BMs occur in 10–30% of cancer patients worldwide, and the incidence of BM has been growing because of improvement of systemic therapeutic effects. Lung cancer is prone to BM. The median interval time for NSCLC to development of BMs is 16 months according to the natural history of NSCLC BMs. Median interval times are 29, 19, 16 and 13 months for Stage I–IV patients, respectively [7]. The present patient had multiple BMs at 16 months after surgery. WBRT is an effective local treatment, usually recommended to patients with multiple BMs. However, WBRT-induced neurocognitive impairment has led physicians to postpone WBRT and to poor patient compliance [8, 9]. Chemotherapy is another choice for patients with multiple BMs, but the efficiency of most chemotherapeutic agents is disappointing because of the inability of drugs to cross the BBB [10, 11]. In addition, some patients refuse chemotherapy for the fear of adverse effects and severely reduce their quality of life [12]. Recently, an increasing number of targeted drug therapies have been used to treat BMs in lung cancer patients. It is reported that small-molecule TKIs can cross the BBB and accumulate in BMs [13]. Small-molecule TKIs significantly prolong the survival of patients with BMs with driver gene mutations, and are well tolerated by patients [14]. The present patient only had multiple BMs without other metastases that could be easily aspiration biopsy. We performed liquid biopsy and postoperative lung pathological tissue assay, but did not find any driver gene mutation.
Neoangiogenesis can promote primary NSCLC proliferation, invasion and metastasis. Formation of new blood vessels around colonized macrometastases is essential for the growth of BMs [15, 16]. Antiangiogenic therapy is a theoretically ideal target therapy for BMs. Vascular endothelial growth factor (VEGF) promotes cancer angiogenesis through binding with its receptor. Bevacizumab, an anti-VEGF recombinant humanized monoclonal antibody, suppresses VEGF-induced angiogenesis. In patients with advanced non-squamous NSCLC, chemotherapy plus bevacizumab achieves superior efficacy to that of chemotherapy alone as a first-line treatment [17]. For NSCLC with EGFR mutation, bevacizumab plus TKI treatment also improves the outcome compared with TKIs alone [18]. BMs were initially a contraindication to treatment with bevacizumab because of the adverse effect of intracranial bleeding. However, the clinical data show that bevacizumab treatment does not increase the risk of cerebral haemorrhage [19]. Bevacizumab is effective to treat patients with large peritumoral edema with mass effect [20]. In the present case, the peritumoral edema with mass effect was quickly reduced after two cycles of treatment, which may have been partly due to the antiedema effects of bevacizumab. Usually, bevacizumab is used in combination with chemotherapeutics, small-molecule TKIs or in combination with other effective treatments because bevacizumab alone is not sufficiently effective against tumors.
The disruption of immune checkpoints contributes to the development and progression of lung cancer. A high rate of tumor lymphocyte invasion has been found in the brain microenvironment of patients with BMs [21]. Recently, combination of immune checkpoint inhibitors (ICIs) with chemotherapy showed superior antitumor efficacy than chemotherapy alone against multiple malignancies. The KEYNOTE-189 study showed that pembrolizumab significantly reduced mortality risk of NSCLC with BM [22]. A further pooled analysis of KEYNOTE-021, 189 and 407 demonstrated that median OS of patients treated with pembrolizumab plus chemotherapy (18.8 months) was 2.5-fold higher than that of chemotherapy alone (7.6 months) in patients with BMs across all PDL-1 subgroups [23]. The application of ICIs in NSCLC patients with BMs is limited because most of the pivotal trials excluded patients with BMs, or only selected patients were allowed. A small amount of evidence for ICI treatment of BMs also comes from a later subgroup reanalysis of the finished clinical trial.
ICI displays antitumor effects by reversing the inhibitory effects of tumor cells on immune cells and driving activated immune cells to attack tumors. Pembrolizumab has been assumed to cross the BBB [24]. Furthermore, pembrolizumab conjugated effector T cells redistribute to the brain after activation because abundant T cell clones and lymphatic vessels have been observed in BMs of NSCLC [25, 26]. The activation of immune cells involves seven steps [27]. The most effective professional antigen-presenting cells, dendritic cells, are inhibited from maturing by VEGF, a factor that also increases immune suppressive myeloid derived suppressor cells (MDSCs) [28]. In addition, VEGF promotes tumor angiogenesis, thus suppressing infiltration of T cells into tumors, and enhancing tumor growth. Bevacizumab might not be able to cross the BBB, but it exhausts plasma VEGF, and subsequently depletes VEGF in tumor and adjacent tissues. The immune suppressive microenvironment has been shown to be reversed by normalizing the tumor vasculature through VEGF inhibition (Fig. 3). This treatment also increases immune cell infiltration into tumors through a variety of mechanisms, including the transformation of immune suppressive macrophages into immune permissive cells, activation of the endothelium, and subsequent increases in intra-tumoral Th1 chemokine and cytokine levels [29]. In chemotherapy-naive patients with non-squamous non-small-cell lung cancer, the IMpower150 trial demonstrated significant improvements in progression free survival and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel [30]. As shown in Table.1, several ongoing clinical trials involving patients with BMs are exploring the efficacy of combined ICI and antiangiogenic therapies in solid cancer, and might provide further evidence in a few years [31, 32]. However, to date, no published evidence supports this non-chemotherapy regimen is effective in patients with NSCLC with BMs. The present patient benefited from pembrolizumab plus bevacizumab treatment and achieved an impressive PFS interval. The results preliminarily demonstrated that the combination of bevacizumab and pembrolizumab was effective and tolerable. Although patients might develop hypopituitarism, an immune-related adverse event, our patient did not have an extracranial tumor and had only mildly symptomatic BMS. The efficacy and safety of bevacizumab plus pembrolizumab in patients with NSCLC with BMs requires further clinical study. The present case demonstrated that pembrolizumab plus bevacizumab was an effective treatment, but it is important to monitor adrenal function regularly in order to diagnose adrenal insufficiency and prevent adrenal crisis.