Is immunotherapy effective for brain metastases from lung cancer?

The brain is a common metastatic site for non-small cell lung cancer (NSCLC). 30% of NSCLC patients will develop brain metastasis during the entire course of the disease. The prognosis of patients will be very poor, with a median overall survival (OS) of about 3-14.8 months, and the current systemic treatment options still cannot meet clinical needs.

immunotherapy is widely accepted as a very effective emerging cancer treatment method. immune checkpoint inhibitor (ICI) is considered to be the most successful immunotherapy so far.

Tumor immunotherapy usually targets immune cells and achieves anti-tumor effects by restoring the function of immune cells, which can bring long-term sustained clinical benefits.

In recent years, the US FDA has successively approved a number of clinical indications for immune checkpoint inhibitors (ICI), mainly including PD-1 inhibitors and CTLA-span/CTLA-span/CTLA -4 inhibitors. There are also many PD-1 monoclonal antibodies approved for marketing in China,Greatly increase the availability of drugs for cancer patients.

But for non-small cell lung cancer patients with brain metastases, most clinical trials exclude patients with brain metastases; only a small part of the group has asymptomatic or controlled brain metastases Patients and the results of the retrospective analysis, we will make a specific analysis today.

Brain metastasis mechanism:

The blood flow cell secretion of the tumor cells firstly starts from the primary effect of the reduction in the blood circulation of the tumor cells. It adheres to the vascular endothelium, and with the help of VEGF and TAM (tumor-associated macrophages ), it migrates to the outside of the blood vessel and continuously grows and metastasizes by stimulating new blood vessels. Once it enters the brain parenchyma, the immune cells in the cranial The environment begins to play a role, and astrocytes and microglia play an important role. Activated astrocytes accelerate tumor proliferation and tissue invasion in the brain, while microglia differentiated into M2 type begin to form a dense capsule-like protective cover around the tumor to prevent the invasion of infiltrating lymphocytes.

used to think that under normal circumstances the brain is an immune organ without lymphocyte infiltration, immune suppression factors, and the brain will secrete IDO, immune-suppressive factors, etc. ,It has only recently become clear that the Central Nervous System (CNS) is not immune exemption but unique immunity, which is continuous immune surveillance through the meninges; and T cells can penetrate the blood-brain barrier and blood-tumor barrier; when brain metastasis occurs, intracranial immune immunity The microenvironment changes, and the activated lymphocytes infiltrate extensively, including both cytotoxic T cells, immunosuppressive or exhausted T cells, and a large number of monocytes infiltration.

Some scholars analyzed 116 specimens with brain metastasis, and showed that the expression of PD-L1 was 26.2%; more than 50% of the specimens showed CD3, CD8 or CD45RO+ TIL infiltration, and the degree of infiltration was related to the brain. Tissue edema is closely related to the prognosis of patients, which is the environmental basis for immunotherapy to play a role.

For lung cancer brain metastasis , the mechanism of immunotherapy determines whether the drug itself passes through the blood-brain barrier is not important. The key to the effect is whether to use more lethal drugs More T cells enter the tissue surrounding the tumor in the brain parenchyma. Animal models show that compared with patients without extracranial metastases, patients with extracranial metastases have a higher response rate to ICI in patients with extracranial metastases; further studies have found that the tumor response is improved The reason is not to increase the number of brain infiltrating lymphocytes, but to complete the killing effect by transporting extracranial T cells into the brain, that is, to mobilize limited TIL and concentrate the advantages of T cells to complete the brain transfer The killing.

In 2016, "Lancet oncology" published a prospective phase II clinical study of pembrolizumab in untreated patients with malignant melanoma and NSCLC brain metastases.The subjects of this study are: patients with untreated malignant melanoma or non-small cell lung cancer with brain metastases; at least one metastasis with a longest diameter between 5-20 mm; no related neurological symptoms or hormone therapy; non-small cell lung cancer Patients need to be positive for PD-L1 expression. Dosing regimen: Pembrolizumab 10 mg/kg, once every 2 weeks. Study endpoint: remission rate of brain metastases.

span8 brain metastases in 18 cases of brain metastases in CL 8% of patients with 4 cases of brain metastases: 56 cases of CCL4spanspan NS Six patients (33%) were in remission; pembrolizumab was observed to be effective and tolerable safety in patients with malignant melanoma and NSCLC brain metastases. This result indicates that pembrolizumab has a certain effect in patients with untreated or advanced brain metastases.

A CheckMate063 & CheckMate 017 & 057 pooled analysis at the ASCO meeting in the same year showed that treated patients with non-small cell lung cancer using dovutumab for brain metastasis. The median OS was longer in the treatment of (8.4 months vs. 6.2 months), and the incidence of adverse reactions of nivolumab was lower than docetaxel.

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Real-world efficacy of nivolumab ( Opdivo ) in the treatment of patients with brain metastases from NSCLC (non-small cell lung cancer). The trial included 1588 NSCLC patients from 153 participating EAP (expande access program) project centers. A total of 409 patients had brain metastases at baseline, accounting for more than a quarter (26%), which means real-world brains. The incidence of metastasis is not low. Of these 409 patients, 29% had received hormone therapy, 18% had received concurrent hormone radiotherapy, and 59% had received brain radiotherapy. It is worth noting that these patients have taken O drugs after multiple treatment failures, and 46% of them have been treated with ≥3 lines in the past. The results showed that the ORR (objective effective rate) of patients with brain metastases was 17%, and the DCR (disease control rate) was 39%, of which 4 cases had complete remission (CR). Therefore, the real world shows that the efficacy of nivolumab in patients with brain metastases after treatment is very close to that of the overall population (the overall population ORR is 18%, DCR is 44%), and the safety is comparable to all patients.

The trial is an international multi-center, randomized phase III study. The study included patients with non-small cell lung cancer who had previous treatment lines ≥1 line, and did not exclude brain metastases and EGFR/ALK mutations. The trial divided these patients into two groups: one group was given intravenous atezolizumab (Atezolizumab, T drug) 1200mg/3 weeks, and the other group was given docetaxel 75mg/m2/3 weeks. The subgroup results showed that in patients with brain transfer, the overall survival of the T drug group was 4.1 months longer than that of the multi-chemotherapy group, and the T drug group had a trend of benefit for OS. For patients without brain transfer, the OS of T drug was prolonged by 3.9 months compared with chemotherapy, and the difference was very significant. It can be seen that atezolizumab immunotherapy improves the overall survival rate of non-small cell lung cancer patients with brain transfer, showing a trend of prolonging overall survival.

WC The clinical prognosis of patients with BM after treatment with immune checkpoint inhibitors.

results are shown generally ORR was 22.7% (no BM) vs.20.6% (the presence of BM) p = 0.484; intracranial ORR (active BM): 27.3% (PD-L1+ 35.7% vs. PD-L1- 11.1%); 2 cases of BM patients had pseudo brain tumor PD (0.8%); BM+ vs. BM- patients with brain tumors have higher PD: 46.3% vs. 11.4%,p<0.001;> multivariate analysis , the baseline brain metastasis status of has nothing to do with the effect of ICI treatment; patients with brain metastases have a higher incidence of intracranial progression, especially those with active brain metastases; Patients with brain metastases who are in good physical condition and not using corticosteroids can receive ICI treatment , but it is recommended to perform routine brain imaging examinations, which is particularly important for patients with active brain metastases.

The results of a prospective study of span NS4SJ 255 patients published on span NS in 2019 using span NSJ 255 in the spanRIC vs. BM- was 20.6% vs. 22.7%. The median PFS and OS of BM+ were shorter than BM-. However, in multivariate analysis, BMs in NSCLC patients treated with ICI were not associated with poor survival. has the best prognosis for patients with stable brain metastases, no need to use steroids at the beginning of treatment, and good ds-GPA (diagnostic graded prognostic assessment).

In general, more and more research data suggest that The efficacy and safety of immune checkpoint inhibitor therapy in patients with brain metastases are consistent with the general population. The next step is to explore combined treatment modes such as radiotherapy combined immunization, anti-vascular combined immunization, and optimization of brain metastasis populations to further improve the efficacy of brain metastasis patients.

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