Among cancer types, lung cancer is the most frequently diagnosed, having accounted for 11.4% of the estimated 19.3 million new cancer cases globally in 2020. Lung cancer is also the leading cause of cancer-related death, representing 18% of almost 10 million deaths (Figure 1).1 These statistics are consistent with those reported by the Centers for Disease Control and Prevention in the United States, where lung cancer has the third highest incidence and the highest rate of cancer-related death.2
Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers and represents a significant percentage of new cases and deaths.3 An acquired chromosome mutation is found in approximately 5% of NSCLC, resulting in fusion between the anaplastic lymphoma kinase (ALK) gene and various fusion partners.4 The most common fusion partner is the echinoderm microtubule-associated protein-like 4 (EML4) gene; the EML4-ALK variant is therefore the most common ALK-positive NSCLC.4 An increased risk of central nervous system (CNS) metastasis is common in the EML4-ALK NSCLC variant.3 Among patients with this variant, 50% to 60% develop brain metastases, and metastatic CNS disease is present at diagnosis among approximately 20% to 30% of patients.3,5 Prostate Cancer Treatment
The approval of tyrosine kinase inhibitors (TKIs) transformed the treatment landscape for advanced metastatic ALK-positive NSCLC from an eminently chemotherapy-based approach to a targeted approach. However, treatment resistance due to the development of secondary ALK mutations and disease progression, particularly brain metastasis, is challenging to manage and requires appropriate selection and sequencing of TKI therapies. A practical approach to the treatment of ALK-positive NSCLC is presented in this article.
Start with genetic testing to confirm an ALK mutation
EML4-ALK transformation and treatment resistance arises from a genetic mutation and, as such, can be diagnosed through genetic testing. These tests include tissue- or plasma-based cell-free DNA techniques or liquid biopsy; blood tests for carcinoembryonic antigen, which is absent or present at a low level in people with an ALK mutation; and imaging of the lung.6,7
Current consensus is that all patients with advanced-stage adenocarcinoma be tested for ALK and other treatable genetic mutations, regardless of sex, race, smoking history, or other risk factors.8 Other experts recommend that all patients who have been diagnosed with NSCLC undergo genetic testing. Furthermore, patients who required genetic analysis at the time of initial diagnosis should be considered for liquid biopsy rather than tissue biopsy, particularly if tissue is challenging to obtain, a delay in diagnosis is expected, or a contraindication to biopsy exists.5
Genetic testing methodologies for use in NSCLC include fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), reverse transcription-polymerase chain reaction, and next-generation sequencing.4,8
Liquid biopsy is minimally invasive and provides a rapid, highly specific diagnosis of ALK mutations.9 The International Association for the Study of Lung Cancer states that a positive diagnosis of ALK rearrangement by liquid biopsy is sufficient to initiate ALK-targeted therapy.10 According to McCusker and colleagues,5 if AKL-positive NSCLC progression is suspected during treatment with a first-generation or second-generation TKI, liquid biopsy is selected over tissue biopsy to diagnose resistance mechanisms due to the high specificity of plasma cell-free DNA for detecting ALK mutations.
TKI options for treating ALK-positive NSCLC
Approval of the first-generation TKI, crizotinib, in 201111 radically changed the treatment landscape and outcomes for patients with ALK-positive NSCLC. Crizotinib is an orally available small molecule that can penetrate the blood-brain barrier and is effective in patients with malignancy that has metastasized to the brain. A comparative study of crizotinib and chemotherapy demonstrated drastically improved progression-free survival (PFS) and a higher objective response rate with crizotinib.4 Crizotinib is approved as a first-line treatment for ALK-positive NSCLC based on the PROFILE 1014 study (ClinicalTrials.gov Identifier: NCT01154140), which demonstrated its superior efficacy and survival advantage compared with platinum-based chemotherapy.12,13
Treatment resistance from mutations in the ALK gene is a significant challenge with TKI therapies; indeed, resistance to crizotinib generally occurs within 2 years after initiating treatment. Second- and third-generation TKIs have been developed to overcome resistance. Ceritinib,14 alectinib,15 and brigatinib16 are second-generation TKIs effective against ALK-positive NSCLC that is resistant to crizotinib. Ceritinib and alectinib, approved in 2015, and brigatinib, approved in 2017, are all indicated for use in the first-line setting. A third-generation TKI, lorlatinib, was approved in March 2021 and is also indicated for use in the first-line treatment of ALK-positive metastatic NSCLC.17,18
ALK mutations are not the same; neither are TKIs
Fusion of the ALK gene with various partner proteins is a characteristic feature of NSCLC. The most common fusion partner is the EML4 protein, of which more than 15 variants have been identified, including the most common:
Data from retrospective analyses suggest that the response to TKIs and the potential to develop resistance differ among ALK-EML4 fusion variants9,20; however, confirmatory evidence from randomized clinical trials has been lacking. Several trials have provided a head-to-head comparison of alectinib and crizotinib (the latter regarded as the first-line standard of care for ALK-positive NSCLC). The ALEX trial (ClinicalTrials.gov Identifier: NCT02075840) was a phase 3 study in previously untreated patients with advanced ALK-positive NSCLC with a mix of EML4 variants 1, 2, and 3a/b, who were randomly assigned to receive alectinib 600 mg twice daily or crizotinib 250 mg twice daily.21 Alectinib was found to have longer PFS and lower toxicity than crizotinib and showed activity against CNS disease.
Subanalysis of the ALEX trial found that the presence of EML4 variants 1, 2, and 3a/b did not affect PFS, objective response rate, or duration of response.22 Moreover, the ALEX trial confirmed the earlier finding that alectinib provides superior PFS compared with crizotinib in untreated ALK-positive NSCLC, regardless of the EML4-ALK variant.22 Similar results were seen in the interim and final analyses of the J-ALEX trial, a phase 3 randomized study that compared alectinib to crizotinib in ALK inhibitor-naive Japanese patients with ALK-positive NSCLC (Table).23
Most patients with NSCLC eventually experience progression, and metastasis to the brain is challenging to treat, particularly with treatment resistance. Patients with CNS involvement have worsening prognosis and quality of life.24 With the availability of 5 TKIs indicated for use in the first-line setting, decision-making on treatment selection and strategy can be challenging. Despite development of resistance, crizotinib remains the first-line treatment of choice in several regions of the world.
In the United States, alectinib and ceritinib are the first-line treatments of choice for advanced ALK-positive NSCLC, particularly in patients with brain metastases. The head-to-head comparative ALEX trial found that alectinib was superior to crizotinib in overall response rate, PFS, and toxicity profile.25 Although ceritinib demonstrated superior efficacy over standard-of-care platinum-based chemotherapy, its toxicity profile is greater than that of chemotherapy, which might limit its clinical use.26
Alectinib is a highly selective ALK inhibitor effective against a broad spectrum of ALK mutations. Studies supporting its efficacy in patients with brain metastases, including patients who have experienced progression with crizotinib, have been reviewed by Tomasini and colleagues.3 The superior efficacy and safety of alectinib compared with crizotinib demonstrated in several randomized, head-to-head trials presents alectinib as the new standard of care for the first-line treatment of ALK-positive NSCLC and in patients resistant to crizotinib.3 Indeed, guidelines from the National Comprehensive Cancer Network (NCCN) recommend alectinib over crizotinib, ceritinib, and brigatinib as the treatment of choice for patients with ALK rearrangement.27 McCusker and colleagues identified alectinib as the first-line TKI of choice for ALK-positive NSCLC based on its PFS advantage, cumulative reduction in incidence of brain metastasis, and favorable toxicity profile.5
A practical approach to treating resistant ALK-positive CNS-metastasized NSCLC
Despite an initial response to crizotinib, most patients with advanced NSCLC experience progression in 1 or 2 years due to treatment resistance. Prevailing evidence suggests that most crizotinib-resistant tumors are still driven by ALK and are sensitive to subsequent TKI therapy, provided that ALK mutations are detectable in plasma or tissue.29 Resistance to TKI therapy raises the question of a subsequent treatment choice for ongoing disease management.
In the setting of CNS progression, a TKI with adequate CNS penetration is essential. Among patients for whom crizotinib fails, the drug has a low cerebrospinal fluid-to-plasma concentration ratio and is associated with a high rate of CNS metastasis. CNS penetration increases with second- and third-generation TKIs (Table28); according to McCusker and colleagues, this penetration might be advantageous in delaying radiotherapy in patients with asymptomatic CNS disease.
With close monitoring, patients with mildly symptomatic CNS disease can be considered for treatment with a second-generation TKI. Patients with symptomatic CNS disease should receive an appropriate TKI in addition to local-regional treatment (stereotactic radiosurgery, whole-brain radiation therapy, or both) based on the number and dimensions of lesions.5 NCCN guidelines provide a comprehensive treatment algorithm for ALK-positive NSCLC.27 A treatment algorithm for ALK-rearranged advanced NSCLC based on available data from which NCCN, European Society of Medical Oncology, and Associazione Italiana di Oncologia Medica (Italian Association of Medical Oncology) guidelines were developed is shown in Figure 2.24
Some patients experience disease progression in the absence of a detectable ALK mutation, which is indicative of TKI treatment failure. For them, treatment options are limited, although platinum-based chemotherapy remains a valid treatment option.5 For Gristina and colleagues,24 lorlatinib, a third-generation ALK-TKI, is the treatment of choice upon progression in a patient taking a second-generation ALK inhibitor, due to the absence of putative mutations. Evidence suggests that, even in ALK-positive patients not presenting with a resistance point mutation, an overall response rate of 32% and median PFS of 5.5 months might be attained with lorlatinib.
Although investigational immunotherapy combined with chemotherapy has been evaluated, the efficacy of this combination in progressive disease, in the absence of a detectable ALK mutation, is inconclusive.
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Cancer Therapy Advisor had no role in this content’s preparation.
Latest News Your top articles for Friday
Haymarket Medical Network Top Picks
Continuing Medical Education (CME/CE) Courses
Please login or register first to view this content.
Rare Lung Cancer Copyright © 2024 Haymarket Media, Inc. All Rights Reserved. This material may not be published, broadcast, rewritten or redistributed in any form without prior authorization. Your use of this website constitutes acceptance of Haymarket Media’s Privacy Policy and Terms & Conditions.