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Physicians' Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians' Education Resource®, LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Ariad Pharmaceuticals.

Community Practice Connections™: ALK-Positive NSCLC: Emerging Strategies to Inform Sequencing, Optimize Outcomes, and Address Unmet Clinical Needs Along the Disease Continuum

Release Date: August 29, 2017
Expiration Date: August 29, 2018
Media: Internet - based

 

Activity Overview

Treatment approaches for anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC) have been shaped by the emergence of targeted therapies that have demonstrated improved clinical efficacy. However, many perplexing challenges in the treatment of ALK-positive NSCLC remain, including the frequent development of treatment resistance and how to best treat patients with these tumors who have brain metastases. Treatment-related toxicities and the need to establish optimal sequencing of therapy together present another layer of complexity in the management of these patients. Moreover, novel ALK-targeted strategies are advancing through clinical investigation and the approval process; this is great news for patients because these may provide more treatment options. To help clinicians with the management of these challenges, this educational activity has been developed, featuring insights from leading experts in NSCLC management. Multiple topics will be explored, including optimal management strategies for treatment-naïve patients, treatment approaches for patients who have relapsed, and tumor testing strategies.

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Ariad Pharmaceuticals.

CME Activity Table of Contents

  • The Treatment-Naïve Patient With ALK-Positive NSCLC
    Commentary featuring Justin F. Gainor, MD, and David R. Gandara, MD
  • The Treatment-Naïve Patient With ALK-Positive NSCLC and CNS Metastases
    Commentary featuring D. Ross Camidge, MD, PhD
  • Sequencing Decisions for Patients With ALK-Positive NSCLC Beyond Disease Progression
    Commentary featuring H. Jack West, MD Evolution of Tumor Biology After Therapy: Biopsy/Rebiopsy/Plasma Cell-Free DNA Assessment
    Commentary featuring Christine M. Lovly, MD, PhD

Instructions for This Activity and Receiving Credit

  • You will need to login to participate in the activity.
  • Each presentation may contain an interactive question(s). You may move forward through the presentation; however, you may not go back to change answers or review videos/content until you finish the presentation.
  • At the end of the activity, “educational content/video files” will be available for your reference.
  • In order to receive a CME certificate, participants must complete the activity.
  • Complete the posttest and pass with a score of 70% or higher, complete the evaluation and then click on request for credit. Participants may immediately download a CME certificate upon completion of these steps.

Target Audience

This educational activity is directed toward oncologists interested in the treatment of lung cancer. Nurse practitioners, physician assistants, nurses, and other healthcare professionals involved in the treatment and management of patients with lung cancer are also invited to participate. This CME-certified activity will also be made available to patients with lung cancer as an educational reference material.

Learning Objectives

At the conclusion of this activity, you should be better prepared to:

  • Assess approaches to address the problem of acquired resistance and relapse in patients with ALK-positive, non‒small cell lung cancer (NSCLC)
  • Determine evolving methods to facilitate and apply testing strategies along the disease continuum in the management of ALK-positive NSCLC
  • Apply clinical trial evidence to inform sequencing of therapies in patients with ALK-positive NSCLC, and proactively address treatment-related toxicities
  • Discuss methods to plan for and manage brain metastases in the care of patients with ALK-positive NSCLC

Faculty, Staff, and Planners' Disclosures

Faculty

D. Ross Camidge, MD, PhD
Professor with Tenure, Division of Medical Oncology
Joyce Zeff Chair in Lung Cancer Research
University of Colorado, Denver, School of Medicine
Denver, CO
 

Disclosure: Grant Research Support: Ariad, Takeda; Consultant: Roche, Pfizer.

Justin F. Gainor, MD
Instructor, Medicine, Harvard Medical School
Attending Physician, Thoracic Oncology
Massachusetts General Hospital
Boston, MA
 

Disclosure: Consultant: Bristol-Myers Squibb, Genentech, Loxo, Clovis, Theravance; Honoraria: Merck, Roche, Incyte, Novartis.

David R. Gandara, MD
Professor of Medicine
Division of Hematology/Oncology
Director, Thoracic Oncology Program
Senior Advisor to the Director
UC Davis Comprehensive Cancer Center
Sacramento, CA

Disclosure: Grant Research Support: Genentech, Novartis, AstraZeneca; Consultant: Genentech, Novartis, AstraZeneca.

Christine M. Lovly, MD, PhD
Assistant Professor of Medicine, Division of Hematology-Oncology
Assistant Professor of Cancer Biology
Vanderbilt University School of Medicine
Vanderbilt Ingram Cancer Center
Nashville, TN

Disclosure: Grant Research Support: Novartis (Grant brokered through Vanderbilt; Dr. Lovly does not directly receive funds); Consultant: Novartis, Ariad, Pfizer.

H. Jack West, MD
Medical Director, Thoracic Oncology Program
Swedish Cancer Institute
Founder & President, GRACE
Seattle, WA
 

Disclosure: Consultant: Ariad, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech/Roche, Guardant Health, Merck, Novartis, TrovaGene. Speakers Bureau: Ariad, Genentech/Roche, Eli Lilly.

The staff of PER® have no relevant financial relationships with commercial interests to disclose.

Disclosure Policy and Resolution of Conflicts of Interest (COI)

As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.

Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.

Off-Label Disclosure and Disclaimer

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.




PER Pulse™ Recap (1 of 3)
The Treatment-Naïve Patient With ALK-Positive NSCLC

Several ALK inhibitors have been approved for the treatment of patients with ALK-positive non–small cell lung cancer (NSCLC), including crizotinib, ceritinib, alectinib, and brigatinib. Lorlatinib recently gained breakthrough therapy status, while entrectinib, X-396, and TPX-005 are in development. Crizotinib was the first of these agents to demonstrate efficacy in the first-line treatment of patients with ALK-positive NSCLC.1 Several second-generation ALK inhibitors have subsequently emerged, including alectinib, brigatinib, and ceritinib.1-7 These second-generation ALK inhibitors have demonstrated efficacy for many patients who have developed resistance to crizotinib. Historically, treatment paradigms have involved the sequential use of a second-generation ALK inhibitor after crizotinib for patients with advanced ALK-positive NSCLC. However, the results of the ASCEND-4 study showed that for previously untreated patients with stage IIIB/IV ALK-positive NSCLC, first-line ceritinib provided significantly greater median progression-free survival (PFS) compared with chemotherapy (16.6 vs 8.1 months; HR, 0.55; P <.00001).8

The J-ALEX study has also shaped the treatment paradigm for treatment-naïve patients with NSCLC. This study compared alectinib to crizotinib in the treatment of Japanese patients with ALK inhibitor-naïve ALK-positive NSCLC.9 At a second interim analysis, the median PFS had not yet been reached for patients treated with alectinib, while the median PFS was 10.2 months with crizotinib.9 There was also a greater incidence of grade 3 to 4 adverse events (AEs) in patients treated with crizotinib than was seen in patients treated with alectinib (52% vs 26%), as well as a greater incidence of dose interruptions (74% vs 29%) and treatment discontinuation (20% vs 9%) due to AEs.9 The phase III Global ALEX study also compared alectinib versus crizotinib for the treatment of patients with treatment-naïve, advanced ALK-positive NSCLC.10 In this randomized, open label study, patients were assigned to receive either 600 mg of alectinib twice daily (a higher dose of alectinib than used in the J-ALEX study) or 250 mg of crizotinib twice daily.10,11 Several other studies are exploring first-generation versus second- or third-generation ALK inhibitors. Although crizotinib has been the standard of care for first-line management of patients with ALK-positive NSCLC, recent investigations may change the standard of care for these treatment-naïve patients. Dr. Gandara and Dr. Gainor discuss the evolution of the treatment paradigm for untreated patients with ALK+ NSCLC.

References

  1. Solomon BJ, Mok T, Kim DW, et al; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer [erratum in N Engl J Med. 2015;373(16):1582]. N Engl J Med. 2014;371(23):2167-2177. doi: 10.1056/NEJMoa1408440.
  2. Kim DW, Mehra R, Tan DS, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial [published correction appears in Lancet Oncol. 2016;17(5):e181]. Lancet Oncol. 2016;17(4):452-463. doi: 10.1016/S1470-2045(15)00614-2.
  3. Shaw AT, Gandhi L, Gadgeel S, et al; study investigators. Alectinib in ALK-positive, crizorinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial [published correction appears in Lancet Oncol. 2017;18(3):e134. doi: 10.1016/S1470-2045(17)30077-3]. Lancet Oncol. 2016;17(2):234-242. doi: 10.1016/S1470-2045(15)00488-X.
  4. Kim DW, Tiseo M, Ahn MJ, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol. 2017;35(22):2490-2498. doi: 10.1200/JCO.2016.71.5904.
  5. Gettinger SN, Bazhenova LA, Langer CJ, et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(12):1683-1696. doi: 10.1016/S1470-2045(16)30392-8.
  6. Ou SH, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol. 2016;34(7):661-668. doi: 10.1200/JCO.2015.63.9443.
  7. Scagliotti G, Kim TM, Crino L, et al. Ceritinib vs chemotherapy in patients with advanced anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer previously treated with chemotherapy and crizotinib: results from the confirmatory phase 3 ASCEND-5 study. ESMO 2016. Abstract LBA42_PR.
  8. Soria JC, Tan DS, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomized, open-label, phase 3 study [published correction appears in Lancet. 2017;389(10072):908. doi: 10.1016/S0140-6736(17)30603-7]. Lancet. 2017;389(10072):917-929. doi: 10.1016/S0140-6736(17)30123-X.
  9. Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017;390(10089):29-39. doi: 10.1016/S0140-6736(17)30565-2.
  10. Peters S, Camidge DR, Shaw AT, et al; ALEX Trial Investigators. Alecitnib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377(9):829-838. doi: 10.1056/NEJMoa1704795.
  11. Gainor JF, Shaw AT. J-ALEX: alectinib versus crizotinib in ALK-positive lung cancer. Lancet. 2017;390(10089):3-4. doi: 10.1016/S0140-6736(17)31074-7.



PER Pulse™ Recap (2 of 3)
The Treatment-Naïve Patient With ALK-Positive NSCLC and CNS Metastases

Many patients with NSCLC develop central nervous system (CNS) metastases, including the subgroup of patients with NSCLC who are ALK-positive. Historical first-line treatment of ALK-positive+ NSCLC (crizotinib) has relatively poor CNS penetration, and development of treatment options that can control CNS metastases may help to improve outcomes. Considerations, such as side effect profiles, may influence the role of whole-brain radiotherapy versus other treatment modalities, but CNS control was found to be an important component of treatment.1

When evaluating CNS drug efficacy data for patients with NSCLC, it is important to consider several points. Comparing endpoints dominated by extracranial data, such as overall response rate, early overall nonprogressive disease, or PFS is not likely to be informative regarding CNS efficacy.2-4 CNS endpoints have to be considered based on whether the CNS is treated or not at baseline. If it is treated, the method of treatment (local or whole brain) should be considered. CNS duration of benefit is also important.2-4 Key studies, such as PROFILE 1014, ASCEND4, and J-ALEX, have shed light on the management of CNS metastases.5-7 Optimal management of CNS lesions associated with NSCLC remains a key treatment focus. Available data from second- and third-line therapies have shown improvements in extending patient survival, including patients with brain metastases.8,9 Dr. Camidge discusses the evidence pertaining to CNS metastases in patients with NSCLC, as well as treatment approaches.

References

  1. Johung KL, Yeh N, Desai NB, et al. Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain metastasis. J Clin Oncol. 2016;34(2):123-129. doi: 10.1200/JCO.2015.62.0138.
  2. Lin NU, Lee EQ, Aoyama H, et al; Response Assessment in Neuro-Oncology (RANO) group. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 2015;16(6):e270-e278. doi: 10.1016/S1470-2045(15)70057-4.
  3. Lin NU, Lee EQ, Aoyama H, et al; Response Assessment in Neuro-Oncology (RANO) group. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group. Lancet Oncol. 2013;14(10):e396-e406. doi: 10.1016/S1470-2045(13)70311-5.
  4. Lin NU, Wefel JS, Lee EQ, et al; Response Assessment in Neuro-Oncology (RANO) group. Challenges relating to solid tumour brain metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life outcomes. A report from the RANO group. Lancet Oncol. 2013;14(10):e407-e416. doi: 10.1016/S1470-2045(13)70308-5.
  5. Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. 2015;33(17):1881-1888. doi: 10.1200/JCO.2014.59.0539.
  6. Solomon BJ, Cappuzzo F, Felip E, et al. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol. 2016;34(24):2858-2865. doi: 10.1200/JCO.2015.63.5888.
  7. Soria JC, Tan DS, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomized, open-label, phase 3 study [published correction appears in Lancet. 2017;389(10072):908. doi: 10.1016/S0140-6736(17)30603-7]. Lancet. 2017;389(10072):917-929. doi: 10.1016/S0140-6736(17)30123-X.
  8. Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomized phase 3 trial. Lancet. 2017;390(10089):29-39. doi: 10.1016/S0140-6736(17)30565-2.
  9. Landi L, Cappuzzo F. Achievements and future developments of ALK-TKIs in the management of CNS metastases from ALK-positive NSCLC. Transl Lung Cancer Res. 2016;5(6):579-587. doi: 10.21037/tlcr.2016.12.05.



PER Pulse™ Recap (3 of 3)
Sequencing Decisions and Evolution of Tumor Biology in Progressive ALK-Positive NSCLC

Alectinib, brigatinib, and ceritinib are all second-generation treatments that have been approved in the treatment of ALK-positive NSCLC; however, these agents have not been compared head-to-head. Ceritinib has demonstrated superior efficacy to single-agent chemotherapy for patients with ALK-positive NSCLC. There is no standard role yet for selection by specific mutation. Immunotherapy is likely relatively less active in patients with ALK-positive NSCLC based on limited data. Cross-resistance of one second-generation ALK-inhibitor versus another has not yet been studied. It is unknown if serial second-generation ALK-inhibitor agents are superior to chemotherapy. Therefore, it is imperative to define a role for molecular testing to help tailor treatment recommendations.

Genomic profiling using next-generation sequencing may help with identifying acquired ALK-resistance mutations. Gainor and colleagues recently explored mechanisms of acquired resistance to first- and second-generation ALK inhibitors and found that a greater incidence and distinct spectrums of mutations emerge with potent second-generation inhibitors.1,2 The ALK G1202R mutation increases greatly after second-generation ALK inhibitor therapy with alectinib or ceritinib. The L1196M mutation often occurs after treatment with crizotinib. These mutations influence sensitivity to available ALK inhibitors.2 ALK-resistance mutations are predictive for sensitivity to lorlatinib. Consequently, it is important to determine accurate tumor molecular characterization when disease progresses, in order to tailor therapy.2 Monitoring of patients who are treated with crizotinib or alectinib can be done with liquid biopsy.3

Many ALK mutations can be detected by next-generation sequencing with free circulating tumor DNA. Resistance mutations that emerge on the ALK gene can differ depending on the treatments used to target an ALK rearrangement.3 Liquid biopsy for ALK gene analysis may be an alternative when tissue biopsy is not feasible or of poor quality and in situations where early detection of ALK mutations associated with resistance can lead to timely change of treatment.3 Dr. West and Dr. Lovly discuss treatment sequencing for patients with progressive NSCLC, as well as tumor testing options.

References

  1. Qiao H, Lovly CM. Cracking the code of resistance across multiple lines of ALK inhibitor therapy in lung cancer. Cancer Discov. 2016;6(10):1084-1086.
  2. Gainor JF, Dardaei L, Yoda S, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 2016;6(10):1118-1133.
  3. Hofman P. ALK status assessment with liquid biopsies of lung cancer patients. Cancers (Basel). 2017;9(8). doi: 10.3390/cancers9080106.







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