Emerging treatment for advanced lung cancer with EGFR mutation.

Review

Emerging treatment for advanced lung cancer with EGFR mutation Cengiz Inal, Emrullah Yilmaz, Bilal Piperdi, Roman Perez-Soler & Haiying Cheng†

1.

Background

2.

Medical need

3.

The role of EGFR TKIs in

†

Albert Einstein College of Medicine, Department of Medical Oncology, Bronx, NY, USA

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 07/13/15 For personal use only.

different settings 4.

Market review

5.

Current research goals

6.

Scientific rationale

7.

Competitive environment (emerging treatment)

8.

Potential development issues

9.

Conclusion

10.

Expert opinion

Introduction: Lung cancer is the leading cause of cancer-related death worldwide. It is usually diagnosed at advanced stage for which platinum-based chemotherapy had been the standard approach, although with limited clinical benefits. Discovery of oncogenic EGFR mutations in lung cancer have shifted the treatment paradigm with molecularly targeted therapies. Areas covered: EGFR tyrosine kinase inhibitors (TKIs) have become the first-line choice in patients with advanced NSCLC harboring EGFR activating mutations. However, resistance to targeted therapy develops inevitably during the course of treatment. Multiple mechanisms of acquired resistance have been discovered, most commonly the secondary mutation of T790M in exon 20. The second- and third-generation EGFR TKIs are holding promise to overcome T790M-associated acquired resistance and currently being tested in clinical trials. In this article, we focus on the emerging approaches to overcome the different mechanisms of resistance to targeted therapies in patients with EGFR-mutant advanced NSCLC. Expert opinion: It is essential to uncover the complex mechanisms underlying the progression of lung cancer after upfront EGFR TKIs. Next generation, in particular, the third generations of EGFR TKIs have been developed against acquired T790M mutation with promising clinical activity and better toxicity profile. Combination of targeted therapies has also been explored. Further studies are needed to detect the real-time changes of the resistance mechanisms and to develop new therapeutic strategies for lung cancer patients with EGFR mutations. Keywords: combination of targeted therapies, EGFR, NSCLC, resistance mechanisms, T790M mutation, tyrosine kinase inhibitors Expert Opin. Emerging Drugs [Early Online]

1.

Background

Lung cancer is the most common cause of cancer-related mortality in the USA [1]. Over the last 15 years, advances in understanding of molecular pathways driving lung cancer have led to development of multiple therapeutic strategies, including treatment targeting epidermal growth factor receptor (EGFR), angiogenesis and other signaling. Lung adenocarcinoma with EGFR mutation has emerged as a distinct subtype of NSCLC in terms of pathogenesis, clinical features and disease course [2,3]. This review focuses on the treatment of EGFR mutation-positive advanced nonsquamous NSCLC. 2.

Medical need

Median overall survival (OS) of patients with advanced-stage NSCLC is about 4 -- 5 months with best supportive care based on historical data [4]. Chemotherapy is effective in the treatment of advanced NSCLC, but its impact on prolonging 10.1517/14728214.2015.1058778 © 2015 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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C. Inal et al.

survival is limited. A meta-analysis showed that it was associated with a 24% reduction in the probability of death at 1 year when compared with supportive care. However, the effect of treatment appeared to decrease significantly after the first 6 months from therapy initiation and the mean potential gain in survival, as compared with supportive care, was approximately 6 weeks [5]. A randomized prospective clinical trial was conducted to compare the four different combinations of platinum-based chemotherapeutic agents in terms of response rate and survival, however, none of the regimens offered a significant advantage over the others [6]. Overall response rate (ORR) was 17 -- 22% and the median OS was 7.4 -- 8.1 months. EGFR mutation in lung cancer Over the past few years, sub-classification of NSCLC has changed from histology to molecular biomarkers after identification of pathways involved in the development of lung cancer. Aberrant EGFR signaling is one of these recently discovered pathways that can drive the lung cancer, especially in non-smoker Asian patient population with adenocarcinoma component. As a result, inhibition of the EGFR pathway has been demonstrated to be a key therapeutic target in the treatment of NSCLC, and strategies to block this pathway include small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. The most common EGFR mutations (~ 85 -- 90%) are inframe deletions in exon 19 and L858R point mutation in exon 21. Mutations in exon 18 and 20 are considered as uncommon mutations (~ 10%). There is a significant association between sensitivity to EGFR TKIs and the types of EGFR mutations. For instance, deletion 19, exon 21 (L858R, L861) and exon 18 (G719X) mutations are sensitizing mutations for EGFR TKIs, whereas exon 20 insertions confer resistance. EGFR mutations can be found in all histologic subtypes of NSCLC. It was observed in 2.7% of patients with squamous cell carcinoma. Its prevalence increases up to 10% in Western patient population with adenocarcinoma and up to 50% of Asian patients, with higher EGFR mutation frequency in Asian, non-smokers, women and non-mucinous cancers [7,8]. 2.1

Existing treatment Over the last several years, multiple EGFR-targeted therapies have been developed including anti-EGFR monoclonal antibodies (such as cetuximab and panitumumab) and smallmolecule EGFR TKIs. Gefitinib and erlotinib are the reversible first-generation EGFR TKIs. In contrast to first-generation, second-generation EGFR TKIs such as afatinib, dacomitinib, neratinib and canertinib are pan-ErbB inhibitors, which irreversibly bind to a cysteine residue at position 797 in EGFR by forming covalent bonds (Table 1). They are more potent than gefitinib and erlotinib. They inhibit EGFR-sensitive mutations as well as T790M in vitro, however, the dose required to overcome 2.2

2

T790M-mediated resistance was associated with significant toxicities due to inhibition of wild-type EGFR in clinical setting [9]. Third-generation EGFR inhibitors such as AZD9291, CO-1686 and HM61713 were designed to specifically inhibit the EGFR T790M mutant with better safety profile. They are in early stage of development with Phase II and III trials for AZD9291 (NCT02151981, NCT02094261) and Phase II trial for CO-1686 (NCT02147990) ongoing. 3.

The role of EGFR TKIs in different settings

The Iressa Pan-Asia Study is the first randomized Phase III study that compared gefitinib with paclitaxel/carboplatin in clinically selected chemotherapy-naı¨ve patients with advanced NSCLC (Asian, non-/light ex-smoker population with adenocarcinoma) [10]. Incidence of EGFR mutation was about 60% in the trial. Gefitinib was demonstrated to be superior to chemotherapy as an initial treatment in subgroup of patients with positive EGFR mutation. It significantly prolonged progression-free survival (PFS), increased the objective response rate, reduced toxic effects and improved quality of life. Gefitinib treatment was detrimental for those without EGFR mutations. Final OS data were published in July 2011 and treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS, likely due to high proportion of patients crossing over to the alternative treatment [11]. First-SIGNAL was another randomized Phase III trial conducted in clinically selected advanced NSCLC in Korea (never-smokers, adenocarcinoma) who were randomly assigned to gefitinib versus cisplatin plus gemcitabine as first-line therapy [12]. The 1-year PFS rates were 16.7% with gefitinib versus 2.8% with chemotherapy. The PFS curves crossed at 7 months, favoring chemotherapy during the first 7 months and gefitinib thereafter. OS was not significantly different between the two treatment arms, however, 113 (75%) of 150 patients in the chemotherapy arm received an EGFR-TKI during the course of their disease after discontinuation of the assigned treatment which seems most likely to be the reason for failure to show a difference in survival. West Japan Oncology Group conducted a Phase III clinical trial (WJTOG 3405) between 2006 and 2009 comparing first-line treatment of gefitinib versus combination of cisplatin and docetaxel in patients with EGFR mutation-positive NSCLC [13]. One hundred and seventy-two patients were included in survival analysis. PFS was significantly longer in gefitinib group compared with chemotherapy arm (9.2 vs 6.3 months; hazard ratio [HR]: 0.489). Follow-up analysis of 5-year OS data showed no difference irrespective of what initial treatment was, probably due to high crossover rate [14]. Similarly designed Phase III study (NEJGSG 002) by North-East Japan Study Group confirmed the benefit of prolonged PFS in EGFR-mutant patients who received first-line treatment with gefitinib compared with standard

Expert Opin. Emerging Drugs (2015) 20(4)

AstraZeneca

Clovis Oncology

Hanmi Pharmaceutical

AZD9291

Rociletinib (CO-1686)

HM61713

Pfizer

Dacomitinib

Pfizer

Boehringer Ingelheim

Afatinib

Canertinib (CI-1033)

Company

Compound

N/A

Structure

Table 1. Second- and third-generation EGFR TKI molecules.


Phase II

No approval for any indication yet

Phase I

Phase III



Phase II

Phase III



Phase III and IV

Stage of development

First-line treatment of advanced NSCLC with EGFR exon 19 deletions or exon 21 (L858R)

Indication


Third-generation, selective inhibitor for both EGFR activating mutations and T790M

Third-generation, oral irreversible EGFR inhibitor

Second-generation, irreversible panHER inhibitor by covalently binding to cysteine 773 of EGFR Third-generation, oral, irreversible EGFR inhibitor

Second-generation, irreversible inhibitor of HER-1 (EGFR), HER-2 and HER-4

Second-generation, irreversible covalent inhibitor of EGFR and erbB-2 (HER2)

Mechanism of action

Emerging treatment for advanced lung cancer with EGFR mutation

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C. Inal et al.

chemotherapy (carboplatin plus paclitaxel) (10.8 vs 5.4 months; HR: 0.3) [15]. Gefitinib group also had a higher response rate to treatment (73.7 vs 30.7%, p < 0.001). OPTIMAL study was a Phase III prospective randomized clinical trial performed in China to compare the efficacy of first-line erlotinib as monotherapy versus the standard chemotherapy regimen (four cycles of gemcitabine plus carboplatin) in patients with chemotherapy-naı¨ve advanced or metastatic NSCLC with activating EGFR mutations [16]. Patients treated with erlotinib had significantly longer PFS (13.1 vs 4.6 months; HR: 0.16). Erlotinib was also associated with less grade 3 or 4 adverse events. OS data presented in 2012 American Society of Clinical Oncology (ASCO) annual meeting did not differ significantly between the two treatment arms (HR: 1.065; p = 0.6849) and in the different subgroups. Lack of difference in OS was thought to be possibly related to a high level of crossover to EGFR TKI therapy in the chemotherapy group. EURTAC was the first randomized trial in Europe targeting a non-Asian population of advanced NSCLC patients harboring EGFR mutations with comparison of erlotinib with standard platinum-based chemotherapy as first-line treatment [17]. It showed superiority of erlotinib in terms of longer median PFS of 9.7 versus 5.2 months in the chemotherapy group (HR: 0.37). Higher percentage of patients achieved a partial response in the erlotinib arm (56 vs 15%). Based on data from EURTAC study, the US FDA approved erlotinib on 14 May 2013 for the first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

unselected NSCLC patient population in multiple Phase III trials (carboplatin/paclitaxel in TRIBUTE trial; cisplatin/ gemcitabine in TALENT trial) [22,23]. Combinations showed no survival benefit compared with chemotherapy alone. There was no difference between treatment arms in terms of time to progression, response rate and quality of life. TALENT trial showed that OS and PFS were increased in erlotinib arm in a small group of patients who had never smoked. Based on these data, CALGB 30406 was conducted in advanced NSCLC patients who were non-smoker or a former light smoker to investigate the efficacy of erlotinib alone versus combined with chemotherapy (carboplatin/paclitaxel) [24]. Both treatment arms have similar efficacy in that clinically selected population. Incidence of grade 3 and 4 adverse events was greater in patients treated with the combination. In a recent Phase II Japanese randomized study (NEJ005/ TCOG0902) comparing concurrent gefitinib plus chemotherapy (carboplatin/pemetrexed) versus sequential gefitinib and chemotherapy as first-line treatment in patients with NSCLC harboring EGFR sensitizing mutations, 80 patients were enrolled [25]. Median PFS was 17.2 months in the concurrent group compared with 15.1 months in the sequential arm (p = 0.41). OS data were immature, but median survival times were not reached yet in the concurrent treatment arm and were 30.0 months in the sequential group (p = 0.049). NEJ009 Phase III trial is currently recruiting EGFR-mutant advanced NSCLC patients to explore survival difference with combination of gefitinib plus carboplatin/pemetrexed versus gefitinib alone as first-line treatment [26]. Sequential (intercalated) treatment Given the lack of clinical benefit from adding EGFR TKI to chemotherapy concurrently, it has been hypothesized that EGFR TKI in combination with chemotherapy are behaving antagonistic in EGFR wild-type tumors. Preclinical studies revealed that erlotinib induces G1 phase arrest and blocks the cytotoxic effect of subsequent pemetrexed in human NSCLC cells, however, cytotoxic synergism was noted with sequential pemetrexed followed by erlotinib regardless of EGFR mutation status [27]. Intercalated administration (pharmacodynamic separation) of EGFR TKI and chemotherapy has been postulated as a reasonable option. This was further investigated in the Asian FASTACT-2 randomized Phase III trial [28]. Four hundred and fifty-one patients were randomly assigned to receive chemotherapy (carboplatin or cisplatin on day 1, gemcitabine on days 1 and 8) plus erlotinib on days 15 -- 28 versus chemotherapy plus placebo. Median PFS was significantly prolonged in the chemotherapy plus erlotinib arm (7.6 vs 6.0 months; HR: 0.57; p < 0.0001). Median OS for patients in the erlotinib versus placebo groups was 18.3 and 15.2 months, respectively (HR: 0.79; p = 0.042). Treatment benefit was noted only in patients with an activating EGFR gene mutation (median PFS 16.8 vs 6.9 months, HR: 0.25, p < 0.0001; median OS 31.4 vs 20.6 months, HR: 0.48, p = 0.0092). Unlike other 3.1.2

First-generation EGFR TKI in combination with chemotherapy as first-line treatment 3.1.1 Concurrent treatment 3.1

Combination of chemotherapy and EGFR TKIs had been initially studied in unselected patient population with advanced-stage NSCLC. Gefitinib was the first EGFR TKI that came to the market with accelerated ‘fast track’ approval by FDA in May 2003 as monotherapy for the treatment of patients with locally advanced NSCLC who had failed ‡ 2 courses of chemotherapies including platinumbased and docetaxel. Its effectiveness was demonstrated in a two parallel designed, randomized Phase II trial (Iressa Dose Evaluation in Advanced Lung cancer 1 and 2) comparing two oral doses of gefitinib in previously treated, unselected advanced NSCLC [18,19]. Subsequent two large Phase III trials conducted in chemotherapy-naive stage III/IV NSCLC patients with randomization to receive gefitinib or placebo in combination with platinum doublet chemotherapy showed no benefit from adding gefitinib to chemotherapy (cisplatin/gemcitabine in INTACT-1 trial and carboplatin/paclitaxel in INTACT-2) [20,21]. Erlotinib has been also combined with different combination of chemotherapy regimens for the treatment of 4




previous Phase III trials, FASTACT-2 reported a survival improvement in patients with EGFR-mutant NSCLC for the first time. In Caucasian patients with advanced NSCLC who were positive for EGFR protein expression and/or with high EGFR gene copy number, the intercalated treatment of chemotherapy (carboplatin/paclitaxel on day 1) plus erlotinib (days 2 -- 15) reported similar results to erlotinib alone [29]. In EGFR-mutant patients, the 12-month OS, 6-month PFS and ORR were superior with erlotinib monotherapy compared with the intercalated therapy. EGFR TKI as second- or third-line treatment In an early Phase III trial (Iressa Survival Evaluation in Lung Cancer), gefitinib versus best supportive care was tested as second- or third-line treatment for unselected patients with locally advanced or metastatic NSCLC [30]. There was no significant survival benefit in either the overall or adenocarcinoma population, however in subgroup analysis, survival was significantly longer in the gefitinib arm for never-smokers and patients of Asian origin. The objective response rate in the overall population was significantly greater in the gefitinib group (8.0 vs 1.3%; p < 0.0001), with the largest differences among patients of Asian origin, never-smokers, women and patients with adenocarcinoma. Subsequent Phase III trial (INTEREST study) compared gefitinib with docetaxel in unselected pretreated advanced NSCLC. It established gefitinib to be non-inferior in OS and similar in tumor response and PFS to docetaxel [31]. Another Phase III trial (BR.21) comparing erlotinib with placebo in patients with NSCLC after failure of first- or secondline chemotherapy showed increased OS in erlotinib arm (6.7 vs 4.7 months; HR: 0.70; p < 0.001) [32]. Data from TAILOR trial, which was a randomized controlled trial conducted at multicenters in Italy comparing docetaxel versus erlotinib as second-line treatment in patients with advanced NSCLC with wild-type EGFR, demonstrated that there was no statistically significant difference in OS, but after treatment effects adjusted for histology, smoking habit, ECOG performance, status, sex, best response to first-line chemotherapy and KRAS mutational status, docetaxel was found to be superior to erlotinib with HR of 0.73 and p-value of 0.05 [33]. 3.2

4.

Market review

An estimated 159,260 Americans died from lung cancer in 2014, accounting for approximately 27% of all cancer-related deaths [1]. The lung cancer 5-year survival rate (16.6%) is lower than many other leading cancer sites, although the survival rate is considerably better (53.5%) when the disease is still localized. However, the large majority of patients with lung cancer are diagnosed with regional (22%) and distant diseases (57%) with 5-year survival rates of 26 and 4%, respectively [34]. OS rates remained poor despite platinum-

based doublet chemotherapy, which has been the traditional treatment for patients with metastatic disease [5,6]. 5.

Current research goals

As our knowledge about the underlying molecular pathogenesis in lung cancer increases, there have been more research efforts to target EGFR pathway in patients with advanced lung cancers. Acquired resistance to targeted therapies has become a major issue and this led to development of secondand third-generation TKIs and also using various combination strategies to increase effectiveness of EGFR inhibition and also to overcome acquired resistance to TKIs. For detection of acquired resistance to targeted therapy prior to radiographic progression, circulating free DNA or circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) in the blood has emerged as forms of ‘liquid biopsy’ that provides a non-invasive method for detection of tumor-related real-time genetic alterations involved in resistance to therapy [35]. Liquid biopsy has some potential advantage over standard tissue biopsy. First of all, it is non-invasive without the risk of procedure-related complications associated with tissue biopsies. It can be repeated multiple times as desired throughout treatment course to monitor genetic alterations in tumor cells and detect development of treatment resistance earlier. Second, obtaining enough tumor material to run molecular studies has sometimes been challenging, especially for cytology-only specimens. It is not rare to have inadequate cells for molecular testing after tumor tissue is used for pathological diagnosis. Lastly, it allows the evaluation of both primary and metastatic lesions in contrast to tissue biopsies, which provide a limited evaluation of one disease site. There are still some limitations of liquid biopsy such as standardization of different techniques among laboratories, optimal tissue sampling (whole blood, serum or plasma), low sensitivity for detection of epithelial-mesenchymal transition (EMT) as CTCs with low or absent expression of EpCAM can be easily missed by currently available system CellSearch (Veridex LLC, Raritan, NJ, USA), which is the only FDA-approved technology for CTC enrichment and enumeration. 6.

Scientific rationale

EGFR is a family of genes that encode widely expressed transmembrane protein tyrosine kinases. It is normally found on the surface of epithelial cells and often aberrantly expressed in a number of human malignancies. It consists of four members including EGFR, ERBB2, ERBB3 and ERBB4. When its ligand binds to the receptor, it activates the intracellular tyrosine kinase activity of EGFR receptor via dimerization, which then triggers the downstream effector pathways leading to cellular proliferation, prevention of apoptosis, angiogenesis and metastasis [36]. In lung cancer, many different types of nucleotide changes have been reported within the EGFR kinase domain encoding


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the ATP-binding pocket (exon 18 -- 21) [37]. This results in autophosphorylation of the cytoplasmic receptor domain, which subsequently activates downstream signaling cascades including the MAPK, mammalian target of rapamycin (mTOR) and Janus kinase signal transducers and activators of transcription (JAK-STAT) pathways [38]. The most commonly found mutations are in-frame deletions in exon 19 and point mutations in exon 21 as a result of substitution of arginine for leucine at position 858 (L858R). They together account for about 85% of EGFR mutations. These oncogenic mutations are constitutively active. They decrease affinity of the mutant TK domain for ATP by which it preferentially bind to drugs such as TKIs over ATP [39]. EGFR exon 20 insertions, which account for 4% of EGFR mutations, are associated with a lack of response to TKIs in preclinical models and in patients [40]. Another mutation in exon 20 involving substitution of methionine for threonine at position 790 (T790M, so-called ‘gatekeeper mutation’) confers resistance to TKIs due to steric hindrance blocking erlotinib to bind and increased affinity of ATP. It represents the most common form of acquired resistance to EGFR TKIs [41]. 7. Competitive environment (emerging treatment)

Second-generation EGFR TKIs Acquired resistance to first-generation EGFR TKIs is a major clinical problem and most commonly characterized by secondary mutations in EGFR such as T790M in exon 20. Multiple second-generation EGFR TKIs were developed to overcome T790M-mediated resistance, however, the results are mostly disappointing due to dose-limiting toxicities. Afatinib is the only second-generation EGFR TKI that reached to FDA approval for first-line treatment of EGFR-mutant advanced NSCLC. It has been tested in a series of Phase II and III clinical trials named LUX-Lung as detailed below (Table 2). Afatinib is an oral, irreversible ErbB-family blocker, activity profile of which includes EGFR activating mutations such as the most common mutations, exon 21 (L858R) and exon 19 deletions as well as the T790M gatekeeper mutation in exon 20 with a lower potency. It covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in down-regulation of ErbB signaling, thereby inhibiting downstream signaling and leading to tumor growth inhibition and apoptosis. LUX-Lung 2 was a single-arm Phase II study to examine the efficacy of afatinib as first- or second line after chemotherapy in patients with EGFR mutation-positive lung adenocarcinoma from Taiwan and the USA [42]. It showed 61% objective ORR with no significant difference in ORR between Taiwan versus the USA or first- versus second-line treatment. Median PFS for all patients was 10.1 months with a median 7.1

6

response duration of 12.9 months. Median OS for all patients was 24.8 months. Nearly all patients had tumor size reductions regardless of the type of EGFR mutation. LUX-Lung 1 was a randomized, multicenter, Phase IIb/III trial comparing afatinib versus placebo in patients with metastatic NSCLC after failure of erlotinib, gefitinib or both, and one or two lines of chemotherapy [43]. Most patients were Asian and never-smokers. It failed to show a difference between groups in terms of OS, however, showed promising results regarding PFS (3.3 vs 1.1 months) and partial response rate of 7 -- 11% favoring afatinib. LUX-Lung 3 was a global, randomized Phase III study comparing first-line afatinib with cisplatin plus pemetrexed chemotherapy in patients with EGFR mutation-positive advanced lung adenocarcinoma [44]. Three hundred and forty-five patients were randomized in 2:1 ratio to 40 mg afatinib daily or up to 6 cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 3 weeks. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy arm. For patients with exon 19 deletions and L858R EGFR mutations, the magnitude of PFS benefit was even larger, with a median PFS of 13.6 months for afatinib and 6.9 months for chemotherapy. OS was not different between afatinib and chemotherapy in the overall study population. A high degree of crossover between treatment arms (62 -- 65%) upon progression of disease was noted. Data from LUX-Lung 3 trial led to FDA approval for afatinib in July 2013. LUX-Lung 4 was a Japanese single-arm Phase II trial conducted in patients with advanced lung adenocarcinoma who progressed during prior treatment with erlotinib, gefitinib or both [45]; 72.6% (45/62) were EGFR mutation positive in their primary tumor and 82.3% (51/62) met the criteria of acquired resistance to erlotinib and/or gefitinib. Five out of 61 patients (8.2%) had a confirmed ORR (partial response), with a median PFS of 4.4 months and median OS of 19.0 months. Afatinib reduced the size of target lesions in 79% of all patients during the treatment period with 9 patients (16%) having at least a 30% reduction in tumor size, but reduction was not durable in 4 patients. Two patients had acquired T790M mutations: L858R + T790M, and deletion in exon 19 + T790M; they had stable disease for 9 months and 1 month, respectively. LUX-Lung 6 was a Phase III clinical trial conducted in Asian patients with advanced-stage EGFR-mutant NSCLC comparing first-line treatment with afatinib versus cisplatin plus gemcitabine [46]. Three hundred and sixty-four patients were randomly assigned (2:1) to receive either oral afatinib (40 mg/day) or combination of gemcitabine plus cisplatin of a 3-week schedule for up to six cycles. Median PFS was significantly longer in the afatinib group (11.0 months) than in the chemotherapy group (5.6 months; HR: 0.28). ORR was significantly higher in afatinib group (66.9 vs 23.0%). Median duration of response was 9.7 months for afatinib and 4.3 months for chemotherapy arm.




Table 2. Major clinical trials for afatinib. Study

Phase Line

Number Patient population of patients

Treatment arms

End points

Important results

LUX-Lung 1

IIb/III

‡2

585

Afatinib 50 mg daily vs placebo

OS PFS, ORR, HRQoL, response duration, safety Confirmed OR (CR or PR) Rate of disease control, time to objective response, duration of objective response, tumor shrinkage, PFS, OS PFS Tumor response, OS, adverse events, PROs

No difference in OS Median PFS longer in afatinib group ORR 7 -- 11% ORR: 61%, majority PR -> 66% in pts with EGFR del19 or L858R, 39% in pts with other mutations Disease control rate: 82 -- 86%

LUX-Lung 2

II

First or 129 second

LUX-Lung 3

III

1

345

Treatment-naive, EGFR mutationpositive advanced lung adenocarcinoma

Afatinib 40 mg daily vs cisplatin plus pemetrexed

LUX-Lung 4

II

‡3

62

Afatinib 50 mg daily

ORR (CR or PR) PFS, OS, safety

LUX-Lung 5

III

‡2

202

Afatinib plus paclitaxel vs investigator’s choice chemo

PFS ORR, OS, safety

Improvement in PFS was observed on A + P arm (5.6 vs 2.8 months) ORR was significantly higher on A + P arm (32.1 vs 13.2%) OS similar

LUX-Lung 6

III

1

364

Japanese pts with EGFR mutationpositive advanced lung adenocarcinoma who progressed after ‡ 12 weeks of prior erlotinib and/or gefitinib Pts with EGFR mutation-positive advanced lung adenocarcinoma who had failed ‡ 1 line of chemotherapy and E/G (after ‡ 12 weeks treatment), followed by progression on afatinib Asian pts with treatment-naive EGFR mutation-positive advanced NSCLC

Afatinib 40 mg daily vs cisplatin plus gemcitabine

PFS ORR, disease control rate, OS

LUX-Lung 7

IIb

1

Ongoing

Pts with treatmentnaive EGFR mutationpositive advanced NSCLC from all around the world

Afatinib vs gefitinib

LUX-Lung 8

III

2

795

Pts with advanced squamous cell carcinoma of the lung following failure of First-line chemotherapy

Afatinib vs erlotinib

PFS, TTF, OS ORR, time and duration of objective response, tumor shrinkage, HRQoL PFS OS, ORR, disease control rate, safety, HRQoL

Median PFS significantly longer in afatinib group (11 vs 5.6 months) ORR higher in afatinib group (66·9 vs 23%) Pending

Patients who failed erlotinib, gefitinib or both, and one or two lines of chemotherapy Patients with EGFR mutation-positive advanced lung adenocarcinoma who had no more than 1 prior chemotherapy and no previous EGFR TKI

Afatinib 50 mg daily vs afatinib 40 mg daily

Prolonged PFS in afatinib group (11.1 vs 6.9 months) Higher response rates with afatinib (69 vs 44%) No CR, PR rate: 8.2% Median PFS 4.4 months Median OS 19.0 months

Median PFS was significantly higher for afatinib (2.7 vs 1.9 months) ORR was similar, but DCR was significantly higher with afatinib (45.7 vs 36.8%)

CR: Complete response; HRQoL: Health-related quality of life; OR: Objective response; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; PRO: Patient-reported outcomes; pts: Patients; TTF: Time to treatment failure.


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Pooled analysis of OS data from these two large Phase III trials (LUX-Lung 3 and LUX-Lung 6) was recently published at Lancet Oncology in February 2015 [47]. It demonstrated that median OS in patients receiving first-line afatinib versus chemotherapy was not different in whole patient population, but in preplanned analyses, afatinib significantly improved OS in patients with deletion 19 mutations in comparison with chemotherapy in both trials, but not for patients with L858R point mutations in exon 21 in either trial. This was the first time that upfront EFGR-TKI significantly improved OS compared with chemotherapy, specifically in patients harboring the EGFR deletion 19 mutation. OS benefit of afatinib could be related to its irreversible blockage of ErbB family, but further prospective studies are needed to analyze the results separately for patients with in-frame deletions in exon 19 and L858R point mutation in exon 21. These two mutations perhaps result in different biological abnormalities leading to variations in sensitivities to EGFR TKIs. In a Phase III LUX-Lung 8 trial comparing afatinib versus erlotinib for the second-line treatment of advanced-stage squamous lung cancer after at least one prior platinum-based chemotherapy, 795 patients were recruited between March 2012 and January 2014. Results were presented in the European Society for Medical Oncology 2014 meeting and showed that PFS was significantly better in afatinib arm (2.4 vs 1.9 months; p = 0.0427). Disease control rate was also better in patients treated with afatinib (45.7 vs 36.8%; p = 0.020). LUX-Lung 5 trial demonstrated continued benefit of afatinib after progression on afatinib monotherapy following failure of either erlotinib or gefitinib. There is an ongoing clinical trial comparing afatinib with gefitinib as first-line treatment of EGFR-mutant lung adenocarcinoma in Phase IIb LUXLung 7 study (NCT01466660). Third-generation EGFR TKIs Second-generation irreversible EGFR TKIs showed promising activity against T790M-mediated resistance. Unfortunately, clinical trials have been largely disappointing due to doselimiting toxicities caused by inhibition of wild-type EGFR. Recently, third-generation EGFR inhibitors, such as AZD9291, CO-1686 and HM61713, have been developed. In preclinical studies, these agents are active against cell lines and murine models harboring T790M mutations. Moreover, they seem to spare wild-type EGFR, therefore aimed to overcome T790M resistance with a better toxicity profile. A Phase I study of AZD9291 in EGFR-mutant NSCLC patients with acquired resistance, ORR was 51% (91/177) with a response rate of 64% in 89 patients with T790M mutation-positive patients and 23% in patients with T790M mutation negative patients [48]. The overall disease control rate in T790M-positive patients was 96% (85/89), which confirms robust efficacy in patients with acquired resistance to EGFR TKIs, especially T790M-positive patients. 7.2

8

Efficacy of rociletinib (CO-1686), an irreversible, highly selective inhibitor of activating and T790M mutations while sparing wild-type EGFR, was evaluated in 88 patients with acquired resistance to EGFR TKI [49]. Data showed promising efficacy against T790M EGFR-mutant NSCLC and doserelated toxicities due to inhibition of wild-type EGFR were not observed. There are three different clinical trials ongoing to evaluate safety and efficacy of rociletinib in patients with EGFR-mutant advanced NSCLC who had not received any EGFR-targeted therapy (TIGER-1, NCT02186301); in patients with or without T790M-positive NSCLC after acquiring resistance to prior EGFR-targeted therapy (TIGER-2, NCT02147990) and in comparison to single agent chemotherapy (pemetrexed or gemcitabine or paclitaxel or docetaxel) in patients with EGFR-mutant NSCLC who had failed at least one prior EGFR TKI and platinum-doublet chemotherapy (TIGER-3, not open for recruitment yet, NCT02322281). HM61713 is another selective inhibitor for both activating and T790M EGFR mutations, but not EGFR wild type [50]. Its safety and efficacy was studied in a Phase I clinical trial, which included patients with EGFR-mutated NSCLC who failed to EGFR TKIs. Disease control rate was 76.5 and 73.1% in dose-escalation and -expansion cohorts, respectively. Out of 27 patients with T790M mutation at baseline biopsy, 18 patients showed decreased size in the target lesions. Seven out of 42 evaluable patients had unconfirmed partial responses, all of which were T790M mutation-positive cases. It showed good safety profile, with most adverse events being grade 1 or 2 and reversible. 7.3

EGFR TKI in combination with different agents Bevacizumab

7.3.1

The VEGF and EGFR pathways are two validated targets for NSCLC. A number of preclinical/clinical studies have been conducted to investigate the antitumor activity of combined anti-HER-1/EGFR and anti-VEGF agents, which showed synergistic effect in xenograft models. A Phase I/II study demonstrated encouraging antitumor activity and good safety profile of bevacizumab plus erlotinib combination in patients with advanced NSCLC [51]. It resulted in a response rate of 14.3%, PFS time of 6.2 months and median survival time of 12.6 months. Subsequent Phase II trial further evaluated the efficacy of combining bevacizumab plus chemotherapy (docetaxel or pemetrexed) versus bevacizumab plus erlotinib versus chemotherapy alone for the second-line treatment of recurrent or refractory NSCLC [52]. PFS and OS results revealed that bevacizumab enhances the activity of chemotherapy. Bevacizumab/erlotinib combination had similar efficacy to bevacizumab plus chemotherapy. Median OS was 13.7 months for erlotinib plus bevacizumab, 12.6 months for bevacizumab and chemotherapy and 8.6 months for chemotherapy alone. However, bevacizumab/erlotinib was favored given its better safety profile compared with chemotherapy containing arms.




BeTa trial was a placebo-controlled, Phase III trial comparing the efficacy of bevacizumab plus erlotinib versus placebo plus erlotinib in patients with recurrent or refractory advanced-stage NSCLC after failure of standard first-line chemotherapy [53]. Addition of bevacizumab to erlotinib did not improve survival (9.3 vs 9.2 months). PFS seemed to be longer in the bevacizumab group (3.4 vs 1.7 months), however, the result could not be defined as significant as it failed to meet its primary end point of improved OS. Addition of erlotinib to bevacizumab in maintenance setting was tested in a global Phase IIIB ATLAS trial [54]. Patients with advanced NSCLC were randomized (1:1) to receive bevacizumab plus either placebo or erlotinib after completion of four cycles of chemotherapy plus bevacizumab. Erlotinib with bevacizumab significantly improved PFS but not OS. Rash and diarrhea were the only grade 3 or 4 adverse events reported at a ‡ 5% higher incidence in the bevacizumab/erlotinib arm in comparison to bevacizumab/placebo arm (rash: 6.8 vs 0.5%, diarrhea: 9.8 vs 1.9%, respectively). Results from a Japanese open-label, randomized clinical trial comparing erlotinib plus bevacizumab versus erlotinib alone as first-line treatment for advanced EGFR mutationpositive non-squamous NSCLC showed that median PFS was significantly longer in bevacizumab/erlotinib group (16 vs 9.7 months) [55]. In multivariate analysis, the benefit was seen across the most subgroups of patients. This is the first randomized study to show a clinically significant treatment effect of combining an EGFR TKI with another biological drug in patients with EGFR-mutant NSCLC. Hydroxychloroquine Hydroxychloroquine (HCQ) is an immunomodulating agent widely used for its antimalarial and antirheumatic effects, but also implicated as possible adjuncts to cancer treatment, specifically in TKI-resistant tumors by disrupting the drugtolerant state via direct inhibition of autophagy. It was observed that initial treatment with HCQ plus EGFR TKI could also prevent the development of drug-tolerant clones. A randomized Phase II trial tested the efficacy of erlotinib plus hydroxychloroquine (EQ) in delaying acquired resistance to erlotinib (E) in TKI-naive patients with EGFR-mutant advanced NSCLC [56]. Combination did not improve 9-month PFS compared with erlotinib alone. Confirmed response rates were 65 and 57%, disease control rates were 92 and 84%, 9-month PFS was 71 and 52% for E and EQ, respectively, but median PFS was the same in each arm (10.8 months). 7.3.2

Insulin-like growth factor-1 receptor inhibitors One well-described mechanism of resistance to EGFR TKI is the activation of the insulin-like growth factor-1 receptor (IGF-1R) pathway [57]. Activation of the IGF-1R pathway has been noted as a consequence of EGFR inhibition in a variety of NSCLC cell lines, leading to cellular proliferation and evasion of apoptosis. Therefore, it has emerged as a novel 7.3.3

target to overcome resistance and enhance the efficacy of EGFR inhibitors in patients with NSCLC. R1507 is a fully human immunoglobulin G1-type monoclonal antibody against IGF-1R. In preclinical studies, the combination of R1507 and erlotinib resulted in enhanced growth inhibition and induction of apoptosis compared with either agent alone [58]. A randomized Phase II study of erlotinib in combination with either R1507 or placebo in patients with advanced-stage NSCLC was conducted. The combination did not provide PFS or survival advantage over erlotinib alone in unselected patients with advanced NSCLC [59]. Cixutumumab (previously IMC-A12) is a fully humanized recombinant IgG1/l monoclonal antibody with high affinity to the extracellular domain of IGF-1R, acting as an antagonist of the IGF-I/IGF-II ligand binding. In preclinical studies, cixutumumab was demonstrated to have strong antitumor activity in vitro and in vivo for the treatment of cancers dependent on IGF-IR signaling for growth and survival [60]. In a Phase I/ II study of erlotinib in combination with cixutumumab, 18 patients with advanced NSCLC were enrolled. The combinations of cixutumumab and full-dose erlotinib were not well tolerated and efficacy in unselected patients with NSCLC seems to be low [61]. OSI-906 is a potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor which has demonstrated in vivo efficacy in tumor models and is currently in clinical testing in two Phase II trials looking at combination with erlotinib as maintenance therapy (NCT01186861) as well as first-line therapy in patients with EGFR-mutant advanced NSCLC (NCT01221077). c-Met inhibitors and antibodies Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to EGFR TKIs in patients with NSCLC. Approximately 5 -- 22% of NSCLC patients with secondary resistance to EGFR TKIs had evidence of amplification of the MET oncogene. Cabozantinib is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2. It has been tested in a single arm Phase II study in combination with erlotinib in patients with EGFR mutation-positive NSCLC following progression of disease on EGFR TKI therapy [62]. Thirty-five patients were treated with combination, 4 patients had partial response and 20/23 demonstrated significant growth rate reduction and > 30% increase in tumor doubling time. Onartuzumab is a humanized monoclonal antibody that blocks ligand activation of MET receptor tyrosine kinase. In a Phase II study, patients with Met-positive tumors (‡ 50% of tumor cells stain 2+ or 3+ intensity by immunohistochemistry) who received onartuzumab + erlotinib had nearly twofold reduction in the risk of disease progression (median, 1.5 vs 2.9 months; HR: 0.53) and threefold reduction in the risk of death compared with erlotinib alone (median, 3.8 vs 12.6 months; HR: 0.37) [63]. Phase III METLung study 7.3.4


9


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evaluating the efficacy of onartuzumab plus erlotinib combination versus erlotinib alone in patients with previously treated (second- or third-line) advanced MET-positive NSCLC showed that the combination did not improve OS, PFS, ORR and was associated with higher rates of adverse events [64]. Tivantinib is a non-ATP-competitive small molecule MET inhibitor. It stabilizes the inactive conformation of MET, disrupting downstream signaling and demonstrates antiproliferative activity in multiple cancer models. A randomized Phase II trial was conducted to prospectively compare the PFS of erlotinib plus tivantinib with erlotinib plus placebo among previously treated, EGFR inhibitor-naive patients with NSCLC [65]. PFS was not significantly different between the groups. In subgroup analysis, results were suggestive of a benefit for the combination among patients with KRAS mutations. Another Phase II study of erlotinib plus tivantinib in patients with EGFR mutation-positive NSCLC who failed in immediately previous EGFR TKI therapy was conducted in Japan [66]. The combination therapy seemed to be beneficial to those with high c-Met expression or in those without resistance mutations in EGFR (i.e., T790M or exon 20 insertions). A Phase III MARQUEE trial explored the efficacy of tivantinib and erlotinib versus placebo and erlotinib in previously treated non-squamous NSCLC patients [67]. The trial did not meet its primary end point of prolonging OS. However, a trend towards clinical benefit was demonstrated in the tivantinib/erlotinib arm in the PFS (3.6 vs 1.9 months) and ORR data (10.3 vs 6.5%). According to the subset analysis, both PFS and OS was longer in patients treated with combined MET-EGFR inhibition when tumors showed at least 2+ positive MET immunostaining in more than 50% of tumor cells. INC280 is a highly selective, oral MET inhibitor with preclinical activity in EGFR mut/MET-activated NSCLC when combined with EGFR TKIs. Partial responses were seen in 6/41 (15%) evaluable patients in a single-arm Phase Ib/II study looking at efficacy of INC280 in combination with gefitinib in patients with EGFR-mutated, MET-positive NSCLC [68]. There are some other c-Met inhibitors currently being tested in combination with EGFR TKIs in early phase clinical trials (MSC2156119J, MGCD265, foretinib). Cetuximab Combined EGFR inhibition, with cetuximab 500 mg/m2 every 2 weeks and erlotinib 100 mg daily, had no significant activity in patients with acquired resistance to erlotinib [69]. However, afatinib plus cetuximab showed encouraging clinical efficacy in patients with acquired resistance to erlotinib or gefitinib [70]. Fifty-three percent of patients had EGFR T790M mutation in that study. In the first 60 evaluable patients, the confirmed OR rate was 40% (95% CI: 27.6 -- 53.5), similar in both T790M-positive (38%) and T790M-negative (47%) tumors. 7.3.5

10

Immunotherapy EGFR-driven lung tumors inhibit antitumor immunity by activating the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway to suppress T-cell function and increase levels of pro-inflammatory cytokines. Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, demonstrated encouraging safety and survival outcomes as monotherapy in advanced NSCLC patients. Interim results from a Phase I study evaluating the safety and efficacy of nivolumab plus erlotinib combination in an EGFRmutant advanced NSCLC cohort, most of whom had progression post prior TKI therapy (20/21 patients) was presented in 2014 ASCO annual meeting [71]. Treatment was associated with acceptable safety profile. Among 20 patients with acquired resistance to EGFR TKI, 3 (15%) had partial and ongoing response (duration of response 6.1, 16.3 and 27.1 weeks); 9 (45%) had stable disease with 3/9 (33%) ongoing and 1 patient had an ongoing immune-related response, with 46% reduction in target lesions. MPDL3280A (an engineered anti-PD-L1) is currently in early Phase IB clinical trial testing in combination with erlotinib in patients with advanced NSCLC with a plan to include patients with EGFR-sensitizing mutation in expansion cohort (NCT02013219). A Phase I trial is also recruiting subjects to assess the safety, pharmacokinetics and anti-tumor activity of MEDI4736 (anti-PD-L1) in combination with gefitinib in patients with locally advanced or metastatic NSCLC who failed prior standard therapies (NCT02088112). Patients with EGFR mutation positive and who are naive/sensitive to EGFR TKIs will be enrolled in the expansion phase. 7.3.6

Poly ADP-ribose polymerase inhibitor Spanish Lung Cancer Group found that high BRCA1 mRNA expression was associated with shorter PFS in patients with acquired EGFR T790M mutation [72]. PFS was 27 months in patients with low BRCA1 levels as opposed to 10 months in those with high BRCA1 levels. That brought the idea of testing olaparib, an inhibitor of poly ADP ribose polymerase (PARP) that can down-regulate BRCA1 expression, in combination with EGFR TKI therapy as first-line treatment in EGFR-mutant advanced lung cancer patients. The results from Phase IB GOAL trial was presented in 2013 ASCO meeting, which confirmed the activity and tolerability of the combination [73]. Multicenter Phase II study opened up in July 2013 in Spain and patient recruitment is still ongoing (NCT01513174). 7.3.7

8.

Potential development issues

Treatment of advanced-stage NSCLC harboring EGFR mutation has transformed dramatically over last several years after discovery of EGFR-targeted therapies. However, sensitizing EGFR mutation can be found in only about 15% of overall patient population. About 30% of those patients with positive




EGFR mutation do not respond to upfront EGFR TKI therapy. Furthermore, patients who initially responded to the therapy inevitably become refractory to EGFR TKIs via multiple different mechanisms. Given heterogeneity of acquired resistance mechanisms, it became a major challenge for clinicians to find the appropriate management strategy for after development of resistance. Resistance to EGFR TKIs can be classified as either primary or secondary (acquired). Primary resistance can be seen in patients with exon 20 insertions or duplications (4% of EGFR mutations) and de novo T790M mutation which is associated with shorter OS and lower response rate upon treatment with upfront reversible EGFR TKI [74]. In one study, pre-treatment T790M was found in 35% (45/129) of patients with erlotinib-treated advanced NSCLC with EGFR mutations [72]. PFS was shorter in patients with pre-treatment T790M mutation (12 vs 18 months; p = 0.001) and intermediate/high expression of BRCA1 gene which is a component of DNA-repair pathway. Interestingly, detrimental effect of pre-treatment T790M mutation on PFS was neutralized in patients with low BRCA1 mRNA levels. Additionally, analysis of pre-treatment samples from 95 patients with EGFRmutant advanced NSCLC who were included in EURTAC trial detected T790M mutation in 62 (65%) patients using a highly sensitive assay [75]. Presence of concomitant T790M mutation was associated with shorter PFS in patients treated with erlotinib (15.8 vs 9.7 months; p = 0.0185), whereas the PFS difference was not statistically significant in patients treated with chemotherapy for those with or without the T790M mutation (6 vs 5.1 months, respectively; p = 0.2427). The multivariate analyses showed that high expression of BCL2L11 (also called BIM: Bcl-2 Interacting Mediator of cell death, which is a pro-apoptotic member of the Bcl-2 protein family) was a biomarker of longer PFS and OS in EGFR-mutant NSCLC. BCL2L11 has a significant role in the induction of apoptosis in response to EGFR TKIs, thus its low expression can be responsible for resistance to apoptosis. It has been first discovered in 2012 that BIM gene polymorphism specifically found in East Asians can lead to loss of the BH3 domain resulting in decreased BIM activity which subsequently causes resistance to apoptosis in response to EGFR TKIs [76]. In some retrospective studies, PFS was significantly shorter upon EGFR TKI treatment in EGFR-mutant lung cancer patients with. These data suggest that BIM gene polymorphism could be postulated as a biomarker of EGFR TKI resistance, but larger prospective studies are required to justify that [77-79]. Histone deacetylase (HDAC) inhibition can restore BIM function and sensitize the cancer cells to EGFR TKI in patients with EGFR-mutant NSCLC in whom resistance is associated with a common BIM polymorphism [80]. There is a Phase I clinical trial ongoing in Japan that tests the combination of vorinostat (HDAC inhibitor) and gefitinib in patients with EGFR-mutant NSCLC with BIM polymorphysim (NCT02151721). Identification of some other predictive markers can be an important

tool for personalizing therapy for patients with EFGRmutated advanced NSCLC. Acquired resistance to EGFR TKIs is commonly associated with a second site exon 20 EGFR T790M mutation in > 50% of cases. Other identified mechanisms include amplification of bypass signaling tracts (i.e., MET, PI3K/AKT/mTOR, HER2/3, JAK2/STAT3, HGF, IGF-1R, AXL, Integrin-b1), EMT and changes in tumor histology (transformation from NSCLC to small-cell lung cancer) [81]. Several resistance factors can play a role together in one tumor or in one individual at different metastatic foci, which is an important consideration in overcoming EGFR TKI resistance. In a study of a Japanese cohort of lung cancer patients with acquired resistance to EGFR TKIs, it was shown that high HGF expression often coexists with other resistance factors, such as T790M and MET amplification [82]. Coexistence of heterogeneous resistance mechanisms creates a hurdle for development of individualized treatment combinations. 9.

Conclusion

Targeting EGFR pathway has changed the treatment algorithm for patients with EGFR-mutant advanced NSCLC and became standard first-line therapy. EGFR TKIs provided significant benefit over systemic chemotherapy in terms of improved PFS, higher response rate and improved quality of life in this patient population. However, about one-third of patients would not respond to upfront targeted therapies and those who initially achieved a response would acquire resistance inevitably at one point. A wide variety of resistance mechanisms have been identified which led to emergence of novel therapies (Table 3). 10.

Expert opinion

EGFR TKI has become the standard first-line treatment for advanced NSCLC with sensitizing EGFR mutations. Erlotinib and afatinib are FDA-approved agents for this indication. They improved PFS and relative risk with more tolerable toxicities compared with systemic chemotherapy. However, it is unavoidable that patients develop resistance to the treatment by different mechanisms, most commonly T790M mutation (> 50%). Next-generation EGFR TKIs have been developed against acquired T790M mutation. Third-generation TKIs have promising clinical activity and better toxicity profile compared with second-generation TKIs, but they are still in early phases of drug development. Many issues in routine clinical practice remain unclear. Bardelli and collaborators showed that resistance to targeted therapies can initiate far before when it becomes clinically evident on radiographic modalities in patients with colorectal cancer [83]. Early detection of resistance may lead to early adjustment of treatment strategy and improved clinical outcome. On the other hand, serial tumor biopsies throughout the treatment course are not only difficult for patients, but also are invasive and might


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Table 3. Biological agents in combination with EGFR TKI. Compound

Company

Target

Stage

Bevacizumab Hydroxychloroquine R1507 Cixutumumab OSI-906 Cabozantinib Onartuzumab Tivantinib INC280 Cetuximab Nivolumab MPDL3280A MEDI4736 Olaparib

Roche Covis Genmab ImClone OSI Exelixis Roche ArQule Incyte Bristol-Myers Squibb Bristol-Myers Squibb Genentech AstraZeneca AstraZeneca

VEGFR Autophagy IGF-1R IGF-1R IGF-1R c-Met c-Met c-Met c-Met EGFR PD-1 PD-L1 PD-L1 PARP

Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase

III II II II/III II II III III I/II I I I I I/II

Combined EGFR inhibitor

Study result

Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Gefitinib Afatinib Erlotinib Erlotinib Gefitinib Gefitinib

Improved PFS but not OS benefit No effect on PFS No effect on PFS Not tolerated Ongoing Significant control of tumor growth No effect on OS, PFS, ORR No effect on OS, but PFS and ORR benefit Partial response in 6/41 Met-positive patients Objective response rate 40% 15% durable PR, 45% SD Ongoing Ongoing 7.1% CR, 69.2% PR, 23% SD

CR: Complete response; ORR: Objective response rate; OS: Overall survival; PD-1: Programmed death-1; PD-L1: Programmed death-ligand 1; PFS: Progression-free survival; PR: Partial response; SD: Stable disease.

not be informative in the light of intra-tumor heterogeneity of resistance mechanisms. Identification of CTCs or ctDNA in bloodstream (so-called ‘liquid biopsy’) of patients with advanced NSCLC has been explored as a useful non-invasive tool for detection of treatment-resistant clones. Although it is promising for future practice, it is not part of routine clinic practice yet due to some limitations such as heterogeneity of CTC populations and lack of sensitivity in detection of EMT. Furthermore, there are still unknown mechanisms of acquired resistance that requires further investigation. To overcome some of discovered resistance pathways, novel treatment combinations have been tested, however, results are mostly discouraging as several resistance mechanisms can coexist in one tumor as well as in each metastatic site in one patient. Furthermore, in one study where multiple serial Bibliography

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Declaration of interest B Piperdi is currently employed at Merck Research Laboratories and owns stock in Merck. 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.

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Affiliation Cengiz Inal1 MD, Emrullah Yilmaz1 MD, Bilal Piperdi2 MD, Roman Perez-Soler1 MD & Haiying Cheng†3 MD PhD † Author for correspondence 1 Montefiore Medical Center/Albert Einstein College of Medicine, Division of Thoracic Oncology, Department of Medical Oncology, 111 E 210th Street Bronx, NY 10467, USA 2 Merck Research Laboratories, Rahway, NJ 07065, USA 3 Assistant Professor, Albert Einstein College of Medicine, Department of Medical Oncology, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Chanin Building, Bronx, NY 10461, USA Tel: +1 718 405 8404; Fax: +1 718 405 8501; E-mail: [email protected]

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Advances on EGFR mutation for lung cancer.

Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer.

ALK co-alterations.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors combined with chemotherapy in first-line treatment in an advanced non-small cell lung cancer patient with EGFR sensitive mutation.

Osimertinib for advanced non-small cell lung cancer harboring EGFR mutation exon 20 T790M, acquired resistant mutation for first- or second-generation EGFR-TKI.

Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer.

EGFR mutation testing practice in advanced non-small cell lung cancer.

Efficacy of multimodal treatment for leptomeningeal metastases in a lung cancer harboring an EGFR mutation.

Effect of hydrothorax EGFR gene mutation and EGFR-TKI targeted therapy on advanced non-small cell lung cancer patients.

Post-Progression Survival after EGFR-TKI for Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutations.

Emerging EGFR antagonists for breast cancer.

Statins augment efficacy of EGFR-TKIs in patients with advanced-stage non-small cell lung cancer harbouring KRAS mutation.

Successful osimertinib treatment for leptomeningeal carcinomatosis from lung adenocarcinoma with the T790M mutation of EGFR.

Is afatinib a treatment option for brain metastases in patients with EGFR mutation-positive non-small cell lung cancer?

CT-guided aspiration lung biopsy for EGFR and ALK gene mutation analysis of lung cancer.

ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer patients with the EGFR T790M mutation.

Long Term Therapeutic Plan for Patients with Non-Small Cell Lung Cancer Harboring EGFR Mutation.

EGFR mutation testing in blood for guiding EGFR tyrosine kinase inhibitor treatment in patients with nonsmall cell lung cancer: A protocol for systematic review and meta-analysis.

EGFR Mutation Positive Stage IV Non-Small-Cell Lung Cancer: Treatment Beyond Progression.

Decoding the EGFR mutation-induced drug resistance in lung cancer treatment by local surface geometric properties.

The Impact of Sequence of Chemotherapy and EGFR-TKI Treatment on Different EGFR Mutation Lung Adenocarcinoma.

Bevacizumab to combat EGFR-TKI resistance in a patient with advanced non-small cell lung cancer harboring an EGFR mutation: A case report.

Analysis of EGFR mutation status in tissue and plasma for predicting response to EGFR-TKIs in advanced non-small-cell lung cancer.

Emerging challenges of advanced squamous cell lung cancer.