One Article | From the latest consensus, how should patients with lung cancer brain metastases be treated?

One of the most common distant metastases of lung cancer is the brain.
Patients with brain metastases from lung cancer have a poor prognosis, and the natural average survival time is only 1 to 2 months.

The rapid development of surgery, radiotherapy technology and medical treatment provides more and more treatment options for patients with lung cancer and brain metastases.

In order to further standardize the treatment of patients with lung cancer brain metastases in China, the "Chinese Guidelines for the Treatment of Lung Cancer Brain Metastases (2021 Edition)" was released recently.

The treatment of patients with lung cancer brain metastasis should be based on systemic treatment for brain metastases, including surgery, whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRT), medical treatment, and other multidisciplinary comprehensive treatments.
Its purpose It is to treat metastatic lesions, improve patients' symptoms and quality of life, and maximize the survival time of patients.

(1) Principles of treatment (2) Medical treatment 1 Chemotherapy is based on cisplatin and carboplatin-based platinum drugs, combined with third-generation cytotoxic drugs can bring survival to patients with non-small cell lung cancer (NSCLC) brain metastases Benefit.

Pemetrexed has good anti-tumor activity in non-squamous NSCLC and is an important drug for the first-line treatment and maintenance treatment of non-squamous NSCLC patients.

Pemetrexed combined with platinum can also control intracranial lesions in patients with NSCLC brain metastases.
The overall survival time (OS) of patients in the chemotherapy group was significantly longer than the natural survival time.

For patients with brain metastases from NSCLC who have previously received WBRT or systemic chemotherapy, temozolomide can be used to improve disease control rate (DCR) and prolong OS.

Sequential or simultaneous application of temozolomide (or combined with other chemotherapeutics) and WBRT, especially simultaneous application, can increase the DCR of intracranial metastases and provide new treatments for patients with NSCLC brain metastases.

For the first-line treatment of patients with extensive-stage small cell lung cancer (SCLC) with asymptomatic brain metastases, systemic chemotherapy can be given priority, and WBRT should be considered after the end of systemic chemotherapy or when brain metastases have progressed.

2 Molecular targeted therapy (1) The results of multiple studies on EGFR-TKIs show that EGFR-TKIs treatment of advanced NSCLC patients with sensitive mutations in the EGFR gene can achieve a better objective remission rate.

For patients with NSCLC brain metastases, the intracranial remission of different EGFR-TKIs has different degrees of difference.

The first generation of EGFR-TKIs includes gefitinib, erlotinib and icotinib.

At present, the studies of gefitinib or erlotinib in patients with EGFR gene-sensitive mutant NSCLC brain metastases are mostly retrospective or phase II clinical studies, and the intracranial objective response rate (ORR) varies greatly between different studies.
About 50% to 80%.

The blood-brain barrier permeability and cerebrospinal fluid concentration of erlotinib are significantly higher than that of gefitinib.

However, a retrospective study compared erlotinib and gefitinib in the first-line treatment of patients with EGFR gene-sensitive mutant NSCLC brain metastases, and the results showed that the difference in intracranial ORR between the two was not statistically significant.

The results of a phase III randomized controlled clinical study (BRAIN study) of icotinib versus WBRT±chemotherapy in patients with EGFR gene-sensitive mutations in NSCLC brain metastases showed that icotinib significantly improved the intracranial ORR of patients with brain metastases ( They were 65% and 37%, respectively, P=0.
001) and intracranial median PFS (10 months and 4.
8 months, respectively, HR=0.
56, P=0.
014).

The second-generation EGFR-TKIs include afatinib and dacomitinib, and there are few intracranial efficacy data in patients with EGFR gene-sensitive mutant NSCLC brain metastases.

The intracranial ORR of afatinib for post-line treatment of patients with EGFR gene-sensitive mutant NSCLC brain metastases was 35%, and the intracranial DCR was 66%.

The retrospective study data of first-line afatinib used in patients with EGFR-sensitive mutant NSCLC brain metastases showed that the intracranial ORR was 72.
9%.The results of a subgroup analysis of brain metastases in the LUX-Lung7 study showed that there was no statistically significant difference in OS between afatinib and gefitinib in patients with EGFR gene-sensitive mutant NSCLC patients with brain metastases at baseline.

Since patients with brain metastases were not included in the ARCHER1050 study, there is still a lack of evidence for dacomitinib in the treatment of brain metastases in NSCLC.

The third-generation EGFR-TKIs include osimertinib, ametinib, and vometinib, which have shown good efficacy in controlling brain metastases in patients with NSCLC.

Animal experiments show that the distribution of osimertinib in brain tissue is higher than that of gefitinib and afatinib.
The peak concentration of the drug (maximum concentration, Cmax) brain/plasma cmax ratio (brain/plasma cmax ratio) In osimertinib, gefitinib and afatinib, they were 3.
41, 0.
21 and <0.
36, respectively.

In the FLAURA study, the analysis of the brain metastasis subgroup of patients showed that the median PFS benefit of osimertinib in the first-line treatment of EGFR gene-sensitive mutation-positive NSCLC patients was significantly better than the first-generation EGFR-TKIs (19.
1 and 10.
9 months, respectively) ).

In the AURA3 study, the results of the analysis of the subgroup of patients with brain metastases showed that the median intracranial PFS (11.
7 and 5.
6 months, respectively) and intracranial ORR (70% and 5.
6 months, respectively) of patients with EGFR T790M mutation-positive NSCLC treated by osimertinib 31%) compared with pemetrexed combined with platinum chemotherapy group.

Based on the results of the APOLLP study of Chinese patients with NSCLC brain metastases, the intracranial ORR of osimertinib for EGFR T790M mutation-positive NSCLC patients after EGFR-TKIs treatment progressed was 68.
8%, and the intracranial DCR was 90.
9%.

Osimertinib also shows good curative effect on NSCLC patients with meningeal metastases.
The BLOOM study results show that for advanced NSCLC patients who have progressed after the first or second generation EGFR-TKIs treatment and have meningeal metastases, follow-up applications The intracranial ORR of osimertinib treatment was 62%, and the intracranial remission time was 15.
2 months. The retrospective analysis of the AURA series of studies showed that for NSCLC patients with EGFR T790M mutations and meningeal metastases, the intracranial ORR of osimertinib was 55%.

The results of another study of NSCLC patients with pial metastasis and EGFR gene sensitive mutations showed that the osimertinib treatment group was better than other treatment groups (including other EGFR-TKIs, chemotherapy, intrathecal chemotherapy, immunotherapy, Whole brain radiotherapy, etc.
) OS was significantly prolonged (17.
0 and 5.
5 months, respectively, P<0.
01), and it was not related to the mutation status of EGFR T790M.

Ametinib and vomitinib are domestic third-generation EGFR-TKIs, and patients with brain metastases were included in the Phase II key registration clinical study.
The intracranial ORR of ametinib in the treatment of EGFR T790M mutation-positive NSCLC patients with brain metastasis is 60.
9%, intracranial DCR was 91.
3%, and intracranial median PFS was 10.
8 months.

The intracranial ORR of vormetinib in patients with EGFR T790M mutation-positive NSCLC patients with brain metastases was 65.
2%, the intracranial DCR was 91.
3%, and the intracranial median PFS was not achieved; the intracranial ORR of the 160 mg dose group was 84.
6%.
The median intracranial PFS was 19.
3 months.

(2) ALK-TKIs Currently, ALK-TKIs that have been approved for marketing in China include crizotinib, aletinib, ceritinib and ensatinib.

Multiple studies have shown that compared with pemetrexed combined with platinum-based chemotherapy, crizotinib has a higher control rate of intracranial metastases in patients with ALK fusion gene-positive NSCLC brain metastases, but compared with second-generation ALK-TKIs, The efficacy of intracranial metastases is not good.

In a phase III clinical study of aletinib versus crizotinib in the first-line treatment of ALK fusion gene-positive advanced NSCLC patients, analysis of the brain metastasis subgroup of patients showed that the intracranial ORR of aletinib was 81%, and the intracranial remission was sustained The time (DOR) was 17.
3 months; the intracranial ORR of crizotinib was 50%, and the intracranial DOR was 5.
5 months. In addition, a study analyzed the results of two phase II clinical studies of NSCLC patients with brain metastases treated with aletinib after crizotinib resistance.
The intracranial ORR of aletinib was 64%, The DOR was 10.
8 months.

Ceritinib's ASCEND series of studies all included different proportions of patients with brain metastases, and the intracranial ORR was 30% to 70%.

The patients enrolled in the ASCEND7 study were all patients with symptomatic or advanced brain metastases and/or meningeal metastases with ALK fusion gene-positive NSCLC patients.

The results showed that whether or not they had received crizotinib treatment or brain radiotherapy before, ceritinib showed good intracranial efficacy.
For NSCLC patients with meningeal metastases, the intracranial ORR was 20%.

The results of a phase II clinical study showed that the intracranial ORR of patients with ALK fusion gene-positive NSCLC brain metastases who progressed after crizotinib treatment with Ensatinib was 70%.

In the phase II clinical study of brigatinib, the results of a subgroup analysis of patients with brain metastases showed that the intracranial ORR of patients with brain metastases who had progressed after treatment with crizotinib in the 90 mg dose group was 42%, and that in the 180 mg dose group The intracranial ORR was 67%.

In a phase III clinical study of brigatinib and crizotinib in the first-line treatment of ALK fusion gene-positive NSCLC, the results of a subgroup analysis of brain metastases showed that the intracranial ORR of the brigatinib and crizotinib groups were respectively 78% and 29%.

In a phase III clinical study of loratinib and crizotinib in the first-line treatment of ALK fusion gene-positive NSCLC patients, the results of a subgroup analysis of patients with brain metastases showed that the intracranial ORR of the loratinib group was 82%, and the intracranial CR The rate was 71%; the intracranial ORR of the crizotinib group was 23%, and the intracranial CR rate was 8%.

(3) ROS1-TKIs Crizotinib is currently the only approved ROS1-TKI in China, which can be used as a treatment option for patients with NSCLC brain metastases.

The summary results of the clinical studies of ALKA-372-001, STARTRK-1 and STARTRK-2 showed that the intracranial ORR of entratinib for patients with ROS1 fusion gene-positive NSCLC brain metastases was 55.
0%. 3 The anti-angiogenic drug bevacizumab combined with chemotherapy is safe and effective for patients with non-squamous NSCLC brain metastases.

In addition, bevacizumab also has a certain effect on brain necrosis and brain edema caused by radiotherapy.

4Immunotherapy immune checkpoint inhibitor programmed death receptor 1 (programmed death protein-1, PD-1) and programmed death receptor ligand 1 (programmed death ligand-1, PD-L1) have significant effects on brain metastases from lung cancer Certain therapeutic effect.

Because most prospective clinical studies of lung cancer immunotherapy have excluded patients with brain metastases, the current studies of PD-1 and PD-L1 monoclonal antibodies in the treatment of lung cancer brain metastases are mostly retrospective analyses, and these studies have shown efficacy.

5 Intrathecal injection Intrathecal injection is to inject drugs directly into the subarachnoid space to increase the concentration of the drug in the cerebrospinal fluid, thereby killing tumor cells.

The route of administration includes intracerebroventricular chemotherapy via lumbar puncture subarachnoid cavity and intracerebroventricular chemotherapy via Ommaya reservoir.

Compared with intrathecal injection via lumbar puncture, Ommaya reservoir is safer and can avoid the risk of accidentally injecting the drug into the epidural space by intrathecal injection; for patients with thrombocytopenia, It can avoid the occurrence of epidural and subdural hematoma.

Commonly used chemotherapeutic drugs for intrathecal injection include methotrexate, cytarabine, and cetepa.

Intrathecal injection of chemotherapy drugs while giving glucocorticoids can reduce the neurotoxicity of chemotherapy drugs and relieve symptoms.

Routine, biochemical and cytological examinations of cerebrospinal fluid during lumbar puncture can help monitor the efficacy and guide treatment.

Intrathecal chemotherapy is an important treatment for NSCLC meningeal metastasis.
There is no clear supporting evidence for brain parenchymal metastasis.

(3) Symptomatic treatment.
Patients with brain metastases from lung cancer are often accompanied by headaches, nausea, and vomiting caused by increased intracranial pressure.
Patients with intracranial hypertension are tumor emergencies.
The first is to actively give dehydration and diuretic treatment to reduce intracranial pressure.
Alternative drugs include mannitol, glycerol fructose and furosemide. Glucocorticoids, especially dexamethasone, can reduce brain edema and improve the quality of life of patients with brain metastases, but it does not improve the prognosis.

The second is to control symptoms, including anti-epileptic and analgesic treatments.
Since anti-epileptic drugs cannot reduce the risk of seizures in patients with NSCLC brain metastases without epilepsy symptoms, they are generally only used for patients with seizure symptoms and are not used for preventive applications.

Patients with obvious headaches can be treated with symptomatic pain relief.

References: Chinese Medical Doctor Association Oncologist Branch, Chinese Medical Care International Exchange Promotion Association Medical Oncology Branch.
Chinese treatment guidelines for lung cancer brain metastases (2021 edition) [J].
Chinese Journal of Oncology, 2021, 43(3):269-281.
DOI: 10.
3760/cma.
j.
cn112152-20210104-00009.
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