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Lung Cancer CME ACCREDITED Watch Time: 42 mins

touchTALKS Addressing the challenges of ALK-positive NSCLC to optimize patient outcomes

Join Dr Robert Doebele as he explores the latest developments in the anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) treatment landscape, including the intracranial efficacy of ALK inhibitors, and how improved understanding of acquired resistance mechanisms and refined molecular testing techniques may optimize outcomes for patients with ALK-positive NSCLC.

 
Addressing the challenge of CNS metastases using ALK inhibitors

Dr Robert Doebele talks us through the efficacy of ALK inhibitors, summarizing the CNS penetration profiles and intracranial efficacy in first- and second-line settings.

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Addressing the challenge of resistance to ALK inhibitors

Dr Robert Doebele explores the mechanisms of resistance to ALK inhibitors, focusing on acquired resistance. He reviews the resistance profiles of ALK inhibitors, as well as summarising the impact of treatment resistance on patient outcomes.

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Addressing the challenge of molecular testing for ALK mutations

After summarising methods for testing ALK status, Dr Robert Doebele discusses the benefits and challenges associated with each method, and shares his expertise.

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Overview & Learning Objectives
Overview

In this activity, Dr Robert Doebele, an internationally renowned expert in lung cancer, discusses the latest developments in the anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) treatment landscape, including data on ALK-inhibitor intracranial efficacy, and how improved understanding of acquired resistance mechanisms and refined molecular testing techniques may optimize outcomes for patients with ALK-positive NSCLC.

This activity has been jointly provided by Oakstone Publishing and touchIME ONCOLOGY. Oakstone Publishing is accredited by the ACCME to provide continuing medical education to physicians.

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Target audience

This activity has been designed to meet the educational needs of oncologists, oncology nurses and other healthcare practitioners who care for patients with ALK-positive NSCLC.

Disclosures

Oakstone Publishing has assessed conflict of interest with its faculty, authors, editors, and any individuals who were in a position to control the content of this CME activity. Any identified relevant conflicts of interest were resolved for fair balance and scientific objectivity of studies utilized in this activity. Oakstone Publishing’s planners, content reviewers, and editorial staff disclose no relevant commercial interests.

Faculty

Dr Robert Doebele Discloses: Consultant/Advisory Boards fees from Anchiano Therapeutics, AstraZeneca, Blueprint Medicines, Genentech/Roche, GreenPeptide Co., Ltd., Rain Therapeutics Inc. and Takeda. Stockholder in Rain Therapeutics Inc. Licensing of IP with Black Diamond, Foundation Medicine, Genentech, Pearl River, Rain Therapeutics and Voronol.

Content Reviewer

Walter Murray Yarbrough, MD has no financial interests/relationships or affiliations in relation to this activity.

Touch Medical Director

Alison Scott, PhD has no financial interests/relationships or affiliations in relation to this activity.

Requirements for successful completion

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Oakstone Publishing and touchIME. Oakstone Publishing is accredited by the ACCME to provide continuing medical education for physicians.

Oakstone Publishing designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In order to receive credit for this activity, participants must review and complete the post-test and evaluation form. A score of 70% or higher is needed to obtain CME credit. Statements of credit are awarded upon successful completion of the post-test and evaluation form.

The European Union of Medical Specialists (UEMS) – European Accreditation Council for Continuing Medical Education (EACCME) has an agreement of mutual recognition of continuing medical education (CME) credit with the American Medical Association (AME). European physicians interested in converting 0.5 AMA PRA Category 1 Credit™ into European CME credit (ECMEC) should contact the UEMS (www.uems.eu).

Date of original release: July 24, 2020. Date credits expire: July 24, 2021.

Learning Objectives

After watching this activity participants should be better able to:

  • Summarize the central nervous system (CNS) efficacy data for ALK inhibitors in the first- and second-line settings for patients with ALK-positive NSCLC
  • Evaluate the mechanisms of acquired resistance to ALK inhibitors in patients with ALK-positive NSCLC
  • Discuss the most appropriate approach to molecular testing for patients with ALK-positive NSCLC
Faculty & Disclosures
Dr Robert Doebele

University of Colorado School of Medicine, Aurora, CO, USA

Robert Doebele is Associate Professor of Medicine in the Division of Medical Oncology at the University of Colorado School of Medicine. Dr Doebele earned his degree in Molecular Biology from Princeton University and his MD/PhD from the University of Pennsylvania School of Medicine, before training in Medical Oncology at the University of Chicago.
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Dr Doebele’s research interests include cancer oncogene addiction, intrinsic and acquired mechanisms of resistance to targeted therapies and therapeutic discovery. In 2013, he was awarded the V Scholar Award from the V Foundation for Cancer Research and was later elected to the American Society of Clinical Investigation in 2018. He is currently Director of the Thoracic Oncology Research Initiative at the University of Colorado Cancer Center.
 

Dr Robert Doebele discloses: Consultant/Advisory Boards fees from Anchiano Therapeutics, AstraZeneca, Blueprint Medicines, Genentech/Roche, GreenPeptide Co., Ltd., Rain Therapeutics Inc. and Takeda. Stockholder in Rain Therapeutics Inc. Licensing of IP with Black Diamond, Foundation Medicine, Genentech, Pearl River, Rain Therapeutics and Voronol.

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Question 1/5
A patient with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) progresses on crizotinib, and you decide to start treatment with a second-generation ALK inhibitor. What would be your reasoning for this?
Correct

All three second-generation ALK inhibitors have demonstrated PFS benefits in patients who have received prior crizotinib, ranging from approximately 5 to 17 months.1-4 They have also all demonstrated significant CNS efficacy, while CNS progression is common with crizotinib.5-8 Progression on crizotinib is usually due to acquired resistance, but second-generation agents are able to overcome these mutations.1-4,9,10

ALK, anaplastic lymphoma kinase; CNS, central nervous system; PFS, progression-free survival.

References

  1. Rothenstein JM, et al. Curr Oncol. 2018;25:S59–67.
  2. Shaw A, et al. Lancet Oncol. 2017;18:874–86.
  3. Novello S, et al. Ann Oncol. 2018;29:1409–16.
  4. Huber RM, et al. J Clin Oncol. 2018;36:abstr 9061.
  5. Soria JC, et al. Lancet. 2017;389:917–29.
  6. Peters S, et al. N Engl J Med. 2017;377:829–38.
  7. Camidge DR, et al. J Clin Oncol. 2018;36:2693–701.
  8. Costa DB, et al. J Clin Oncol. 2015;33:1881–8.
  9. Katayama R. Cancer Science. 2018;109:572–80.
  10.  Gainor JF, et al. Cancer Discov. 2016;6:1118–33.
Question 2/5
Your patient is a 61-year-old woman who has never smoked and has a new diagnosis of advanced non-small cell lung cancer (NSCLC). Which molecular alterations would you test for?
Correct

The 2020 National Comprehensive Cancer Network guidelines for NSCLC recommend molecular testing for EGFR mutation, ALK, ROS1, and BRAF, and that these be done as part of broad molecular profiling.1 Based on recent US Food and Drug Administration approvals, testing for NTRK1/2/3, RET fusions, and MET exon 14 are also recommended.2-4

ALK, anaplastic lymphoma kinase; BRAF, v-raf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; ERCC1, Excision Repair Cross-Complementation Group 1; KRAS, Kirsten rat sarcoma viral oncogene; MEK, MAPK/ERK kinase; MET, mesenchymal to epithelial transition (MET) proto-oncogene, receptor tyrosine kinase; NSCLC, non-small cell lung cancer; NTRK, neurotrophic receptor tyrosine kinase; RET, rearranged during transfection proto-oncogene; ROS1, c-ros oncogene 1.

References

  1. National Comprehensive Cancer Network. NCCN Guidelines Version 1. 2020. Non-Small Cell Lung Cancer.
  2. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc
  3. www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-capmatinib-metastatic-non-small-cell-lung-cancer
  4. www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions (FDA press release web links, all accessed July 2020).
Question 3/5
You undertake molecular profiling of your patient with NSCLC and decide to use liquid biopsy because it is fast, minimally invasive and...
Correct

Analysis of circulating tumour DNA has been proposed as an alternative or a complementary minimally invasive method for the detection of molecular alterations in patients with NSCLC. This method has advantages such as patient comfort, quick results, ability to cover multiple actionable mutations at the same time, and allows for serial monitoring. However, ctDNA does not give information about histology (progression to small cell lung cancer), and ctDNA may not be present in all plasma samples; if the ctDNA test is negative, it is advisable to follow-up with a tissue test wherever possible due to the potential for false negative results using a plasma-based test.

ctDNA, circulating tumour DNA; NSCLC, non-small cell lung cancer.

Reference
Herbreteau G, et al. J Thorac Dis. 2019;11:S113–26.

Question 4/5
Molecular testing shows that your patient, a 61-year-old female who has never smoked, has ALK-positive NSCLC. Magnetic resonance imaging reveals that she has brain metastases. In terms of current guidelines, what are your preferred options for first-line therapy, assuming you have access to these treatments?
Correct

The 2020 NCCN guidelines for NSCLC recommend alectinib as the preferred first-line therapy, followed by brigatinib or ceritinib. In some instances, crizotinib may be useful.1 In this case, the patient already has brain metastases, and therefore a second-generation ALK inhibitor is preferable, as they have demonstrated superior CNS efficacy versus crizotinib.2-4

ALK, anaplastic lymphoma kinase; CNS, central nervous system; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer.

References

  1. National Comprehensive Cancer Network. NCCN Guidelines Version 1. 2020. Non-Small Cell Lung Cancer.
  2. Soria JC, et al. Lancet. 2017;389:917–29.
  3. Peters S, et al. N Engl J Med. 2017;377:829–38.
  4. Camidge DR, et al. J Clin Oncol. 2018;36:2693–701.
Question 5/5
Your patient receives alectinib and achieves a complete response. At the 12-month follow-up she complains of headaches, nausea, and a persistent cough. Magnetic resonance imaging shows that she has disease progression. Molecular testing using ctDNA reveals a I1171T alectinib-resistance mutation. What do you do next?
Correct

The clinical approach to patients with ALK-positive NSCLC with acquired resistance may incorporate repeat molecular testing to inform decision making based on ALK resistance mutation status following disease progression on second-generation ALK inhibitors.1 Lorlatinib, the third-generation ALK inhibitor, is approved for second-line therapy, and therefore would be an option in this case.1,2 Choice of sequence of ALK inhibitors may be affected by identification of specific ALK resistance mutations, such as the I1171T mutation, which confers alectinib resistance, but which is sensitive to ceritinib. Therefore, ceritinib would also be an option for this patient.1,3

ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer.

References

  1. Gainor JF, et al. Cancer Discov. 2016;6:1118–33.
  2. National Comprehensive Cancer Network. NCCN Guidelines Version 1. 2020. Non-Small Cell Lung Cancer.
  3. Katayama R. Cancer Science. 2018;109:572–80.
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