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3rd Generation EGFR TKIs – A Major Breakthrough for NSCLC Treatment

Nikolaos Panagiotopoulos, David Lawrence

Nikolaos Panagiotopoulos, David Lawrence, Department of Cardiothoracic Surgery, University College London Hospitals UCLH, London, the United Kingdom

Correspondence to: Nikolaos Panagiotopoulos, Consultant Thoracic Surgeon University College London Hospitals UCLH 16-18 Westmoreland Street London, the United Kingdom.
Email: Nikolaos.panagiotopoulos@nhs.net
Telephone: +0044 7752194604
Received: August 5, 2015
Revised: September 1, 2015
Accepted: September 5, 2015
Published online: Decembert 28, 2015

ABSTRACT

Dengue is an important tropical arboviral infection. The lung disease in dengue is limited mentioned. In this short, editorial, lung disease in dengue is summarized, detailed and discussed.

© 2015 ACT. All rights reserved.

Key words:EGFR; EGFR Mutation; TKI; T790M Mutation; C01686; AZ9291

Panagiotopoulos N, Lawrence D. 3rd Generation EGFR TKIs – a Major Breakthrough for NSCLC Treatment. Journal of Respiratory Research 2015; 1(1): 5-6 Available from: URL: http://www.ghrnet.org/index.php/jrr/article/view/1377

EDITORIAL

In 1986 Stanley Cohen won the Nobel Prize for his discovery of the epidermal growth factor (EGF)[1]. Its receptor was isolated in 1988 when Mendelsohn and colleagues first suggested EGFR as an anticancer agent[2]. But it was not until May 2004 when 2 pivotal studies revealed the correlation between somatic mutations in the kinase domain of EGFR and the strong response of advanced NSCLC to EGFR tyrosine kinase inhibitors (TKIs)[3, 4].

It is well established that 10- 15% of lung adenocarcinomas diagnosed in the United States harbour activating mutations in the EGFR gene[5]. The remarkable efficacy of small molecule EGFR TKIs in this unique subset of patients has revolutionized the therapeutic approach to lung cancer and created a treatment paradigm for other molecular defined subsets of cancer. Multiple randomized phase 3 studies have demonstrated that EGFR TKIs are superior to chemotherapy in patients with stage IV EGFR- mutated disease, with excellent response rates (58-75%) and progression- free survival[6-8]. Thus, first generation EGFR TKIs such as erlotinib, gefitinib are now standard first- line therapy for advanced non- small cell lung cancer (NSCLC) with sensitising EGFR mutations. Second generation EGFR TKIs (afatinib, dacomitinib) with covalent irreversible binding to the receptor and with the potential to target heterodimers of the Erb-B receptors gave further promise regarding response, progression free survival and overall survival, particularly in patients with exon 19 deletions[9-11].

This unprecedented success of these agents logically leads to clinical questions:

-Is this therapy enough to achieve long –term remission and cure?

-Are new generation EGFR TKIs better as first line treatment?

-Are EGFR TKIs beneficial in earlier stages of disease?

Although significant improvement in clinical outcomes has been achieved with these agents no reports of definitive treatment exist main reason being the development of acquired resistance (AR). Different mechanisms have been responsible for AR including secondary EGFR mutation (predominantly T790M), activation of parallel or downstream signalling pathways, phenotypic transformation such as epithelial to mesenchymal transition (EMT) and small cell lung (SCLC) transformation. The most common type of AR is mutation in codon 790 (T790M) in EGFR exon 20, which accounts for 50-60% of cases with AR to gefitinib/erlotinib[12].

In April 2015 two articles were published in the New England Journal of Medicine describing the use of third generation EGFR TKIs (AZ9291 and C01686) in patients with NSCLC and EGFR-sensitising mutations progressing under first or send generation TKIs[8, 13]. Both substances were targeting the T790M mutation and the trials were similar in design with a conventional phase I part followed by an extension cohort at a predefined dose.

C01686 (Rociletinib) is a third- generation TKI targeting the T790M mutation. This study demonstrated an overall response rate (ORR) OF 59% in T790M – mutant patients and 29% in non T790M- mutant. The study included 130 patients but ORR is reported in 92, including 46 with the T790M mutation. The estimated median progression-free survival (PFS) is 13.1 months for patients with the mutation and 5.6 in those without it. Two different galenic forms of the drugs were tested sequentially, first a free-base form at dose up to 900mg twice a day, then a hydrogen bromide salt form designed to improve pharmacokinetics at doses between 500-1000mg twice daily.

The main side effect in this trial was hyperglycaemia, affecting 22 % of cases and requiring dose reduction and antiglycaemic medication. Asymptomatic QT prolongation was also reported and other adverse effects like diarrhoea, rash, and fatigue were rare and mild. 48% of patients required dose reduction.

The second study published in New England Journal of Medicine evaluated the AZ9291 in 253 patients with NSCLC and T790M mutation. It demonstrated an ORR of 51%, including 61% of ORR in T790M mutation population and only 21% in no T790M mutation. Similarly PFS was 9.6 months and 2.8 months respectively. The dose was 80mg once daily and was well tolerated with frequent side effects including diarrhoea, skin rash and nausea.

In conclusion third generation EGFR TKIs have demonstrated excellent and promising results in patients having developed acquired resistance through a T790M mutation. Patient selection remains extremely important and identification of the mechanism for acquired resistance is the key for the use of appropriate EGFR TKI. Further trials are necessary to compare these promising agents with already existing chemotherapy regimens to define optimal sequence of use.

CONFLICT OF INTERESTS

The authors have no conflicts of interest to declar.

REFERENCES

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

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9.Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol 2013;31:3335-41.

10.Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-34.

11.Yang JC, Sequist LV, Schuler MH, et al. Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): Pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy (CT). ASCO Meeting Abstracts 2014;32:8004.

12.Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors[J] Oncogene. 2009;28(Suppl 1):S24–S31.

13.Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42.

Peer reviewer:Hideki Kawai, MD, PhD, Department of Thoracic Surgery, Akita Red Cross Hospital, Kamikitate, Akita, Japan.

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