic Lymphoma Kinase Inhibitors

AP26113 is a reversible, dual EGFR/anaplastic lymphoma kinase inhibitor that has selective activity against mutant EGFR, including EGFR T790M, compared with wild-type EGFR in preclinical studies.54 AP26113 is being evaluated in a phase I/II trial currently, with a planned expansion cohort of patients with EGFR-mutant lung cancer who have experienced disease progression on an EGFR TKI (ClinicalTrials.gov identifier: NCT01449461).

Conclusions

EGFR TKIs have dramatically altered the treatment paradigm for EGFR-mutant lung cancers. However, their utility is limited by the universal development of acquired resistance. Second-generation EGFR TKIs have been developed with the intent to improve responses in the first-line setting and to provide additional treatment options in the acquired resistance setting. Despite encouraging preclinical data suggesting efficacy, most of the second-generation EGFR TKIs have not shown meaningful clinical activity after acquired resistance to gefitinib and erlotinib. The most promising clinical activity has been seen with dacomitinib and afatinib in patients with EGFR-mutant lung cancer in the TKI-naïve, first-line setting. In the acquired resistance setting, preliminary data are promising for afatinib in combination with cetuximab, although final results are not yet available. Initial studies evaluating the most recently developed EGFR TKIs, such as AP-26113 and CO-1686, are just beginning phase I trials.

Dr. Yu has disclosed that she have no financial interests, arrangements, affiliations, or commerical interests with the manufacturers of any products discussed in this article or their competitors. Dr. Riely has disclosed that he has consulted for AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim GmbH; Chugai Pharmaceutical Co., Ltd; ARIAD Pharmaceuticals, Inc.; Tragara Pharmaceuticals, Inc.; Daiichi Sankyo, Inc.; Novartis AG; Abbott Molecular; and Celgene Corporation. He has also received grants from Infinity Pharmaceuticals; Bristol-Myers Squibb Company; Novartis AG; Chugai Pharmaceutical Co., Ltd; Pfizer Inc.; Merck & Co., Inc.; and GlaxoSmithKline plc.

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    Bahleda R, Soria J, Harbison C. Tumor regression and pharmacodynamic (PD) biomarker validation in non-small cell lung cancer (NSCLC) patients treated with the ErbB/VEGFR inhibitor BMS-690514 [abstract]. J Clin Oncol 2009;27(Suppl):Abstract 8098.

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  • 54

    Miret JJ, Wang F, Anjum R. AP26113, a potent ALK inhibitor, is also active against EGFR T790M in mouse models of NSCLC. Presented at the 14th World Conference on Lung Cancer; July 3–7, 2011; Amsterdam, The Netherlands.

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  • 55

    Atagi S, Katakami N, Hida T. LUX-Lung 4: a phase 2 trial of afatinib (BIBW 2992) in advanced NSCLC patient spreviously treated with erlotinib and gefitinib. Presented at the 14th World Conference on Lung Cancer; July 3–7, 2011; Amsterdam, The Netherlands.

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Correspondence: Gregory J. Riely, MD, PhD, Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York, NY 10065. E-mail: rielyg@mskcc.org
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    Bahleda R, Soria J, Harbison C. Tumor regression and pharmacodynamic (PD) biomarker validation in non-small cell lung cancer (NSCLC) patients treated with the ErbB/VEGFR inhibitor BMS-690514 [abstract]. J Clin Oncol 2009;27(Suppl):Abstract 8098.

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  • 54

    Miret JJ, Wang F, Anjum R. AP26113, a potent ALK inhibitor, is also active against EGFR T790M in mouse models of NSCLC. Presented at the 14th World Conference on Lung Cancer; July 3–7, 2011; Amsterdam, The Netherlands.

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  • 55

    Atagi S, Katakami N, Hida T. LUX-Lung 4: a phase 2 trial of afatinib (BIBW 2992) in advanced NSCLC patient spreviously treated with erlotinib and gefitinib. Presented at the 14th World Conference on Lung Cancer; July 3–7, 2011; Amsterdam, The Netherlands.

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