Rearrangements in the anaplastic lymphoma kinase (ALK) gene occur in up to 7% of all patients with advanced non–small cell lung cancer (NSCLC).¹ Such rearrangements usually involve fusion of ALK with the gene for echinoderm microtubule-associated protein-like 4 (EML4), generating constitutively active ALK proteins that cause dysregulated oncogenic signaling and tumor proliferation.² ALK alterations are more common in patients who are younger, nonsmokers or light smokers, and have adenocarcinoma histology. Fortunately, such tumors are highly responsive to treatment with ALK tyrosine kinase inhibitors (TKIs), which have revolutionized the management of ALK-positive advanced NSCLC.³ A systematic review found that ALK inhibitors can significantly increase survival compared to standard chemotherapy,⁴ and ALK TKIs are now considered standard of care for such patients as evidenced by multiple clinical oncology guidelines.^5-7

ALK Inhibitors for ALK-Positive Metastatic NSCLC

Crizotinib was the first ALK TKI approved by the U.S. Food and Drug Administration (FDA) for the treatment of ALK- or ROS1-positive metastatic NSCLC. Due to development of resistance to crizotinib arising from secondary ALK mutations or off-target alterations, most crizotinib-treated patients eventually require a switch to another inhibitor. The need for more effective agents, including those active against crizotinib-resistant disease and for patients with central nervous system (CNS) involvement, has given rise to multiple second- and third-generation ALK TKIs. Treatment with next-generation ALK inhibitors can result in significantly longer progression-free survival than crizotinib without substantially increasing the rate of adverse events.⁸ Consequently, first-line therapy with crizotinib has largely been supplanted by next-generation ALK TKIs, agents that have demonstrated higher response rates against crizotinib-resistant and crizotinib-naive disease. Currently, five ALK inhibitors are approved for adults with ALK-positive metastatic NSCLC: crizotinib, alectinib, ceritinib, lorlatinib, and brigatinib. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend the use of alectinib, lorlatinib, and brigatinib (all preferred) for ALK-positive advanced NSCLC as well as ceritinib, while crizotinib may be useful in certain circumstances.⁷ Patients with an ALK rearrangement and PD-L1 expression level ≥ 1% should receive first-line therapy with an ALK TKI rather than an immune checkpoint inhibitor, since immune checkpoint inhibitors are ineffective and potentially toxic for patients with ALK-positive NSCLC.⁷

First-Line Trials of ALK Inhibitors

Several second- and third-generation TKIs have been developed that are active against many ALK resistance mutations. First-line treatment with alectinib, ceritinib, lorlatinib, or brigatinib was shown to be superior to crizotinib or chemotherapy, as applicable, in patients with ALK-rearranged disease (Table 1).^{9-13,15,47-49} These newer inhibitors were also found to be active against brain metastases and CNS disease.

Lorlatinib is a highly-potent, third-generation ALK/ROS1 inhibitor that is active against a broad range of ALK-resistance mutations.¹⁴ It was designed to better penetrate the blood-brain barrier and has greater efficacy in patients with CNS metastases compared to crizotinib. In the randomized phase III CROWN trial in ALK-positive advanced NSCLC, first-line treatment with lorlatinib resulted in a significantly higher confirmed objective response rate (76% vs 58%), a greater percentage of patients alive at 12 months without disease progression (78% vs 39%), and superior progression-free survival at 12 months compared with crizotinib (80% vs 35%).¹⁵ Additionally, lorlatinib significantly reduced CNS disease progression, resulting in higher rates of intracranial response (66% vs 20%) and duration of intracranial response ≥ 12 months (72% vs 0%). The FDA approved lorlatinib in 2021 for the first-line treatment of adults with ALK-positive metastatic NSCLC. Recent 36-month follow-up data confirmed the efficacy and safety of lorlatinib vs crizotinib in this setting, supporting the use of lorlatinib in patients with untreated ALK-positive NSCLC with and without brain metastases.¹⁶

Another second-generation TKI, ensartinib, selectively inhibits wild-type ALK and variants, but it has not yet been approved in the United States. Interim analysis of phase III data indicated a significantly longer progression-free survival with ensartinib compared to crizotinib in ALK inhibitor–naive patients, with a higher intracranial response rate in those with baseline brain metastases.¹⁷

Selecting an ALK Inhibitor as First-Line Therapy

Several factors should be considered when selecting an ALK inhibitor as first-line therapy, including patient-specific factors such as Asian descent and comorbidities. Recent data suggest that molecular risk assessment can identify high-risk patients with specific ALK variants, other genomic alterations, or immune checkpoint biomarkers that might affect response to ALK TKIs and development of resistance, and thus impact selection of initial therapy.¹⁸

Although head-to-head comparisons of second- and third-generation ALK TKIs are lacking, lorlatinib was shown in a meta-analysis to have significantly longer progression-free survival than alectinib in ALK inhibitor–naive non-Asian patients (no significant differences were noted in the Asian subgroup).¹⁹ Moreover, a systematic review of alectinib, brigatinib, and lorlatinib trials found that progression-free survival was significantly greater with lorlatinib in both previously untreated and ALK inhibitor–naive patients, suggesting lorlatinib may be the best treatment option in this setting.²⁰ These data support consideration of the use of lorlatinib as first-line therapy for patients with ALK-positive advanced NSCLC.

Further assessment of these agents in minority populations is needed, according to Narjust Duma, MD, Assistant Professor of Medicine, Harvard Medical School. “Pivotal trials of ALK inhibitors in advanced NSCLC largely enrolled younger, male, White patients, so the efficacy and safety of these agents in minority patient populations should be confirmed,” she noted.

Pivotal trials of ALK inhibitors in advanced NSCLC largely enrolled younger, male, White patients, so the efficacy and safety of these agents in minority patient populations should be confirmed. Narjust Duma, MD

CNS Metastasis

Patients with ALK-positive advanced NSCLC are at increased risk for brain metastases, a major cause of morbidity and mortality.²¹ Next-generation ALK TKIs have better CNS penetrance and greater efficacy than crizotinib, with responses to alectinib and ceritinib seen in crizotinib-naive patients and those with prior TKI therapy, and in patients with or without baseline brain metastases.^21-24 Lorlatinib has also demonstrated intracranial and extracranial efficacy against ALK-positive NSCLC, with responses achieved in patients with or without baseline brain metastases who had progressed after treatment with at least one second-generation ALK TKI.^25-27

ALK Testing

Use of approved ALK inhibitors requires confirmation of an ALK rearrangement in tumor tissue by means of an FDA-approved companion diagnostic test based on immunohistochemistry or fluorescence in situ hybridization.²⁸ Other techniques, such as RT-PCR and next-generation sequencing, can detect less common ALK mutations and alterations in other oncogenes. There is growing interest in the use of liquid biopsies to detect ALK rearrangements in circulating tumor cells or cell-free tumor DNA, particularly when tumor tissue is not readily available, but currently this approach is not used in routine clinical practice.^29,30

Certain clinicopathologic features, such as smoking status and tumor histology, are associated with the presence of ALK rearrangements in lung adenocarcinoma and strengthen the need for ALK testing in selected patients. Additional histologic and clinical characteristics, such as male sex and younger patient age, also should be considered.³¹ NSCLC molecular testing guidelines indicate which genes—including ALK—should be routinely screened and preferred testing methodologies.³² Ideally, molecular testing should be performed prior to initiating first-line therapy to inform treatment decisions. Yet a significant proportion of patients are never tested, potentially missing the opportunity to provide effective oncogene driver-directed therapy.³³

At least 15 EML4-ALK fusion variants have been identified that differ with respect to gene breakpoint location, and each may be associated with distinct biological properties, response to treatment, and resistance to ALK TKIs.^18,34 Genomic analysis of ALK variants and comutations that confer a poorer prognosis (eg, TP53) could be of prognostic and predictive value and might suggest earlier use of more aggressive therapies. Currently, ALK variants are not routinely analyzed, but this area is evolving and may prove clinically important in the future.

Adverse Events

Although generally less toxic than chemotherapy, significant adverse effects can occur with ALK TKIs. A meta-analysis of ALK inhibitor trials found that adverse events occurred in almost all patients, with serious adverse events in over 20% (> 40% with brigatinib and ceritinib).³⁵ In a systematic review, the pooled absolute risk of severe adverse events was 34.5%.³⁶

Common adverse events with ALK inhibitors include gastrointestinal toxicities, fatigue, edema, increased AST/ALT, and increased phosphokinase; vision disorders, peripheral neuropathy, and cognitive effects can also occur (Figure 1). Treatment-related adverse events can differ among ALK TKIs. For example, there is a slightly increased risk for hepatotoxicity, bradycardia, and photosensitivity-type rash with alectinib; more gastrointestinal toxicity and QT interval prolongation with ceritinib; early-onset pulmonary events with brigatinib; and hyperlipidemia and neurocognitive effects with lorlatinib.^37-43 According to Tejas Patil, MD, Assistant Professor at the University of Colorado Cancer Center, neurocognitive effects associated with lorlatinib could be related to its greater CNS efficacy. “Lorlatinib was specifically designed to be a very effective CNS-penetrant drug, properties which may also account for some of its neurocognitive side effects,” he indicated. Patients and family members should be educated about possible adverse events. “It is important to educate both patients and family members about toxicities,” Dr. Duma emphasized, “particularly since some patients may not notice cognitive impairments. Effective, constant interaction is essential because patients can remain on these drugs for years and adverse events evolve over time, so communication must also evolve.”

Lorlatinib was specifically designed to be a very effective CNS-penetrant drug, properties which may also account for some of its neurocognitive side effects. Tejas Patil, MD

Certain treatment-related toxicities with ALK inhibitors require special consideration since they could be severe or limit therapy. In another meta-analysis, pulmonary adverse events such as interstitial lung disease/pneumonitis were seen with alectinib, lorlatinib, and ceritinib (2.6%, 1.8%, and 1.1%, respectively); overall, 65% were grade 3/4.⁴³ The risk for high-grade QTc prolongation is also increased, suggesting the need for routine EKG monitoring.⁴⁴ Some toxicities may require additional treatments (eg, supplemental oxygen, statins) and increased monitoring that can further increase costs. “Cost of therapy can be an issue for some patients on a limited income,” said Dr. Duma. “Those who are on government insurance programs, for example, don't qualify for drug assistance programs, so providers sometimes select an ALK inhibitor based on whatever their insurance will pay for.”

Quality-of-life effects of ALK inhibitors should be discussed with patients and weighed against possible survival benefits. This is important since the improved efficacy of these agents means some patients survive longer and can remain on treatment for years, and certain adverse events may arise over time. “Patients with ALK-positive lung cancers will be on ALK-directed therapies for a very long time,” noted Dr. Patil, “so chronic toxicities, even if only grade 1 or 2, are important. Clinicians need to think about which therapies to use based on side effect profiles, and this must be individualized for each patient.” Assessment of risk factors and prompt management of treatment-related toxicities are essential for mitigating potential serious adverse events, minimizing costs, and maintaining therapy. Clinicians should refer to published guidelines on prophylaxis and management of treatment-related adverse events as well as drug prescribing information for further details (Figure 2).^14,45,46

Conclusion

Next-generation ALK TKIs can significantly improve outcomes for many patients with ALK-positive NSCLC, but important questions still must be addressed. These include the optimal treatment following progression on a first-line ALK TKI, the impact of ALK variants on selection of therapy, and the role of next-generation inhibitors in combined-modality regimens for patients with brain metastases. Ongoing trials are continuing to evaluate ALK inhibitors in combination with other targeted agents, immune checkpoint inhibitors, and radiation therapy to further increase efficacy and improve treatment of ALK inhibitor resistance.