Targeting lung cancer brain metastases: a narrative review of emerging insights for anaplastic lymphoma kinase (ALK)-positive disease

Introduction

Background

Despite advances in systemic and molecularly targeted therapies, the development of brain metastases is common and remains associated with a poor, often terminal, prognosis. The annual incidence of brain metastases is estimated at 8 to 15 per 100,000 in the total population and 8–10% in individuals with cancer (1). These figures likely underestimate the true incidence due to increased cancer survival, the development of asymptomatic lesions, and fewer autopsies performed (2,3). Lung cancers comprise upwards of 60% of all brain metastases, and the incidence proportion of brain metastasis formation in patients with lung cancer ranges from 16% to 20% in select populations (1,2,4,5). Among lung cancer subtypes, non-small cell lung cancer (NSCLC) is disproportionately associated with brain metastasis formation, reflective of its prevalence relative to small cell lung cancer (6,7). Approximately 5% of NSCLC is associated with ALK rearrangement, whereas Kirsten rat sarcoma virus (KRAS) mutation is seen in 20–33%, epidermal growth factor receptor (EGFR)-positive disease in 10–15%, and both c-ros oncogene (ROS1) and RET rearrangement in ~2% of cases (8-12). Among these subtypes, patients with EGFR and ALK alterations appear to have a particularly high risk for brain metastasis formation with a majority of patients developing brain metastases within 5 years of diagnosis (13-15). This high central nervous system (CNS) tropism for ALK- and EGFR-positive disease therefore has significant implications for a patient’s clinical course. Synchronous diagnosis or CNS progression within months of diagnosis is seen in 25–40% of patients with ALK-positive lung cancer, compared to a 20% synchronous diagnosis rate across all subtypes of NSCLC (5,13,16-23). Accordingly, early detection and management of brain metastases in patients with ALK-positive NSCLC represents an important opportunity for medical, neurologic, and thoracic oncologists.

Brain metastases arise through complex mechanisms that are incompletely understood. However, a prevailing hypothesis, named the metastatic cascade, suggests that neoplasms must follow a sequence of interrelated steps to deposit in distant sites such as the brain (24,25). The series of events includes: (I) proliferation and invasion of surrounding tissues including blood vessels, with lung cancers likely migrating as cohesive groups of cells (26); (II) survival within the blood stream through inactivation of natural killer immune cells in part due to interactions with platelets (27-29); (III) adherence to the endothelium facilitated by selectins on tumor-bound platelets or neutrophil-associated extracellular traps (30,31); (IV) increasing vascular permeability by binding of ATP, released by platelets, to endothelial P2Y₂ receptors (32); and (V) eventual transepithelial migration through complex microenvironmental signaling pathways that are again mediated through cancer cell-platelet interactions (33,34). ALK-positive disease likely exploits circular RNAs, specifically F-circEA-2a, produced by the EML4-ALK fusion gene to facilitate migration of and invasion by cancer cells (35). Expression of EML4-ALK also increases epithelial mesenchymal transition-inducing transcription factors, likely via Crk-like protein and MAP kinase activation, that may promote migration (36). Additionally, work by Sevenich et al. has demonstrated that cathepsin S, expressed by tumor cells and leading to enzymatic breakdown of the junctional adhesion molecule JAM-B, likely mediates neoplastic migration across the highly selective blood brain barrier (BBB) (37). Alternatively, access to adjacent brain parenchyma can occur when metastatic depositions within blood vessel lumina directly rupture the epithelium, including at the BBB, circumventing traditional transepithelial migration (38). Emerging data also support the role of long noncoding RNAs in essentially all of these processes, including the initiation, migration, and brain colonization of metastatic cells through interactions with tumor and microenvironmental RNA and DNA (39).

Many metastatic colonies enter a potentially prolonged dormant, stem cell-like state to avoid clearance from the new site of disease (40). This period of quiescence may represent a larger cellular program meant to facilitate metastasis or could arise from numerous factors including a hostile foreign microenvironment containing plasmin released from reactive astrocytes; local immunosuppression; and limited angiogenesis (41). Therefore, metastatic cells that survive appear to be particularly well adapted to evade immune clearance and to respond to subtle survival signals to avoid apoptosis, with evidence of contribution from serpins (41-44). The pathway allowing for emergence of dormant cancer cells into a replicative state may occur through a paradoxical, prometastatic role of astrocytes as a consequence of de novo cancer cell-astrocyte gap junctions (45). Through cytosolic double-stranded DNA and cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) signaling, metastatic cells precipitate the release of inflammatory cytokines and produce activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway that supports cancer cell growth and facilitates colony survival (45). Successful metastatic colonies that emerge from the dormant state then proliferate. Neovascularization plays a key role in the establishment and survival of a metastatic colony, which is in part regulated by vascular endothelial growth factor (VEGF); suppression of VEGF has been shown to reduce proliferation of brain metastases (46). Combined with historically poor intracranial drug concentrations, selection for these resilient metastatic colonies reduces the efficacy of traditional treatment modalities and highlights the need for highly efficacious, brain-penetrant targeted agents.

Rationale and knowledge gap

The management of brain metastases remains challenging with poor clinical outcomes. Fortunately, molecularly targeted therapies have demonstrated improved efficacy likely owing to increased CNS penetrance, which in conjunction with local therapies of radiotherapy and surgery will continue to improve prognoses. Given the rate of development of agents and studies with heterogeneous patient populations, it can be difficult for a practicing oncologist to remain up to date on the best available evidence.

Objective

This review describes general principles of management for lung cancer brain metastases—including discussions of the role for surgery and radiation therapy (RT)—and the promising, emerging systemic treatments for ALK-positive NSCLC that may complement or delay traditional management strategies. We present the following article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-638/rc).

Methods

Table 1 below describes the selection process for relevant references.

Management of ALK-positive brain metastases

Several modalities are considered for the treatment of brain metastases, with evolving knowledge of tumor molecular characteristics and genetics yielding an ever-increasing number of targeted therapies. Below we describe key management considerations, including the role of local therapies such as surgery and radiation as well as emerging data for the role of precision treatments in the management of ALK rearranged NSCLC.

General principles

Following lesion biopsy or resection, the diagnosis of ALK rearranged NSCLC requires molecular testing that may be performed through next-generation sequencing, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, or immunohistochemistry. As this integrated diagnosis may take several weeks to return, it is useful to consider the clinical and histologic features that may suggest ALK-positive NSCLC. These characteristics include a younger age at diagnosis (median 6^th decade of life for ALK-positive disease vs. 8^th decade among all lung cancer types); never or minimal (<10 pack-years) tobacco use history; and adenocarcinoma histology with abundant signet ring cells (47-49). Molecular characterization should not delay the initiation of indicated and urgent local therapies, such as neurosurgical resection of a symptomatic intracranial mass, though systemic therapies will ultimately require these data. In the case of delayed diagnostic information, the initiation of traditional chemotherapy is reasonable, which can be transitioned to targeted therapy when ALK rearrangement has been confirmed.

As part of the pre-treatment evaluation for individuals with stage II to IV NSCLC, the National Comprehensive Cancer Network (NCCN) guidelines recommend brain magnetic resonance imaging (MRI) without and with gadolinium contrast to complete systemic evaluation given the high likelihood of brain metastasis (50). This is further supported in ALK-positive NSCLC by the risk of synchronous or early CNS progression. Accordingly, the identification of brain metastases can occur during screening as well as on diagnostic imaging performed for incipient symptomatology. Symptoms that may implicate an intracranial lesion include neurocognitive or behavioral changes; new and often progressive weakness, numbness, or language difficulties; alterations in level of consciousness; overt seizure-like activity; and headaches of changing frequency or character.

When considering treatment for a patient with newly identified or an increasing burden of intracranial metastatic disease, a multifaceted evaluation is undertaken. This assessment includes determination of the current symptom burden, the patient’s pre-morbid and current performance status, the number and location(s) of the intracranial lesion(s), and treatment received to date.

Two main scoring systems are used for performance status evaluation: the Karnofsky Performance Status (KPS) and Eastern Cooperative Oncology Group (ECOG) scales. These semi-quantitative scores provide a high-level description of the patient’s day-to-day function, which in concert with objective data such as age, systemic disease control, and diagnostic results including imaging and tumor genetics help clinicians formulate rough estimates of prognosis. Another tool used for prognostication is the graded prognostic assessment (GPA), which provides disease-specific median survival estimates based a cumulative score between 0 and 4 (51). The GPA for NSCLC incorporates KPS, age, number of brain metastases, presence of extracranial metastases, and EGFR and ALK aberrations in its calculation with a weighted contribution of 0-, 0.5-, or 1-point each; lower scores are associated with shorter median survival.

Where available, multidisciplinary team involvement is preferred, with input from medical and/or thoracic oncology, neurosurgery, radiation oncology, and neuro-oncology. Larger academic institutions may have tumor board meetings where a collaborative treatment plan is recommended and relevant clinical trials are considered.

Local therapies

Despite an enlarging armamentarium of molecularly targeted therapies, upfront treatment with surgical resection of and/or RT for presumed brain metastases is often considered in patients with a favorable performance status and prognosis.

The role for neurosurgery for diagnostic and therapeutic benefit is contingent on patient demographics including age, sex, and history of known primary malignancy; selection of patients to whom surgery is offered is not trivial. To help with this critical decision point, a collaborative effort between the American Society of Clinical Oncology (ASCO), Society for Neuro-Oncology (SNO), and American Society for Radiation Oncology (ASTRO) recently produced guidelines regarding patient selection and appropriateness for treatment (52). In their systematic review and expert panel, they proposed surgery be offered to patients with:

• Suspected brain metastases lacking a diagnosis of primary malignancy for whom surgery would elucidate the underlying process.
• Large tumors with mass effect.
• Multiple brain metastases whose residual intracranial and systemic disease is controllable with other measures.

The greatest benefit for surgery is likely in patients with minimal extracranial disease burden, with scant evidence for survival benefit in patients with widely metastatic disease (52).

Even in patients with an established diagnosis of NSCLC and imaging felt highly suspicious for metastasis, further tissue sampling may be appropriate for diagnostic purposes. Somatic driver mutations—such as ALK, EGFR, and KRAS—are, in principle, conserved in all sites of malignancy. However, pioneering work by Brastianos et al. demonstrated that additional, divergent genetic alterations are seen in sites of metastasis, seemingly conserved between metastatic lesions but clonally unique from the primary tumor, which may implicate selection for or facilitation of distant spread (53). This concept was corroborated in work by Shih et al., which identified candidate drivers of lung adenocarcinoma brain metastasis—specifically amplifications of MYC, MMP13, and YAP1—that were higher in frequency compared to control genomic data of sites of primary disease gathered from The Cancer Genome Atlas (54). By evaluating multiple tumor pairs, their team was able to assess temporal trends and determined that these amplifications tended to occur after divergence of metastatic and primary lineages, likely representing a selection of a pro-metastatic subpopulation (54). However, these alterations may be sufficient but not necessary to produce metastases, with pathways such as phenotypic transitions and epigenetics invoked as additional contributory mechanisms (55-58). Notably, these subclones may be resistant to targeted agents or reveal novel therapeutic targets. As such, early involvement by neurology or neuro-oncology, where available, and neurosurgery is strongly advised.

Following surgery, it is common to pursue RT. Although limited randomized data exist regarding the combination of surgery and RT compared to radiation alone, in patients with a single brain metastasis, results have generally favored a two-modality approach when technically feasible (59-61). For patients with one or two resected brain metastases, post-operative radiation to the resection cavity reduces the otherwise high rate of local recurrence, which is estimated to be 50–60% in one year in patients not receiving radiation (60-64). In patients with a KPS ≥70, Vogelbaum et al. do not specify a preferred radiation modality and consider stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), or a combination as equivalent at this time (52).

In patients for whom surgery is not reasonable due to technical limitations, extent of disease, or discordance with patient goals of care, RT or radiosurgery is considered. As with surgery, the performance status of a patient is highly relevant when balancing the risks and benefits of RT. Notably, few randomized trials of radiation treatment have enrolled patients with lower functional status, i.e., KPS <70 or ECOG >2. However, the 2016 QUARTZ trial—in which included patients were deemed unsuitable for SRS or surgery—did include a large subset (~38%) of patients with KPS <70, and on subgroup analysis demonstrated no difference in overall survival with the inclusion of WBRT as compared to optimal supportive care alone in this population (65). However, the median time from diagnosis to randomization was 25 days, and treatment was delayed (65). Despite these limitations, these results have helped inform the recommendations from ASCO-SNO-ASTRO that propose not offering radiation to patients with brain metastases as well as either (I) KPS ≤50 or (II) KPS <70 with no systemic treatment options (52). Similar to patients undergoing resection for oligometastatic disease, there is no preferred radiation modality for individuals with greater than four unresected brain metastases (52).

In individuals with sufficient performance status and oligometastatic disease—defined as one to four unresected brain metastases—SRS is preferred over WBRT or WBRT with SRS (52). This recommendation reflects the understanding that SRS is associated with fewer long-term neurocognitive effects, though there is concern that SRS may yield less durable intracranial disease control. To mitigate the risk for cognitive decline with WBRT, memantine and hippocampal avoidance have been recommended (52). These measures have demonstrated preservation of a subset of cognitive outcomes for patients without hippocampal metastases and with an expected survival of at least four months (66).

Systemic therapy

There is emerging evidence that systemic therapy may be preferred in the upfront setting over the localized therapies described above, particularly in patients with asymptomatic intracranial disease (50,52). Even in situations when local therapy would be considered standard, such as in patients with symptomatic or large brain metastases, retrospective studies suggest that tyrosine kinase inhibitors (TKIs) demonstrate significant intracranial activity with associated clinical improvement (67,68). Thus, effective systemic therapies may delay or eliminate local strategies with associated neurologic morbidity, such as WBRT. This discussion will focus on systemic management of ALK rearranged NSCLC according to the best available evidence and consensus recommendations from ASCO-SNO-ASTRO and the NCCN.

For patients with ALK rearranged NSCLC with asymptomatic brain metastases, such as those identified on screening imaging or incidentally found in work-up of another process, consensus recommendations from ASCO-SNO-ASTRO propose upfront treatment with alectinib, brigatinib, or ceritinib (52). These TKIs can be continued until evidence of intracranial progression is noted, and in some cases it may be reasonable to continue an ALK inhibitor following CNS progression if deemed manageable with local therapies such as small and/or oligometastatic progression. However, it is important to note that ceritinib has lower efficacy and is generally not a preferred ALK TKI; lorlatinib likely represents a better upfront treatment. The data supporting these recommendations follow.

A 2019 meta-analysis pooled the results of 20 studies of treatment with various ALK inhibitors; 15 were single arm and five were randomized (69). Agents under investigation included crizotinib, ceritinib, entrectinib, alectinib, brigatinib, ensartinib, and lorlatinib with various comparator agents or in single arm designs. The intracranial overall response rate (iORR) for all agents was 48% with a pooled complete remission rate of 21% (69). Relevant to the current ASCO-SNO-ASTRO guidelines, the iORR for alectinib was 79%, brigatinib was 48%, and ceritinib was 45%; notably the iORR for crizotinib is 18–33% (69,70).

In CNS-specific subgroup analyses of the ALEXA and ALESIA trials, patients treated with alectinib, a second generation ALK-inhibitor, had improved intracranial response compared to patients who received crizotinib, a first-in-class ALK-inhibitor that also targets ROS1 and MET. The ALEX study compared alectinib 600 mg twice-daily (b.i.d.) to crizotinib 250 mg b.i.d. in patients without prior systemic treatment. Among the 122 patients with intracranial lesions at baseline, 59% (38/64) on alectinib experienced CNS response vs. 26% (15/58) on crizotinib; median duration of intracranial response was also notably longer on alectinib with 3.7 months on crizotinib against no end point reached with alectinib (23). For patients who previously received intracranial radiotherapy and with measurable CNS metastases at baseline, iORRs were 85.7% (6/7) on alectinib and 71.4% (5/7) on crizotinib (71). Furthermore, patients with measurable and non-measurable CNS disease at baseline who had not received prior RT also demonstrated much higher iORR at 74.4% (29/39) on alectinib compared to crizotinib (24.3%, 9/37) (71). For the Japanese cohort of the J-ALEX study, which compared alectinib 300 mg b.i.d. to crizotinib 250 mg b.i.d., a longer time to CNS progression was noted in patients receiving alecitinib as compared to crizotinib [hazard ratio (HR) =0.22, P value <0.0001] (72,73). The CNS outcomes analyses demonstrated a significantly lower rate of intracranial progression in patients without baseline brain metastases (HR for alectinib of 0.19, P value <0.05) as well as lower one year cumulative incidence rates of CNS progression on alectinib (5.9%) vs. crizotinib (16.8%), acknowledging a higher baseline rate of CNS disease for patients in the crizotinib arm (n=29 vs. 14) (73). These data support the idea that ALK inhibitors with good CNS efficacy can treat existing and potentially delay the development of brain metastases. These results were corroborated in the ALESIA study, which randomized untreated Asian patients 2:1 to either alectinib 600 mg b.i.d. or crizotinib 250 mg b.i.d. Patients receiving alectinib demonstrated superior iORR of 73% vs. 22% (5/23) on crizotinib; a higher complete response rate was also seen at 50% vs. 13% (74). A recent retrospective cohort study also evaluated the intracranial ORR of alectinib in 20 ALK-inhibitor naïve patients (cohort 1), 32 patients who developed intracranial progression with or without extracranial progression after treatment with crizotinib (cohort 2), and 13 patients with intracranial-only progression while on second-generation ALK-inhibitors other than crizotinib (cohort 3) (75). The ORRs were 81.8% in cohort 1, 76.5% in cohort 2, and 42.8% in cohort 3; most patients reported robust improvement in neurologic symptoms and the need for corticosteroids decreased significantly (75). Although these results support the role for alectinib in clinical practice, the small sample size and treatment heterogeneity necessitates cautious interpretation.

Patients with brain metastases and crizotinib-refractory disease on the ALTA trial received low- and high-dose brigatinib, with resulting iORRs of 46% on 90 mg daily and 67% on 180 mg daily dosing (76,77). In the ASCEND and ASCEND-2 trials, patients with baseline brain metastases receiving ceritinib were found to have disease control rates slightly lower than brigatinib (65–74% vs. 83%) with iORR of 45% among the 20 patients in ASCEND-2 with active/target brain lesions at enrollment (78,79).

The third generation ALK/ROS1 inhibitor lorlatinib was specifically designed to penetrate the BBB and has demonstrated significant CNS activity, even in patients who have previously failed a brain penetrant TKI such as alectinib. Work by Solomon et al. demonstrated the potential for this agent in a single arm expansion cohort study of lorlatinib in patients with ALK-positive metastatic NSCLC. Among 141 patients with brain metastases, the iORR was 63% (53/84 patients with measurable intracranial disease) across all cohorts including treatment naïve participants and those with prior-TKI use (80). In another single arm trial of lorlatinib in patients with prior use of at least one ALK inhibitor, approximately 64% (52/81) of patients with baseline brain metastases demonstrated intracranial response with a median response duration of 12.4 months (81). The effect was further substantiated in the CROWN trial, in which 296 patients with advanced, untreated metastatic ALK rearranged NSCLC were randomized to receive lorlatinib or crizotinib (82). There were 38/149 (26%) patients in the lorlatinib arm with brain metastases at baseline vs. 40/147 (27%) on crizotinib (82). A higher proportion (66%) of patients receiving lorlatinib demonstrated intracranial response with 61% experiencing complete response; those receiving crizotinib had a much lower intracranial response at 20% (82).

A summary of key studies is seen in Table 2.

Attempts to compare—and potentially supplement—the effects of TKIs with RT have also been explored. A recent retrospective study of 52 patients combined ALK-inhibitor therapy and RT, wherein 20 patients received an ALK-inhibitor plus RT vs. 32 receiving an ALK-inhibitor alone (83). In this cohort, there was no significant difference in time to treatment failure between the two groups, supporting a targeted monotherapy approach to treatment that would spare the potential sequelae of RT. These data built upon two earlier series of patients with EGFR-positive NSCLC with brain metastases who received RT or EGFR-TKIs in the upfront setting; despite prolonged intracranial time to treatment failure, overall survival was not different across groups (84,85).

Of note, the aforementioned studies do not discriminate by subtypes of ALK-positive disease, which may have an important impact on clinical outcomes. Within ALK-positive NSCLC, many variants exist that appear to predict response to targeted treatment, with variants 1, 2, and 3a/b being the most common (86,87). Among these, variant 3a/b—associated with G1202R pathogenic variant—is resistant to crizotinib, ceritinib, brigatinib, and alectinib, whereas variants 1 and 2 may be relatively more sensitive to ALK inhibition (86-89). However, this differential response was not seen in a single institutional series of 135 patients with ALK-positive NSCLC receiving first-line crizotinib (n=65) or chemotherapy (n=70) when comparing all patients with variant 1 vs. non-variant 1 disease who received crizotinib (90). Further, in the subset of patients with baseline brain metastases treated with upfront crizotinib (n=18), there was inferior time to treatment failure for variant 1 disease, which was also noted to have more aggressive radiographic features (90). The impact of group heterogeneity and small sample size necessitates careful interpretation of these results, but more insight into the behavior of ALK variants will be needed to determine their implications for clinical course.

Regarding safety and tolerability, a 2019 meta-analysis evaluated 19 studies comprising 3,307 patients on ALK-inhibitor therapy including alectinib, brigatinib, ceritinib, and crizotinib (91). In this, they found that adverse events (AEs) were nearly universal and serious adverse events (SAEs) were seen in over 40% of participants receiving ceritinib and brigatinib (91). The most common SAEs involved the respiratory system for all four agents—including pneumonia, respiratory failure, thrombosis, and pleural effusion—followed by nervous or alimentary system sequelae; alectinib was associated with the lowest rate of SAEs overall (91). Headaches and fatigue were counted among relevant CNS AEs. The third-generation ALK TKI lorlatinib is associated with a high frequency of mild to potentially severe symptoms including hypercholesterolemia, hypertriglyceridemia, edema, peripheral neuropathy, cognitive effects, fatigue, mood changes, and vision abnormalities (92). Given the relatively high proportion of patients with grade 3 or 4 AEs while on lorlatinib, patients in whom lorlatinib is considered as first-line must be carefully selected and monitored (82). Conversely, sequential ALK inhibitor therapy may yield a hypermutated phenomenon that could confer resistance to later lorlatinib, which therefore leads to a critical clinical decision point (93-95).

Following the ALEX trial, alectinib has become the most widely used ALK TKI in the upfront setting given the favorable balance of disease control and lower risk for SAEs. However, treatment resistance—and eventual disease progression—is of significant concern (87,93,96). To delay treatment resistance, combination therapy with a backbone of ALK inhibition has been explored. In light of the complementary action and potential efficacy of anti-VEGF therapy in reducing brain metastasis proliferation, a small, single institution phase 1/2 study recently evaluated the combination of alectinib and bevacizumab in 11 patients with ALK rearranged NSCLC (97). Of the 9 patients with CNS disease at baseline, iORR was 77.8% (7/9) with 44.4% (4/9) demonstrating complete CNS response; median CNS progression-free survival was not reached (97). This combination regimen was also well tolerated.

Consolidating the above, a second-generation ALK TKI or lorlatinib should be considered first-line therapy over other systemic agents including platinum-pemetrexed regimens and crizotinib. This is true even in patients with baseline brain metastases given good intracranial effect. These agents have demonstrated robust systemic and CNS disease control and can prevent or delay the development of new brain metastases. Our institutional experience is that alectinib is the preferred agent as it provides a favorable profile of both efficacy and tolerability, though any available second-generation agent or lorlatinib can be considered.

Symptomatic management

In the acute setting, many of the symptoms associated with brain metastases arise from or are exacerbated by peritumoral edema and mass effect. Accordingly, symptoms may be relieved by administration of corticosteroids such as dexamethasone. Despite the ubiquity of its use, the dosing and frequency of dexamethasone administration is not protocolized and varies by institution. A reasonable range of dexamethasone doses would be 4–24 mg total daily dose, which can be administered once or twice daily (98). Note that dexamethasone doses less than 16 mg daily may not be inferior for symptom relief as compared to higher doses, and brain metastasis symptoms and edema may not produce any noticeably increased response to higher doses (99). Lastly, b.i.d. dosing has demonstrated non-inferior symptom relief as compared to every six hours dosing but has a much lower incidence of side effects (100). Corticosteroids are helpful adjuncts prior to and sometimes during local and systemic therapy, but they are meant to bridge to definitive treatment.

For patients with brain metastases on ALK inhibitors, the neurologic side effects of TKIs such as cognitive dysfunction and peripheral can be particularly problematic. Neurologic assessment and clinical history can help tease apart the underlying etiology and whether symptoms are treatment- or disease-related. Given the frequency of these adverse effects, attention should be directed toward early screening of mood, cognitive function, pain, dysesthesias, numbness, or weakness in patients on ALK inhibitors. Neuropsychological evaluation and cognitive rehab may be beneficial in patients with cognitive dysfunction, and stimulants may also be considered for fatigue-related cognitive dysfunction and inattention. Neuropathy symptoms should be managed according to published guidelines (101,102); physical/occupational therapy and consideration of pharmacologic agents such as duloxetine may be helpful. Dose reduction of the TKI should also be considered.

Future directions and challenges

There are ongoing challenges to the use of systemic therapies, largely arising from limitations in crossing the BBB or the adverse effects that can develop with highly penetrant agents. Although compromise to BBB integrity accompanies larger metastatic lesions, the presence of drug efflux pumps actively limits the effective concentration of pharmacotherapy and inadvertently reinforces the metastatic niche (103). Therefore, it will be important to consider the molecular weight, lipophilicity, polar surface area, hydrogen bond donor count, permeability, and efflux for any proposed compounds (104). The development of new, highly CNS-penetrant agents will have to contend with both the BBB as well as the potential for side effects, as has been highlighted in the neurologic and extra-CNS SAE profile seen with lorlatinib.

An additional concern is the method used to determine response to treatment within studies. To facilitate comparison across trials, it will be important to use consistent and validated response criteria when assessing patients with brain metastases and their neurologic function. While many trials continue to use the one-dimensional measurements of RECIST, more recent trials incorporate the Response Assessment in Neuro-Oncology (RANO) criteria for brain metastases (105). The inclusion of neurologic outcomes data and SAEs will also allow for more nuanced agent selection in eligible patients.

Ongoing trials for ALK rearranged NSCLC include a study (NCT04849273) of TPX-0131, a novel oral ALK inhibitor, which includes patients with asymptomatic brain metastases or leptomeningeal disease, as well as an international study evaluating the use of alectinib with bevacizumab in patients with ALK rearranged NSCLC, including patients with treated brain metastases (NCT03779191). There is also an ongoing basket trial of entrectinib, an inhibitor of NTRK, ROS1, and ALK, which includes patients with primary or secondary CNS disease (NCT02568267).

The inclusion of patients with brain metastases in trials of ALK inhibitor therapy will be crucial given the propensity for CNS disease, which should include symptomatic patients who may benefit from local therapy and may help elucidate synergistic approaches with surgery and/or RT. Furthermore, the development of new studies focused on delaying resistance to ALK TKIs, likely through a combinatorial approach, will inform future treatment regimens.

Conclusions

The advent of targeted therapies such as alectinib, brigatinib, ceritinib, and lorlatinib has changed the treatment paradigm for ALK rearranged NSCLC. These agents have yielded improved systemic and CNS disease control—including reducing the risk of developing CNS disease—and may help delay local therapies in some circumstances. Second- and third-generation ALK inhibitor therapy is now considered first-line for ALK rearranged NSCLC, but surgery and RT remain important for the control of large, widespread, and symptomatic intracranial disease. Furthermore, the development of resistance to ALK inhibitors will continue to affect progression-free survival unless effective combination therapies are established; some promise has been shown with bevacizumab and alectinib. Ongoing and future work will help surmount these challenges, offering hope to patients with an as-yet incurable disease.

Acknowledgments

Funding: This article was supported by the National Institutes of Health (2K12CA090354-21 to TAN).

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Jessica J. Lin and Justin F. Gainor) for the series “ALK-Positive NSCLC” published in Translational Lung Cancer Research. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-638/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-638/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-638/coif). The series “ALK-Positive NSCLC” was commissioned by the editorial office without any funding or sponsorship. NW received royalties from Wotlers Kluwer, served on the Advisory Board for Seattle Genetics in 2021 and received institutional research funding for clinical trial from Merck. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Ostrom QT, Wright CH, Barnholtz-Sloan JS. Brain metastases: epidemiology. In: Handbook of Clinical Neurology. Amsterdam:Elsevier, 2018:27-42.
2. Lamba N, Wen PY, Aizer AA. Epidemiology of brain metastases and leptomeningeal disease. Neuro Oncol 2021;23:1447-56. [Crossref] [PubMed]
3. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep 2012;14:48-54. [Crossref] [PubMed]
4. Sacks P, Rahman M. Epidemiology of Brain Metastases. Neurosurg Clin N Am 2020;31:481-8. [Crossref] [PubMed]
5. Singh R, Stoltzfus KC, Chen H, et al. Epidemiology of synchronous brain metastases. Neurooncol Adv 2020;2:vdaa041. [Crossref] [PubMed]
6. Stark AM, Stöhring C, Hedderich J, et al. Surgical treatment for brain metastases: Prognostic factors and survival in 309 patients with regard to patient age. J Clin Neurosci 2011;18:34-8. [Crossref] [PubMed]
7. Nussbaum ES, Djalilian HR, Cho KH, et al. Brain metastases. Histology, multiplicity, surgery, and survival. Cancer 1996;78:1781-8. [Crossref] [PubMed]
8. Devarakonda S, Morgensztern D, Govindan R. Genomic alterations in lung adenocarcinoma. Lancet Oncol 2015;16:e342-51. [Crossref] [PubMed]
9. O'Byrne KJ, Gatzemeier U, Bondarenko I, et al. Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 2011;12:795-805. [Crossref] [PubMed]
10. Gainor JF, Tseng D, Yoda S, et al. Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in ROS1-Positive Non-Small-Cell Lung Cancer. JCO Precis Oncol 2017;2017:PO.17.00063.
11. D'Angelo A, Sobhani N, Chapman R, et al. Focus on ROS1-Positive Non-Small Cell Lung Cancer (NSCLC): Crizotinib, Resistance Mechanisms and the Newer Generation of Targeted Therapies. Cancers (Basel) 2020;12:3293. [Crossref] [PubMed]
12. Drilon A, Lin JJ, Filleron T, et al. Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients With RET-Rearranged Lung Cancers. J Thorac Oncol 2018;13:1595-601. [Crossref] [PubMed]
13. Shi AA, Digumarthy SR, Temel JS, et al. Does initial staging or tumor histology better identify asymptomatic brain metastases in patients with non-small cell lung cancer? J Thorac Oncol 2006;1:205-10. [Crossref] [PubMed]
14. Shin DY, Na II, Kim CH, et al. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol 2014;9:195-9. [Crossref] [PubMed]
15. Tomasini P, Serdjebi C, Khobta N, et al. EGFR and KRAS Mutations Predict the Incidence and Outcome of Brain Metastases in Non-Small Cell Lung Cancer. Int J Mol Sci 2016;17:2132. [Crossref] [PubMed]
16. Rangachari D, Yamaguchi N, VanderLaan PA, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer 2015;88:108-11. [Crossref] [PubMed]
17. 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;34:123-9. [Crossref] [PubMed]
18. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167-77. Erratum in: N Engl J Med 2015;373:1582. [Crossref] [PubMed]
19. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-94. Erratum in: N Engl J Med 2015;373:1582. [Crossref] [PubMed]
20. Guérin A, Sasane M, Zhang J, et al. Brain metastases in patients with ALK+ non-small cell lung cancer: clinical symptoms, treatment patterns and economic burden. J Med Econ 2015;18:312-22. [Crossref] [PubMed]
21. Fallet V, Cadranel J, Doubre H, et al. Prospective screening for ALK: clinical features and outcome according to ALK status. Eur J Cancer 2014;50:1239-46. [Crossref] [PubMed]
22. Kang HJ, Lim HJ, Park JS, et al. Comparison of clinical characteristics between patients with ALK-positive and EGFR-positive lung adenocarcinoma. Respir Med 2014;108:388-94. [Crossref] [PubMed]
23. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:829-38. [Crossref] [PubMed]
24. Fidler IJ. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 2003;3:453-8. [Crossref] [PubMed]
25. Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer 2004;4:448-56. [Crossref] [PubMed]
26. Friedl P, Locker J, Sahai E, et al. Classifying collective cancer cell invasion. Nat Cell Biol 2012;14:777-83. [Crossref] [PubMed]
27. Labelle M, Hynes RO. The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discov 2012;2:1091-9. [Crossref] [PubMed]
28. Kopp HG, Placke T, Salih HR. Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Res 2009;69:7775-83. [Crossref] [PubMed]
29. Palumbo JS, Talmage KE, Massari JV, et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 2005;105:178-85. [Crossref] [PubMed]
30. Läubli H, Borsig L. Selectins promote tumor metastasis. Semin Cancer Biol 2010;20:169-77. [Crossref] [PubMed]
31. Cools-Lartigue J, Spicer J, McDonald B, et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest 2013; Epub ahead of print. [Crossref] [PubMed]
32. Schumacher D, Strilic B, Sivaraj KK, et al. Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor. Cancer Cell 2013;24:130-7. [Crossref] [PubMed]
33. Reymond N, d'Água BB, Ridley AJ. Crossing the endothelial barrier during metastasis. Nat Rev Cancer 2013;13:858-70. [Crossref] [PubMed]
34. Smeda M, Przyborowski K, Stojak M, et al. The endothelial barrier and cancer metastasis: Does the protective facet of platelet function matter? Biochem Pharmacol 2020;176:113886. [Crossref] [PubMed]
35. Tan S, Sun D, Pu W, et al. Circular RNA F-circEA-2a derived from EML4-ALK fusion gene promotes cell migration and invasion in non-small cell lung cancer. Mol Cancer 2018;17:138. [Crossref] [PubMed]
36. Kogita A, Togashi Y, Hayashi H, et al. Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition. Int J Oncol 2014;45:1430-6. [Crossref] [PubMed]
37. Sevenich L, Bowman RL, Mason SD, et al. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat Cell Biol 2014;16:876-88. [Crossref] [PubMed]
38. Al-Mehdi AB, Tozawa K, Fisher AB, et al. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med 2000;6:100-2. [Crossref] [PubMed]
39. Liu SJ, Dang HX, Lim DA, et al. Long noncoding RNAs in cancer metastasis. Nat Rev Cancer 2021;21:446-60. [Crossref] [PubMed]
40. Luzzi KJ, MacDonald IC, Schmidt EE, et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 1998;153:865-73. [Crossref] [PubMed]
41. Valiente M, Obenauf AC, Jin X, et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 2014;156:1002-16. [Crossref] [PubMed]
42. Malladi S, Macalinao DG, Jin X, et al. Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell 2016;165:45-60. [Crossref] [PubMed]
43. Douma S, Van Laar T, Zevenhoven J, et al. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 2004;430:1034-9. [Crossref] [PubMed]
44. Kim YN, Koo KH, Sung JY, et al. Anoikis resistance: an essential prerequisite for tumor metastasis. Int J Cell Biol 2012;2012:306879. [Crossref] [PubMed]
45. Chen Q, Boire A, Jin X, et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 2016;533:493-8. [Crossref] [PubMed]
46. Masuda C, Sugimoto M, Wakita D, et al. Bevacizumab suppresses the growth of established non-small-cell lung cancer brain metastases in a hematogenous brain metastasis model. Clin Exp Metastasis 2020;37:199-207. [Crossref] [PubMed]
47. Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res 2011;17:2081-6. [Crossref] [PubMed]
48. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:4247-53. [Crossref] [PubMed]
49. Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 2009;15:5216-23. Erratum in: Clin Cancer Res 2009;15:7110. [Crossref] [PubMed]
50. Ettinger DS, Wood DE, Aisner DL, et al. Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022;20:497-530. [Crossref] [PubMed]
51. Sperduto PW, Mesko S, Li J, et al. Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient. J Clin Oncol 2020;38:3773-84. [Crossref] [PubMed]
52. Vogelbaum MA, Brown PD, Messersmith H, et al. Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline. J Clin Oncol 2022;40:492-516. [Crossref] [PubMed]
53. Brastianos PK, Carter SL, Santagata S, et al. Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov 2015;5:1164-77. [Crossref] [PubMed]
54. Shih DJH, Nayyar N, Bihun I, et al. Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma. Nat Genet 2020;52:371-7. [Crossref] [PubMed]
55. Massagué J, Obenauf AC. Metastatic colonization by circulating tumour cells. Nature 2016;529:298-306. [Crossref] [PubMed]
56. Lambert AW, Pattabiraman DR, Weinberg RA. Emerging Biological Principles of Metastasis. Cell 2017;168:670-91. [Crossref] [PubMed]
57. Sela Y, Li J, Kuri P, et al. Dissecting phenotypic transitions in metastatic disease via photoconversion-based isolation. Elife 2021;10:e63270. [Crossref] [PubMed]
58. McDonald OG, Li X, Saunders T, et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet 2017;49:367-76. [Crossref] [PubMed]
59. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494-500. [Crossref] [PubMed]
60. Brown PD, Ballman KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 2017;18:1049-60. [Crossref] [PubMed]
61. Mahajan A, Ahmed S, McAleer MF, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol 2017;18:1040-8. [Crossref] [PubMed]
62. Kayama T, Sato S, Sakurada K, et al. Effects of Surgery With Salvage Stereotactic Radiosurgery Versus Surgery With Whole-Brain Radiation Therapy in Patients With One to Four Brain Metastases (JCOG0504): A Phase III, Noninferiority, Randomized Controlled Trial. J Clin Oncol 2018; Epub ahead of print. [Crossref] [PubMed]
63. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998;280:1485-9. [Crossref] [PubMed]
64. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2011;29:134-41. [Crossref] [PubMed]
65. Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet 2016;388:2004-14. [Crossref] [PubMed]
66. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol 2013;15:1429-37. [Crossref] [PubMed]
67. Lin JJ, Jiang GY, Joshipura N, et al. Efficacy of Alectinib in Patients with ALK-Positive NSCLC and Symptomatic or Large CNS Metastases. J Thorac Oncol 2019;14:683-90. [Crossref] [PubMed]
68. Dutta SW, Mack ML, Aliotta E, et al. Intracranial disease control for EGFR-mutant and ALK-rearranged lung cancer with large volume or symptomatic brain metastases. J Neurooncol 2020;149:357-66. [Crossref] [PubMed]
69. Zhang Z, Guo H, Lu Y, et al. Anaplastic lymphoma kinase inhibitors in non-small cell lung cancer patients with brain metastases: a meta-analysis. J Thorac Dis 2019;11:1397-409. [Crossref] [PubMed]
70. 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;33:1881-8. [Crossref] [PubMed]
71. Gadgeel S, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol 2018;29:2214-22. [Crossref] [PubMed]
72. 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;390:29-39. [Crossref] [PubMed]
73. Nishio M, Nakagawa K, Mitsudomi T, et al. Analysis of central nervous system efficacy in the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. Lung Cancer 2018;121:37-40. [Crossref] [PubMed]
74. Zhou C, Kim SW, Reungwetwattana T, et al. Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALESIA): a randomised phase 3 study. Lancet Respir Med 2019;7:437-46. [Crossref] [PubMed]
75. Zou Z, Xing P, Hao X, et al. Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study. BMC Med 2022;20:12. [Crossref] [PubMed]
76. 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;35:2490-8. [Crossref] [PubMed]
77. Camidge DR, Kim DW, Tiseo M, et al. Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials. J Clin Oncol 2018;36:2693-701. [Crossref] [PubMed]
78. Kim DW, Mehra R, Tan DSW, 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. Lancet Oncol 2016;17:452-63. [Crossref] [PubMed]
79. Crinò L, Ahn MJ, De Marinis F, et al. Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2. J Clin Oncol 2016;34:2866-73. [Crossref] [PubMed]
80. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 2018;19:1654-67. [Crossref] [PubMed]
81. Bauer TM, Shaw AT, Johnson ML, et al. Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer. Target Oncol 2020;15:55-65. [Crossref] [PubMed]
82. Shaw AT, Bauer TM, de Marinis F, et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med 2020;383:2018-29. [Crossref] [PubMed]
83. Thomas NJ, Myall NJ, Sun F, et al. Brain Metastases in EGFR- and ALK-Positive NSCLC: Outcomes of Central Nervous System-Penetrant Tyrosine Kinase Inhibitors Alone Versus in Combination With Radiation. J Thorac Oncol 2022;17:116-29. [Crossref] [PubMed]
84. Magnuson WJ, Lester-Coll NH, Wu AJ, et al. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. J Clin Oncol 2017;35:1070-7. [Crossref] [PubMed]
85. Saida Y, Watanabe S, Abe T, et al. Efficacy of EGFR-TKIs with or without upfront brain radiotherapy for EGFR-mutant NSCLC patients with central nervous system metastases. Thorac Cancer 2019;10:2106-16. [Crossref] [PubMed]
86. Sabir SR, Yeoh S, Jackson G, et al. EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients. Cancers (Basel) 2017;9:118. [Crossref] [PubMed]
87. 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;6:1118-33. [Crossref] [PubMed]
88. Lin JJ, Zhu VW, Yoda S, et al. Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer. J Clin Oncol 2018;36:1199-206. [Crossref] [PubMed]
89. Yoshida T, Oya Y, Tanaka K, et al. Differential Crizotinib Response Duration Among ALK Fusion Variants in ALK-Positive Non-Small-Cell Lung Cancer. J Clin Oncol 2016;34:3383-9. [Crossref] [PubMed]
90. Qiao M, Zhao C, Liu Q, et al. Impact of ALK variants on brain metastasis and treatment response in advanced NSCLC patients with oncogenic ALK fusion. Transl Lung Cancer Res 2020;9:1452-63. [Crossref] [PubMed]
91. Hou H, Sun D, Liu K, et al. The safety and serious adverse events of approved ALK inhibitors in malignancies: a meta-analysis. Cancer Manag Res 2019;11:4109-18. [Crossref] [PubMed]
92. Bauer TM, Felip E, Solomon BJ, et al. Clinical Management of Adverse Events Associated with Lorlatinib. Oncologist 2019;24:1103-10. [Crossref] [PubMed]
93. Yoda S, Lin JJ, Lawrence MS, et al. Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer. Cancer Discov 2018;8:714-29. [Crossref] [PubMed]
94. Ou SHI, 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;34:661-8. [Crossref] [PubMed]
95. Griesinger F, Roeper J, Pöttgen C, et al. Brain metastases in ALK-positive NSCLC - time to adjust current treatment algorithms. Oncotarget 2018;9:35181-94. [Crossref] [PubMed]
96. Lin JJ, Riely GJ, Shaw AT. Targeting ALK: Precision Medicine Takes on Drug Resistance. Cancer Discov 2017;7:137-55. [Crossref] [PubMed]
97. Lin JJ, Muzikansky A, Kennedy E, et al. Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study. ESMO Open 2022;7:100342. [Crossref] [PubMed]
98. Sarin R, Murthy V. Medical decompressive therapy for primary and metastatic intracranial tumours. Lancet Neurol 2003;2:357-65. [Crossref] [PubMed]
99. Vecht CJ, Hovestadt A, Verbiest HB, et al. Dose-effect relationship of dexamethasone on Karnofsky performance in metastatic brain tumors: a randomized study of doses of 4, 8, and 16 mg per day. Neurology 1994;44:675-80. [Crossref] [PubMed]
100. Weissman DE, Janjan NA, Erickson B, et al. Twice-daily tapering dexamethasone treatment during cranial radiation for newly diagnosed brain metastases. J Neurooncol 1991;11:235-9. [Crossref] [PubMed]
101. Jordan B, Margulies A, Cardoso F, et al. Systemic anticancer therapy-induced peripheral and central neurotoxicity: ESMO-EONS-EANO Clinical Practice Guidelines for diagnosis, prevention, treatment and follow-up. Ann Oncol 2020;31:1306-19. [Crossref] [PubMed]
102. Loprinzi CL, Lacchetti C, Bleeker J, et al. Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update. J Clin Oncol 2020;38:3325-48. [Crossref] [PubMed]
103. Eichler AF, Chung E, Kodack DP, et al. The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol 2011;8:344-56. [Crossref] [PubMed]
104. Shi Y, Mader M. Brain penetrant kinase inhibitors: Learning from kinase neuroscience discovery. Bioorg Med Chem Lett 2018;28:1981-91. [Crossref] [PubMed]
105. Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol 2015;16:e270-8. [Crossref] [PubMed]