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This activity is supported by an educational grant from Ariad Pharmaceuticals.
Release Date: August 29, 2017
Expiration Date: August 29, 2018
Media: Internet - based
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.
This activity is supported by an educational grant from Ariad Pharmaceuticals.
Instructions for This Activity and Receiving Credit
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.
At the conclusion of this activity, you should be better prepared to:
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
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
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
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
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
Disclosure: Consultant: Ariad, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech/Roche, Guardant Health, Merck, Novartis, TrovaGene. Speakers Bureau: Ariad, Genentech/Roche, Eli Lilly.
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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.
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.
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.
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