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Targeting ALK fusion oncogenes – optimizing patient outcomes for NSCLC

Introduction

This touchFEATURE on anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) provides a concise overview of the occurrence of ALK mutations in NSCLC and an understanding of the roles of ALK fusion and mutation testing. It also considers the technologies available to improve the diagnosis and management of patients, as well as reviewing the development of treatment resistance and how it should be managed. The use of sequential therapy and future therapy options are also examined to help improve patient outcomes.

NSCLC is the most common form of lung cancer and accounts for approximately 85% of all lung cancers.1 ALK rearrangements are responsible for 3–7% of NSCLCs, predominantly of the adenocarcinoma subtype.2

In the past decade, a deeper understanding of the pathobiology of NSCLC has led to the development of small molecules that target genetic mutations and fusions known to play critical roles in the progression to metastatic disease. The emergence of these targeted therapies has transformed the treatment paradigm for NSCLC. The ALK fusion protein inhibitor, crizotinib, received FDA approval in 2013, and has demonstrated an objective response rate (ORR) >65% in phase III studies in both first- and second-line settings.3,4 Since then, the next-generation ALK inhibitors, ceritinib5 and alectinib,6 have been approved in both the first- and second-line settings and, more recently, brigatinib7 and lorlatinib8 have been approved as second-line treatments.

Although several treatment options exist for patients with ALK+ NSCLC, clinical unmet needs remain for this patient population and the development of novel ALK inhibitors continues.

Learning Objectives

  • Describe the occurrence of ALK mutations in NSCLC
  • Discuss the potential importance for ALK mutation testing and the available technologies
  • Explain the practical use of first- and second-line targeted therapies in ALK+ NSCLC, the development of resistance and how to manage resistance
  • Identify additional NSCLC therapy education resources.

ALK in the development of NSCLC – how does it work?

A large proportion of patients with NSCLC are diagnosed at advanced stages of the disease and only a small proportion survive for more than 5 years.9 Therapies have been developed targeted at activating mutations such as the fusion of the kinase domain of the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase gene (EML4-ALK) re-arrangement, which can be found in 3–7% of patients with NSCLC and is mutually exclusive with KRAS and epidermal growth factor receptor (EGFR) mutations.2 

The EML4-ALK fusion constitutively activates a crucial cell division-cell proliferation cascade and, as a result, ALK+ NSCLC tends to be more aggressive and is associated with a higher rate of relapse compared with other NSCLC types.10

Why do we need more ALK inhibitors?

Resistance to crizotinib inevitably develops.10 The emergence of treatment resistance prompted the development and FDA approval of the next-generation ALK inhibitors, ceritinib,14,15 alectinib16,17 and brigatinib.18 Ceritinib and alectinib have demonstrated responses in >50% of patients with crizotinib-refractory disease, or who were unable to tolerate the treatment,14,16 while brigatinib has demonstrated a response rate of 56% in this population.19

Resistance to next-generation ALK inhibitors can develop as mutations emerge.13 However, different ALK inhibitors appear to be active against different mutation profiles, so identification of the mutation may inform treatment decisions for some patients.20

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Dr. Sanjay Popat
Consultant Thoracic Medical Oncologist, Royal Marsden NHS Trust, London, UK

Dr. Sanjay Popat is a Consultant Thoracic Medical Oncologist at the Royal Marsden Hospital and Reader in Cancer Medicine at Imperial College. He is an internationally recognized expert in the treatment of lung cancer, thymic cancer, and mesothelioma. His research interests include identification and validation of biomarkers that influence tumour development and treatment, as well as the development of novel treatment strategies through clinical trials.

Dr. Popat chairs the British Thoracic Oncology Group (BTOG), and is immediate past Chair of the Advanced Diseases Sub-group of the UK NCRI Lung Cancer Clinical Studies Group. He is active in the European Thoracic Oncology Platform (ETOP), the European Organisation for Research and Treatment of Cancer (EORTC) Lung Group, and the International Thymic Malignancy Interest Group (ITMIG).

Disclosures: Honoraria and consulting from AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, EMD Serono, Guardant Health, Medscape, Merck Sharp & Dohme, Novartis, OncLive, Pfizer, Roche, Takeda, Tesaro, touchIME. Research grant from Boehringer Ingelheim.

Professor Federico Cappuzzo
Director of Oncology and Hematology Department, AUSL della Romagna-Ravenna, Italy

Professor Federico Cappuzzo has been the Director of Medical Oncology at AUSL della Romagna-Ravenna since April 2016 and, since January 2017, the Director of the Hematology and Oncology Department. Prior to taking up these positions, he obtained his degree in Medical Oncology from Milan University in 1996. He also received an ESMO Fellowship to work at the Institut Gustave Roussy in Villejuif (Paris), followed by a position at the thoracic oncology unit at the Medical University of South Carolina in Charleston (USA). He was Assistant Professor at the Ospedale Bellaria in Bologna for 6 years and then Assistant Professor in Medical Oncology at the Istituto Clinico Humanitas IRCCS in Rozzano (Milan), and a visiting Associate Professor in Medical Oncology at the University of Colorado in Denver (USA). More recently, he was the Director of Medical Oncology Department at the Istituto Toscano Tumori-Ospedale Civile in Livorno.

Prof. Cappuzzo is a member of the Italian Association of Medical Oncology (AIOM), the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO) and the International Association for the Study of Lung Cancer (IASCL) and since 2006 has been a Member of the editorial board of Lung Cancer. Since January 2016, he has been the Chairman of the Educational Committee of IASLC. In 2006, 2009 and 2012, he received research grants from the Italian Association for Cancer Research (AIRC) on targeted therapies in lung cancer and is the author of more than 200 papers in peer-reviewed journals, mainly in translational research in lung cancer.

Disclosures: Consultant and advisor for AstraZeneca, Boheringer, Bristol-Myers Squibb, Lilly, Pfizer, Roche, Takeda.

Professor Luis Paz-Ares
Chairman of the Medical Oncology Department at the Hospital ‘12 de Octubre’, Madrid, Spain

Professor Luis Paz-Ares is currently Chairman of the Medical Oncology Department at the Hospital Doce de Octubre, Associate Professor at the Universidad Complutense, and Head of the Lung Cancer Unit at the CNIO (National Oncology Research Center), all in Madrid, Spain.

He obtained his degree in Medicine and PhD from the Universidad Autónoma de Madrid, and undertook a postdoctoral ESMO Research Fellowship in Medical Oncology at the Beatson Oncology Centre, University of Glasgow, Glasgow, Scotland where he also completed a Master’s degree in Clinical Pharmacology. He gained a Master’s degree in Clinical Unit Management at the UNED-Fundación Universidad Empresa, Madrid, Spain. Prof. Paz-Ares was Chair of the Medical Oncology Department at the Virgen del Rocío University Hospital in Seville. He was Head of the Pharmacology Unit and was responsible for early clinical studies of thoracic and genitourinary tumours at the University Hospital ‘12 de Octubre’ in Madrid, and visiting Research Fellow in the Prostate Cancer Programme at the Dana-Farber Cancer Institute in Boston, MA, USA.

Prof. Paz-Ares’s research focuses on lung cancer and the development of new therapeutic strategies, both in the lab and in the clinic. He has published more than 240 papers in peer-reviewed journals (as well as many book chapters) including the New England Journal of Medicine, Lancet, Lancet Oncology, Journal of Clinical Oncology and many others. He is an active member of various scientific societies (including ASCO, ESMO, ELCC, IASLC and others) and collaborative groups (European Organisation for Research and Treatment of Cancer [EORTC], the Spanish Lung Cancer Group and the International Germ Cell Cancer Collaborative Group). At the beginning of 2017 he received the Lilly Foundation Award for Biomedical Research (Clinical) and the Ramiro Carregal Oncology Award for his research work.

Disclosures: Honoraria from AstraZeneca Spain, Bayer, Bristol-Myers Squibb, Clovis Oncology, Lilly, Merck Serone, Merck Sharp & Dohme, Novartis, PharmaMar, Pfizer, Roche, Servier.