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Introduction
Around 80-90% of all lung cancer cases are non-small cell lung cancers (NSCLC)(1). Anaplastic lymphoma kinase (ALK) rearrangements occur in 3-5% of NSCLC. The most frequent ALK rearrangement is the EML4-ALK fusion, a potent oncogene driver on its own. Other ALK gene fusions have been associated with NSCLC, such as KIF5B-ALK, TFG-ALK, and KLC1-ALK(1).
ALK tyrosine kinase inhibitors (TKIs) are now the first-choice treatment for patients with advanced ALK-positive non-small-cell lung cancer, since crizotinib, the first-generation ALK inhibitor, demonstrated a higher efficacy than chemotherapy. More effective ALK TKIs from the second (alectinib, brigatinib, and ensartinib) and third (lorlatinib) generations have now proven to be superior to crizotinib in several phase-3 trials(1,3).
Patients with NSCLC who have central nervous system (CNS) metastases face a very challenging clinical situation, and the presence of these metastases is negatively correlated with the prognosis. The ALK gene is responsible for the proper embryogenesis of the CNS; thus, the ALK rearrangements considerably increase the risk of CNS metastases occurrence in NSCLC patients. Brain metastases are present in 10-20% of newly diagnosed NSCLC cases, and they can occur in 25-50% of cases in the course of the disease(4). In the NSCLC patients with ALK rearrangements, brain metastases are detected in 23.8% newly diagnosed cases, and occur in 58.4% of patients in three years from the diagnosis(5).
The blood-brain barrier (BBB) and medications’ transport-related proteins, such as P-glycoprotein, prevent pharmaceuticals from penetrating the CNS. Neurosurgery and radiation therapy were the only available treatments for CNS metastases, until recently(6). However, the ALK TKIs, with their high BBB penetrance, have shown promising results in CNS metastases response rates and in CNS metastases progression-free survival (PFS) in clinical trials.
According to the recommendations of the European Society of Medical Oncology (ESMO) guideline on oncogene-addicted metastatic NSCLC, alectinib, brigatinib or lorlatinib should be given as first-line treatment for ALK positive metastatic NSCLC. Alectinib, brigatinib or ceritinb are recommended for the patients who progress under the treatment with crizotinib. Lorlatinib was initially only recommended as a third-line ALK TKI, and it is still recommended for those who progress under a second-generation ALK TKI, being still a viable option as a third-line treatment in ALK-positive NSCLC patients(1).
Materials and method
We have searched the platforms PubMed and Google Scholar using the keywords “NSCLC”, “ALK”, “brain”, and “metastases”. For the query containing these terms, we have selected phase-3 clinical trials of ALK TKIs, retrospective studies on radiation therapy and association of radiation therapy with ALK TKIs in ALK-positive NSCLC patients and clinical practice guidelines, no older than seven years. We have made another query, using the previously mentioned terms and the keyword “epidemiology”. For this query, we have selected articles containing epidemiological data on ALK-positive NSCLC, no older than 10 years.
Clinical trials investigating the impact
of ALK TKIs on brain metastases in NSCLC patients
In the recent years, as the ALK TKIs development continued, new clinical trials have emerged, including some head-to-head trials comparing second and third generations of ALK TKIs with crizotinib. The results of some ALK TKIs head-to-head trials on CNS metastases are summarized in Table 1.
The phase-3 trial ALEX compared alectinib with crizotinib in untreated ALK-positive NSCLC patients. The primary end point was investigator assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. The hazard ratio (HR) for disease progression or death was 0.47 [95% confidence interval (CI); 0.34-0.56; p<0.001]. As for the time to CNS progression, the HR was 0.16 (95% CI; 0.1-0.28; p<0.001). CNS progression was recorded in 12% of the subjects in the alectinib group and in 45% of the subjects from the crizotinib group. Alectinib demonstrated higher effectiveness and reduced toxicity compared to crizotinib when used as the initial treatment for ALK-positive NSCLC(7).
The J-ALEX trial compared alectinib with crizotinib in a Japanese population, in subjects who were either chemotherapy-naive, or had received one line of chemotherapy. Median PFS was significantly improved in the alectinib group: not reached at the time of data cutoff for alectinib group and 10.2 months for the crizotinib group, HR 0.34 (99.7% CI; 0.17-0.71; p<0.0001). This study also showed alectinib to reduce the risk of CNS lesions progression. Notably, alectinib showed consistently improved progression-free survival compared with crizotinib in patients who had received one previous line of chemotherapy and in those who were chemotherapy-naive(8).
The ALTA-1L phase-3 clinical trial compared brigatinib with crizotinib in subjects who had not received any ALK TKI before. The primary objective was PFS, and the secondary end points included the objective response rate and intracranial response. The 12-month PFS with brigatinib was 67% versus 47% with crizotinib, and the hazard ratio for disease progression or death was 0.49 (95% CI; 0.33-0.74; p<0.001). The confirmed objective response rate was 71% with brigatinib and 60% with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% with brigatinib and 29% with crizotinib. Furthermore, the 12-month survival without intracranial disease progression in subjects with brain metastases at baseline was 67% in the brigatinib group and 21% in the crizotinib group (HR 0.27; 95% CI; 0.13-0.54). In the group of patients with ALK-positive NSCLC who had not been treated with an ALK inhibitor before, those who were given brigatinib presented a significantly longer period without disease progression compared to those who were given crizotinib(9).
The CROWN is an ongoing phase-3 trial comparing lorlatinib with crizotinib in patients who had received no previous systemic treatment for metastatic disease. In an unplanned analysis of the data from the start of the study to the cutoff date of 20 September 2021, the three-year PFS was 64% for lorlatinib and 19% for crizotinib (HR 0.27; 95% CI; 0.18-0.39). Median time to intracranial progression was not reached in the lorlatinib group for patients with or without baseline brain metastases, being 7.3 months in the crizotinib group for patients with baseline brain metastases (HR 0.1; 95% CI; 0.04-0.27) and 30.8 months in the crizotinib group for patients without baseline brain metastases (HR 0.02; 95% CI; 0.002-0.14). The latest, extensive data from CROWN trial demonstrate the long-lasting advantage of lorlatinib compared to crizotinib in patients with newly diagnosed ALK-positive non-small-cell lung cancer. These findings endorse the use of lorlatinib as the initial therapy option for patients, regardless of whether they have brain metastases at the start of treatment(3).
Local therapy versus systemic therapy
When determining the treatment for patients who have recently been diagnosed with or have an increasing amount of intracranial metastatic illness, a comprehensive evaluation is conducted. This examination involves evaluating the patients’ current level of symptoms, their functional condition before and after the illness, the number and location of any brain lesions, and the treatments they have received so far.
Although there are now more options for targeted therapies at the molecular level, many doctors still recommend starting the treatment for suspected brain metastases with surgery or radiation therapy in patients who have a good performance status and prognosis.
According to the American Society of Clinical Oncology (ASCO) guideline on treatment of brain metastases, for patients who have a good level of physical ability and have a small number of untreated brain metastases (between one and four), stereotactic radiosurgery (SRS) is the recommended treatment option, rather than whole-brain radiation therapy (WBRT) or a combination of WBRT and SRS. This proposal acknowledges that SRS is linked to a reduced occurrence of long-term neurocognitive consequences. However, there is apprehension that SRS may result in less long-lasting control of intracranial diseases. To reduce the risk of cognitive impairment associated with whole-brain radiation therapy, experts have suggested the use of memantine and the practice of hippocampal avoidance. Recent evidence suggests that systemic therapy may be more advantageous than localized therapies, especially for patients with silent intracranial illness(10).
The use of both radiation therapy (RT) and tyrosine kinase inhibitors for brain metastases remains a topic of debate and disagreement. Initial findings indicated that NSCLC patients with ALK rearrangement who underwent radiation for brain metastases showed enhanced survival. The addition of radiation to the initial ALK-TKI crizotinib, a first-generation drug, resulted in a notable increase in the rate of positive response and the length of time without disease progression in patients with brain metastases, as demonstrated in many studies(5).
However, more recent studies suggest that in ALK-positive NSCLC patients with CNS metastases who are treated with second- or third-generation ALK TKIs, radiation therapy could be postponed until after CNS disease progression(11).
A retrospective study (Thomas et al., 2022) that aimed to compare the time to progression in patients with EGFR mutations or ALK rearrangements treated with TKIs alone versus treated with TKIs and RT revealed no significant difference among the two groups. Among patients undergoing radiation therapy, there was a higher prevalence of larger metastases, neurologic symptoms, and the use of steroids. There were no significant differences between the groups that received TKI alone and the groups that received CNS radiation therapy in addition to TKI. This was observed across all study outcomes, including time to progression (11.4 versus 13.4 months; p=0.98; ALK) and time to intracranial progression (18.1 versus 21.8 months; p=0.65; ALK). The findings suggest that the use of CNS-penetrant TKIs may allow for the postponement of local radiotherapy in certain patients, without any detrimental impact on disease development. However, it should be noted that these results are still preliminary evidence(4).
Similar results were achieved in another retrospective study (Dutta et al., 2020) on EGFR/ALK positive patients with high intracranial tumor burden. Out of the patients who received TKI alone or TKI + RT, 93.8% (15 out of 16) and 58.3% (14 out of 24) achieved at least a partial response at around threee months, respectively. Among patients who had not received TKI treatment before and had brain metastases at the time of cancer diagnosis, eight out of 13 patients achieved a complete response when treated with TKI alone, four out of 11 patients achieved a complete response when treated with TKI and SRS, and one out of five patients achieved a complete response when treated with TKI and WBRT. Intracranial metastatic burden and presence of neurological symptoms were not predictive for overall survival. The median overall survival for the 21 patients with high intracranial burden was 35.4 months (95% CI; 21.9-48.8 months), which was not statistically different from the 36 patients with less burden (median 36.8 months; 95% CI; 8-65.7 months)(12).
Future developments
There are currently ongoing trials for ALK rearranged NSCLC. One of these trials (NCT04849273) is studying TPX-0131, a new oral ALK inhibitor. This trial includes patients who have asymptomatic brain metastases or leptomeningeal disease. Another international study (NCT03779191) is evaluating the use of alectinib with bevacizumab in patients with ALK rearranged NSCLC, including those who have already received treatment for brain metastases. Additionally, there is an ongoing basket trial of entrectinib, a substance that inhibits NTRK, ROS1 and ALK. This trial includes patients who have either primary, or secondary CNS illness. The trial is registered with the identifier NCT02568267(13).
Conclusions
The development of new ALK TKIs, with a better penetrance of the blood-brain barrier, has already improved the prospects of the ALK-positive NSCLC patients with CNS metastases. The significant increase in progression-free survival, intracranial PFS and intracranial overall response rate has made it possible for local therapies, such as radiation therapy or surgery, to be deferred for those patients under treatment with second- or third-generation ALK TKIs.
Corresponding author: Alexandru-Ioan Pintea E-mail: andrupintea@gmail.com
Conflict of interest: none declared.
Financial support: none declared.
This work is permanently accessible online free of charge and published under the CC-BY licence.
