Non-small cell lung cancer and brain metastasis
Previously, non-small cell lung cancer (NSCLC) brain metastases had a poor prognosis, with a median survival time of 7 months. But tumor-specific mutations have triggered a wave of targeted therapies for these brain metastases and can improve overall survival time. ALK rearrangement can be seen in about 2%–7% of NSCLC, so it has become a therapeutic target for advanced NSCLC. Professors Zhang Isabella and Lu Bo from the United States recently published a related review in The Lancetonology, which is now introduced as follows:.
Crizotinib is the first approved anti-ALK tyrosine kinase inhibitor after showing excellent comprehensive effects, but this effect has not been translated into the control of intracranial lesions. The central nervous system (CNS) is a common site of involvement in disease progression. Up to 60% of patients will experience metastasis at this site during treatment with crizotinib: this is due to poor intracranial penetration of the drug and the inherent resistance of the tumor mechanism.
The second-generation ALK inhibitors have better control of intracranial lesions, but they are inconsistent, which requires us to explore other treatment options. This article is a review of the role of ALK in CNS metastasis, ALK targeted therapy of intracranial lesions, and resistance to current treatments.
The role of the blood-brain barrier
The blood-brain barrier protects the brain from the penetration of toxic substances, but also makes it difficult for the systemic medication to reach the brain parenchyma. From the perspective of blocking, the blood-brain barrier has several characteristics: for example, the continuous tight connection between endothelial cells and the complex supporting structure including pericytes and astrocytes can regulate the blood-brain barrier through paracrine Permeability; high resistance, about 100 times that of peripheral capillaries, selectively blocking some polar molecules.
Part of the systemic treatment that crosses the blood-brain barrier is expelled by efflux transporters. The most common efflux transporters are P-glycoprotein, multidrug resistance protein 1-6, ABCG2.
In the case of metastasis, the integrity of the blood-brain barrier is impaired. At this time, the vascular structure there is more like the vascular structure of the tumor-originating tissue, and the damaged tight junction appears as a highly permeable vasculature. Strategies for increasing the permeability of the blood-brain barrier include physically destroying its barrier through radiotherapy, hypertonic agents, high-intensity beam ultrasound, and bradykinin analogs.
More targeted programs related to ALK inhibitors can inhibit the drug from pumping out and more efficiently transport it to brain parenchyma and tumor cells.
ALK rearrangement
ALK gene-related translocations can be found in about 2-7% of NSCLC, the most common is EML4-ALK translocation. Rearrangement leads to autophosphorylation and continuous activation of ALK, thereby activating the RAS and PI3K signaling cascade (see inset). RAS activation may result in more aggressive tumor characteristics and worse clinical prognosis.
ALK rearrangement of non-small cell lung cancer targeted therapy mechanism. It can directly target ALK rearrangement proteins (such as LDK378, X396, CH5424802); in addition, it can target upstream effectors (such as EGFR), or downstream pathways (such as PLC, JAK-STAT, KRAS-MEK-ERK, AKT-mTOR- Aurora A kinase) to inhibit cell cycle progression, survival, proliferation, and vascularization; it can target DNA repair; it can also target protein formation that stimulates cell growth (eg, EGFR ligands, VEGF).
Similar to patients with EGFR mutations, patients with ALK rearrangement may be younger, smoke less or not smoke than wild-type patients, and almost all are adenocarcinoma-type NSCLC.
Several studies have evaluated the prognostic significance of ALK rearrangement in NSCLC, but the results are mixed. Studies have shown that ALK rearranged NSCLC doubles the risk of disease progression or recurrence at 5 years, and promotes multiple metastases. Patients with ALK rearrangement have more metastases when diagnosed, and the risk of metastasis to the pericardium, pleura, and liver is greater. There are also studies claiming that ALK rearrangement and wild-type patients are similar in terms of relapse, disease-free survival, and overall survival; there are also studies showing that ALK rearrangement improves overall survival in stage I-III NSCLC patients.
As for whether ALK rearrangement NSCLC is more likely to be transferred to the brain, the data is highly variable. Studies have found that 3% of patients with NSCLC brain metastasis can see ALK translocation and 11% can see amplification. This study shows that the copy number of ALK gene in metastasis tends to increase, which may be due to the selective advantage of ALK translocation tumor cells during metastasis.
The role of crizotinib in brain metastasis
Pfizer’s crizotinib is a small molecule inhibitor approved by the US Food and Drug Administration (FDA) for the ALK rearrangement progression NSCLC, targeting ALK, MET and ROS tyrosine kinases. By inhibiting ALK and MET tyrosine kinases, crizotinib can inhibit the tyrosine phosphorylation of activated ALK.
A number of studies including comparing crizotinib with standard chemotherapy regimens for patients with advanced progressive ALK rearranged NSCLC have shown that the former has better progression-free survival, tumor efficiency, and overall quality of life. Other studies have shown that the overall objective intracranial effective rate and disease control rate of crizotinib at 12 weeks were 18% and 56%, respectively; the median time of intracranial progression after application of this drug in previously untreated patients was 7 Months. The control of intracranial lesions at 12 weeks was close to that of systemic lesions.
The overall effectiveness and duration of control of patients who had previously undergone intracranial radiotherapy had improved. The overall intracranial effective rate was 33%, the disease control rate at 12 weeks was 62%, and the median time to progression was 13.2 months . It is important that patients who continue to use crizotinib have progressed, but their overall survival time is longer than those who have not continued to use the drug during the progression.
Recently, crizotinib as a first-line treatment phase 3 trial included 79 patients who had previously undergone radiotherapy for brain metastases and found that the median time for intracranial progression was equivalent to the chemotherapy group. The important point of this study is that all patients were treated with radiotherapy first, and the previous PROFILE study showed that radiotherapy can improve the efficacy and therefore excessively emphasized the intracranial effect caused by crizotinib alone.
Related knowledge about ALK rearrangement brain metastasis comes from case reports and subgroup analysis of clinical trials. When analyzing these data, it is important to judge the characteristics of the patients as described in the case report, because many studies have included various cases without distinction: symptomatic and asymptomatic metastases, pre-treatment Multiple treatments such as radiotherapy, different medications, and different follow-ups. In the study of second-generation ALK inhibitors, it is also necessary to distinguish whether crizotinib has been used before.
The data indicate that the intracranial effectiveness of crizotinib varies. Many patients show partial to complete remission of extracranial lesions, but CNS tumors have progressed, and therefore need to undergo chemotherapy or consider the u
se of second-generation drugs.
Although crizotinib is generally effective, most patients with ALK-rearranged NSCLC will still have metastases or progression during treatment. Early studies have shown that CNS is the main site of treatment failure during treatment with crizotinib in nearly half of patients. Recent studies have shown that failure of CNS treatment is seen in 70% of patients! This is due to the poor CNS permeability of crizotinib, but also due to the limited passive diffusion and the active pumping of P-glycoprotein.
A study has determined the concentration of the drug in the cerebrospinal fluid during crizotinib treatment in patients with ALK rearranged lung cancer brain metastases: 0.617 ng / mL, while the concentration in serum is 237 ng / mL. The explanation for the progression of the CNS-based lesions is that the metastasis process is more aggressive than the primary tumor, or mutations in the crizotinib-binding domain.
The role of second-generation ALK inhibitors in brain metastasis
Novartis’s ceritinib is a second-generation ALK-specific tyrosine kinase inhibitor approved by the FDA, and also targets IGF-1R, insulin receptor and ROS1. Through other pathways, ceritinib inhibits ALK autophosphorylation and the downstream STAT3 pathway. In a phase 1 study, the effective rate of patients without crizotinib was 62%. In view of this, two phase 2 studies are being developed and are being implemented.
Roche’s alectinib has already received FDA approval for its breakthrough progress in treatment. Studies have found that in patients with ALK rearranged NSCLC who have not been treated with crizotinib, the effective rate of alectinib is 93.5% (43/46 cases), and the relevant phase 3 study is currently underway.
Preclinical pharmacology studies have already shown that alectinib has better CNS drug permeability than crizotinib, and the CNS drug concentration of the drug is 63-94% of the serum concentration. This may be because alectinib is different from crizotinib and ceritinib, P glycoprotein has no effect on it, and cannot be actively excreted from the intracranial environment.
In a study of crizotinib-resistant patients, 21 of the 47 patients included were asymptomatic brain metastases or patients with brain metastases but no treatment, 6 patients achieved complete remission after alectinib, 5 One patient achieved partial remission and eight patients had stable tumors.
In this study, 5 patients underwent cerebrospinal fluid measurement and found that there was a linear relationship between serum and cerebrospinal fluid unconjugated drug concentration. It is speculated that the lowest concentration in cerebrospinal fluid is 2.69 nmol / L, which exceeds the half inhibitory concentration of ALK inhibitors reported previously. In the second phase of the study, 14 patients who did not receive crizotinib were treated with alectinib, and 9 patients survived progression-free for more than 12 months.
Another breakthrough treatment approved by the FDA, ARIAD Pharmaceuticals’ brigatinib not only inhibits ALK, but also targets EGFR and ROS1. A study on the drug found that 16 of the crizotinib-resistant patients had already had intracranial metastasis when they started the drug, and 4 of these 5 patients showed imaging after taking the drug. effective.
There are few studies on the CNS activity of first- and second-generation tyrosine kinase inhibitors, but there are multi-center randomized phase 3 trials.
The Role of ALK Inhibitors in Pial Metastasis
There are few studies on pial meningeal metastasis in ALK rearrangement lesions because of the poor overall prognosis and the difficulty of quantifying the therapeutic effect. Some people studied 125 cases of NSCLC pial meningeal metastasis and found that overall survival after whole brain radiotherapy (WBRT) did not improve, but the survival time after subarachnoid chemotherapy was longer.
In a retrospective analysis of 149 cases of NSCLC pial meningeal metastasis, the overall survival of patients after subarachnoid chemotherapy, EGFR inhibitors, and WBRT was improved. There are also few reports of cases showing that in patients with ALK rearranged pial meningeal metastases, intracranial lesions in patients with crizotinib plus subarachnoid use of methotrexate have improved. But the data is scarce and no conclusion can be made.
The role of other second-generation drugs in pial meningeal metastasis is not yet conclusive, but the currently used intracranial chemotherapy regimen plus alectinib or tyrosine kinase inhibitors appears to be the most effective.
Counterattack against tyrosine kinase inhibitor resistance
Many crizotinib patients developed acquired resistance, and many occurred in the CNS. An attempt to enhance the intracranial effect of crizotinib is dose escalation. In some case reports, the single dose of crizotinib has been increased from 250 mg to 1000 mg in the standard regimen; some have been combined with other drugs while increasing crizotinib to 600 mg.
In dose-increasing usage, the effect has been improved to a certain extent; the explanation for this is that crizotinib has a large dose, and the combination of drugs improves the effectiveness of ALK rearrangement tumors for other drugs.
The current second-generation ALK inhibitors seritinib, alectinib and brigatinib have a maximum effective rate of 58-70%. Studies have shown that certain mutations that make the second-generation tyrosine kinase inhibitors resistant can be targeted by other tyrosine kinase inhibitors.
There is evidence that the fusion of EML4-ALK is related to Hsp90, which plays an important role in the growth of many types of tumors. ALK rearrangement NSCLC cells, such as ganetespib, AUY922, retispamycin, IPI-504 and other drugs, can cause apoptosis and tumor regression through the degradation of ALK fusion protein.
The combination therapy of crizotinib plus IPI-504 can already achieve a very exciting tumor regression effect. In addition, crizotinib-resistant tumor cells also showed sustained sensitivity to Hsp90 inhibitors. Currently there are related Phase 1 and Phase 2 trials.
To overcome the resistance of crizotinib, there are also plans for downstream or other activation pathways. For example, there are related studies on mTOR, PI3K, IGF-1R, etc. The next-generation sequencing technology is expected to develop other anti-drug technologies and further experiments against cyclin-dependent kinases, aurora kinases and epigenetic regulators.
Adjust ALK inhibitors to improve their CNS permeability or activity
The second-generation ALK inhibitors with unique properties can cross the blood-brain barrier, thus selectively solving the problem of increasing the dose within the CNS. In a mouse model, the permeability of X-396 in the brain is equivalent to crizotinib, X-396 can theoretically reach more than four times the half inhibitory concentration in cerebrospinal fluid, and the concentration of crizotinib in cerebrospinal fluid is It is half of the half inhibition concentration! The increased efficacy of X-396 may be combined with hydrogen ions and increased intracranial effect at the same concentration when combined with ALK.
X-396 is currently undergoing clinical trials to assess whether it is clinically effective. The structure of other second-generation drugs is similar to that of X-396, and the cerebrospinal fluid-plasma concentration ratio of the drugs has also increased, which will have a better effect on intracranial tumors.
Theoretically, there are ways to increase the permeability of CNS by reducing the molecular volume, increasing its fat solubility, and modifying it to avoid binding to common efflux proteins on the blood-brain barrier. Alectinib has strong CNS permeability because of poor binding to P glycoprotein. Another second-generation ALK inhibitor PF-06463922 is designed to avoid its outflow at the blood-brain barrier and tumor surface and specifically increase the permeability to CNS and tumor. The principle is
to reduce molecular weight, increase fat solubility, Changed the number of hydrogen bonds.
Regulate the blood-brain barrier to increase permeability
Another solution to increase the concentration of drug cerebrospinal fluid is to increase the permeability of the blood-brain barrier. As mentioned earlier, the blood-brain barrier has a passive and active role: P glycoprotein is the main factor that actively removes substances. Therefore, one of the solutions is to inhibit the binding of P glycoprotein to the drug.
In the mouse model, the addition of elacridar can make the intracranial concentration of crizotinib up to 70 times after 24 hours, and the plasma concentration is normal, which may be due to saturation of intracranial absorption. Since the combined effect of the drugs is good, human trials should be considered, and attention should be paid to the study in combination with ceritinib and other drugs.
Another research direction focuses on vasoactive kinin, such as the application of kinin analogues to regulate the blood-brain barrier through prostaglandins and nitric oxide. Animal experiments have shown that this regimen can increase the CNS intake of the drug and increase overall survival. Vasoactive kinin combined with ALK inhibitors can increase the intracranial body, and can be quantitatively studied through cerebrospinal fluid sampling or clinical prognosis.
Adjustment of tumor microenvironment
Substantial evidence has shown that metastatic tumor cells are more likely to invade abnormal microenvironments such as blood vessels, lymphatic vessels and extracellular matrix. This abnormal microenvironment increases tumor progression, metastasis, and treatment resistance, which is particularly important for mutations leading to more metastases.
One theory is that normalizing the physiological state of healthy tissue can improve the patient’s prognosis. One of the main goals of normalization is to deal with the disordered vascular structure. The vascular perfusion of these blood vessels is reduced, which reduces the drug reaching the target tissue and causes local hypoxia. Hypoxia not only increases tumor progression and metastasis, but is also a sign of tumor invasiveness and reduces the effects of oxygen-dependent treatments such as radiotherapy.
VEGF inhibitors have been used to reduce disordered angiogenesis and restore the vascular microenvironment. In the mouse glioblastoma model, the VEGF inhibitor bevacizumab reduces hypoxia and enhances the effect of radiotherapy. This type of benefit can also be seen in cytotoxicity treatment when blood vessels are normalized, but no studies have been conducted on the combination of ALK and VEGF inhibitors.
ALK rearranges the role of NSCLC midbrain radiotherapy
The age of patients with ALK rearrangement tumors is relatively low, which is one of the key issues to be considered when treating intracranial lesions, because many patients are still working, have young children, and need to take care of their families. This requires protection of cognitive functions, especially important cognitive functions.
With the discovery of ALK inhibitors, the survival expectancy of these patients has been calculated in years, and priority should be given to long-term control with minimal long-term side effects. Patients with ALK rearranged NSCLC have prolonged survival even if they have brain metastases, which changes the purpose of treatment from simple palliative to maintaining the quality of life and cognitive function of patients.
Due to the prolonged survival time, patients with smaller metastases are strongly recommended to consider stereotactic radiosurgery, because WBRT will destroy the formation of memory and the recall of information. Nonetheless, diffuse brain metastasis still requires WBRT, which may be an opportunity to utilize the damaged blood-brain barrier and simultaneously apply targeted drugs to increase the concentration of cerebrospinal fluid.
There are few data on the side effects of crizotinib combined with radiotherapy. Therefore, patients receiving crizotinib for intracranial lesions must stop the drug for at least 1 day before radiotherapy. In some patients, crizotinib was used again after radiotherapy in the brain, and it was found that crizotinib is still effective for extracranial lesions after radiotherapy, which is also consistent with the low CNS permeability of drugs before radiotherapy.
Studies have reported that patients with ALK rearrangement brain metastases have significantly longer survival time after radiotherapy than patients with ALK wild-type. This may be due to increased permeability of the blood-brain barrier and decreased P-glycoprotein expression within weeks of radiotherapy. Despite the increased risk of side effects from combination therapy, it is easier to conduct combined therapy studies with fewer side effects of ALK inhibitors, and the enhanced permeability after radiotherapy can be further targeted again.
The point to be emphasized is the sequence of targeted therapy and radiotherapy. Various related studies have shown that ALK inhibitors can benefit from continued application, but there is no comparison of different ALK inhibitors. Studies have shown that the use of crizotinib after WBRT can also improve the control of intracranial lesions. In conclusion, the data indicate that ALK inhibitors can be recommended after radiotherapy, and may improve drug efficacy.
Guidelines and future directions
In cases of progress or brain metastasis, multidisciplinary discussions involving oncology, radiotherapy, neurosurgery, etc. need to be considered. The National Comprehensive Cancer Treatment Network recommends that patients with asymptomatic brain metastases need to use crizotinib alone. For the progression of intracranial lesions, SRS or WBRT should be considered when there are symptoms, followed by the application of ALK inhibitors. If the lesion can be treated with SRS, consideration should be given to avoiding whole brain radiotherapy so as not to affect cognitive function.
The guidelines recommend that crizotinib or ceritinib can still be used in patients with asymptomatic progression. Case reports indicate that the duration of progression-free survival varies between crizotinib and radiotherapy after radiotherapy. The effectiveness of second-generation ALK inhibitors should encourage clinicians to use these drugs as the disease progresses to enhance intracranial treatment.
Due to the high probability of intracranial relapse when applying ALK inhibitors, frequent MRI examinations are required after radiotherapy to assess the progress of metastases. For WBRT-treated metastases, it is recommended to perform MRI every 3 months. Of course, ALK rearrangements will benefit from it.
If the metastasis is further exacerbated, the clinician should change the ALK inhibitor used, and if symptoms appear, they should be re-radiated; from the perspective of risk-benefit ratio, they still prefer to be re-treated. For ALK rearranged intracranial lesions, if radiotherapy plus ALK inhibitors progress, the combination of pemetrexed seems to be the best option.
The modification of ALK targeted inhibitors to overcome the common drug resistance, enhance its permeability to CNS, and improve its binding force and effect after reaching the target, more and more research in this regard. In the near future, the concentration of these drugs in the CNS will be higher and can be applied sequentially when intracranial drug resistance appears.
With the increase in available DNA testing techniques, patients may be advised to repeat biopsies to assess the mechanism of drug resistance as they progress, which will guide clinical application of tyrosine kinase inhibitors that are more effective.
Conclusion
The brain metastasis rate of all cancers is increasing. One of the programs to increase the efficacy is to make an article about the genetic abnormalities of specific cancers, such as ALK rearrangement. In patients w
ith ALK rearranged lung cancer, crizotinib has shown to be superior to standard chemotherapy, but its control of intracranial lesions is still not ideal. This problem, and the emergence of mutations related to the effects of crizotinib, have triggered the emergence of many second-generation anti-ALK agents that act on different pathways or increase the permeability of the blood-brain barrier.
In the second-generation anti-ALK preparations, such as ceritinib, although the P glycoprotein still partially pumps it out, it has shown substantial control of intracranial lesions. The intracranial effect depends on the efficacy of the drug and the blood brain Barrier permeability may have other unexplained factors.
Because ALK-targeted drugs are relatively new, there is still little research on the combination of this drug and radiotherapy in the case of brain metastases, but this is also one of the important and potentially effective programs in the combination therapy. In conclusion, it has been clarified that patients with ALK rearrangement NSCLC can actively survive longer after benefiting from the new targeted drugs.
As far as the cognition and function of CNS metastatic lesions are concerned, further research on new treatment options is needed to solve the problems of quality of life and functional prognosis. There is also an urgent need to study drug resistance mechanisms. Of course, the first thing that matters is that clinicians should strengthen the study of patients with brain metastasis to clarify the optimal time for the application of first- and second-generation tyrosine kinase inhibitors in NSCLC patients, as well as the optimal time for brain radiotherapy.
