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touchFEATURE Targeting ALK fusion oncogenes – optimizing patient outcomes in NSCLC

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.

Overcoming treatment resistance to ALK inhibitors in NSCLC – what to do next?

Dr. Sanjay Popat, Consultant Thoracic Medical Oncologist, Royal Marsden NHS Trust, London, UK, provides an overview of this educational programme focusing on anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). He introduces important topics, such as the unmet clinical need, the occurrence of ALK mutations and the emergence and approval of ALK inhibitors following the identification of ALK as a treatment target and the limitations and solutions that have been discovered with these

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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

Targeting ALK in NSCLC – why is it so important?

Dr. Sanjay Popat reviews the current unmet needs for patients with ALK+ NSCLC and discusses the poorer prognosis seen in ALK+ patients compared with NSCLC overall. He considers the impact of emerging resistance to ALK inhibitors and examines how the resistance profiles of the different ALK inhibitors vary. In addition, he discusses the importance of treatment activity in the central nervous system and how next-generation ALK inhibitors differ from crizotinib.

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Practicalities of ALK fusion oncogene testing – what does this mean in the clinic?

Professor Federico Cappuzzo, Director of Oncology and Hematology Department, AUSL della Romagna-Ravenna, Italy, reviews the importance of testing for ALK fusion proteins in NSCLC looking at the number of patients affected by the rearrangement and the demographics of such patients. He discusses in depth the different types of diagnostic tests available, highlighting the advantages and the challenges associated with each. As resistance to ALK inhibitors develops, he evaluates the importance of monitoring for resistance mechanisms and considers the importance of re-testing for ALK mutations in cases of progressive disease.

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The emergence of targeted therapies has transformed the treatment paradigm for NSCLC. Mutations in EGFR, KRAS and ALK fusion oncogenes are mutually exclusive in patients with NSCLC2 and, therefore, it is important to test patients for such mutations.11 ALK testing is recommended for all metastatic lung adenocarcinomas, large cell lung carcinomas and unknown subtypes.12 While few squamous cell carcinomas have an ALK rearrangement, ALK testing of metastatic squamous cell carcinomas may be considered.12 Several molecular ALK mutation testing methods are available; the most common are immunohistochemistry, fluorescent in-situ hybridization (FISH), and polymerase chain reaction (PCR)-based techniques.11 Resistance to next-generation ALK inhibitors can occur and novel ALK mutations have been detected.13 Acquired resistance mutations confer differential sensitivities to the different ALK inhibitors and may inform the sequencing of next-generation ALK inhibitors.13 Ideally, subsequent biopsies should be performed in order to determine the optimal ALK inhibitor to use.

Further resources
ESMO OncologyPro, an educational portal for Oncologists, is a web resource providing Oncology News, Guidelines, Oncology in Practice, Educational library and meeting resources including information on ALK+ NSCLC
ALK Positive is a patient-driven support group, dedicated to advancing research and advocacy to change the future of ALK-positive lung cancer
Cancer.NET is an ASCO-approved US patient website giving detailed information on a range of cancers, including NSCLC

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.<sup>18</sup> 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

How is the treatment landscape changing for patients with ALK+ NSCLC?

Since the identification of the ALK fusion protein as a treatment target in 2007, the development of ALK inhibitors has been rapid with approved molecules undergoing an extensive clinical trials programme. As the development of treatment resistance is common, new molecules are in development and clinical data for these in the post-crizotinib setting are now available. Professor Luis Paz-Ares, Chairman of the Medical Oncology Department at the Hospital ‘12 de Octubre’, Madrid, Spain, discusses the emerging clinical data for the next-generation ALK inhibitors, the differing progression-free survival rates seen19,21–24 and the key differences between the available ALK inhibitors. He also briefly reviews the safety profiles25–28 and examines how ALK-targeted therapies might be sequenced.

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Results from a global phase II study of the next-generation ALK inhibitor lorlatinib showed a high overall response rate and high intracranial response rate for patients with advanced ALK+ NSCLC.23 Ropotrectinib is a potent multi-kinase inhibitor targeting ALK ROS1 and NTRK fusions. It is currently being assessed in dose-escalation Phase I studies, with stable disease observed in 4 of 16 patients with ALK+ advanced solid tumours. The majority of adverse events were grade 1 or 2 and ropotrectinib was well -tolerated. Dose-limiting toxicities were grade 3 dizziness and grade 3 dyspnoea/hypoxia, which occurred in two patients with NSCLC. Dose escalation is ongoing as the maximum tolerated dose has not been reached.29

Managing the ALK+ patient in the clinic: a case study

Professor Federico Cappuzzo and Professor Luis Paz-Ares discuss a male patient with NSCLC. The discussion considers the initial diagnosis, assessments performed and the rationale for those choices. The treatment of the patient upon disease progression is reviewed and the different options available evaluated. The practicalities of rebiopsy are also covered, highlighting the importance of the procedure in guiding treatment choices.

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How can we optimize outcomes for patients with ALK+ NSCLC?

Dr. Sanjay Popat, Professor Federico Cappuzzo and Professor Luis Paz-Ares debate and discuss the optimal management of ALK+ NSCLC patients.

Key topics include patients with both symptomatic and asymptomatic brain metastases, the optimal sequence for using ALK inhibitors, the value of a repeat biopsy in cases of progressive disease and the future treatment landscape, looking at the role of immunotherapy in this patient population.

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Brain metastases have been reported in 15–35% of patients with ALK+ NSCLC.30 Brain metastases are associated with many complications including neurocognitive, psychological and physical impairments, severe comorbidity and a decreased life expectancy. Treatment for patients with brain metastases may include chemotherapy, but can also involve radiotherapy (whole-brain radiotherapy or stereotactic radiosurgery) which can affect quality of life.30
The incidence of brain metastases in patients with ALK+ NSCLC previously treated with ALK inhibitors ranges from 40%–70%, suggesting inadequate penetration of the CNS by some ALK inhibitors.31 This poor penetration may allow the CNS to act as a disease sanctuary site,32 reducing the overall effectiveness of treatment and survival times. However, the next-generation ALK inhibitors ceritinib and alectinib have demonstrated intracranial response rates of 35.7% and 42.6%, respectively in patients who had previously received crizotinib.33,34 In the same patient population, the intracranial response rates were 67% for brigatinib35 and 87% for lorlatinib.23

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Overview & Learning Objectives

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

After watching this touchFEATURE, you should:

  • 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.
Faculty & Disclosures
Dr Sanjay Popat

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).

Dr Sanjay Popat discloses: 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 and touchIME. Research grant from Boehringer Ingelheim.

Prof. Federico Cappuzzo

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.

Prof. Federico Cappuzzo discloses: Consultant and advisor for AstraZeneca, Boheringer, Bristol-Myers Squibb, Lilly, Pfizer, Roche, Takeda.

Prof. Luis Paz-Ares

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.

Prof. Luis Paz-Ares discloses: Honoraria from AstraZeneca Spain, Bayer, Bristol-Myers Squibb, Clovis Oncology, Lilly, Merck Serone, Merck Sharp & Dohme, Novartis, PharmaMar, Pfizer, Roche and Servier.

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  2. Golding B, Luu A, Jones R, et al. The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC). Mol Cancer 2018;17:52
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  4. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–2177.
  5. FDA U.S. Food & Drug Administration. FDA broadens ceritinib indication to previous untreated ALK-positive metastatic NSCLC. Available at: Last accessed March 2019.
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  8. FDA U.S. Food & Drug Administration. FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. Available at: Last accessed March 2019.
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  12. NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer. V3.2019. Available at: Last accessed March 2019.
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  15. Soria JC, Tan DSW, Chiari R, et al., First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 2017;389:917–929.
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