The Emerging Role of Targeted Therapy and Immunotherapy in the Management of Brain Metastases in Non-Small Cell Lung Cancer

Lung cancer is the worldwide leading cause of cancer-related mortality in men and second leading in women. Brain metastases (BM) account for 10% of non-small cell lung cancer (NSCLC) patients at initial presentation, with another 25–40% developing BM during the course of their disease. In the last decade, the field of precision oncology has led to the discovery of a multitude of heterogenous molecular abnormalities within NSCLC as well as the development of tyrosine kinase inhibitors that target them. In this review, the focus will be on targeted therapy and immunotherapy that show efficacy in BM rather than conventional treatment for multiple BM (such as surgical resection, WBRT, or stereotactic radiosurgery).

inTRODUCTiOn Lung cancer is the worldwide leading cause of cancer-related mortality in men and second leading in women (1). Brain metastases (BM) account for 10% of non-small cell lung cancer (NSCLC) patients at initial presentation (2), with another 25-40% developing BM during the course of their disease (3). The general metastatic NSCLC population survival is approximately 12 months, with a median progression-free survival (PFS) range from 3 to 6 months (4). BM are associated with poor prognosis, and the median survival ranges from 2.4 to 4.8 months for patients with BM who receive whole-brain radiation therapy (WBRT) (5). While the standard of care for BM remains radiotherapy, determining the optimal treatment between high-dose-focused radiations via stereotactic radiosurgery (SRS) alone versus WBRT remains controversial. A retrospective multi-institutional retrospective study showed a survival advantage in patients with fewer than four BM less than 4 cm in size (n = 189 for NSCLC) who were treated with SRS compared to those treated with WBRT [adjusted hazard ratio (HR) for NSCLC, 0.58; 95% confidence interval (CI), 0.38-0.87; P = 0.01] (6).
The treatment of BM is important in maintaining a good quality of life and limiting cognitive impairment and neurological dysfunction. In the last decade, the field of precision oncology has led to the discovery of a multitude of heterogenous molecular abnormalities within NSCLC as well as the development of tyrosine kinase inhibitors (TKIs) that target them (7).
Patients with untreated BM have been excluded from most clinical trials of systemic therapy for two reasons: (1) historically poor prognosis and (2) presumed poor blood-brain barrier (BBB) penetration by experimental drugs. Thus, the efficacy of these drugs in controlling NSCLC-related BM remains controversial.
In this review, the focus will be on targeted therapy and immunotherapy that show efficacy in BM rather than conventional treatment for multiple BM (such as surgical resection, WBRT, or SRS), or some combination of the three.

AnAPLASTiC LYMPHOMA KinASe (ALK)-ReARRAnGeD nSCLC
The control and prevention of BM have emerged as an important therapeutic issue as systemic therapies with TKIs continue to improve the duration of disease control for patients with oncogene-driven NSCLCs (8). BM have been reported in about 24% of ALK-rearranged NSCLC patients at diagnosis, making intracranial activity an important feature of all ALK-targeted therapies (9).
Furthermore, a retrospective pooled analysis of single-arm phase 1 and 2 studies of crizotinib in advanced ALK-positive NSCLC, PROFILE 1007 (13) and 1005 (12), demonstrated a median overall survival (OS) of 29.6 months for 120 patients who were allowed to continue crizotinib beyond progressive disease (PD) because they continued to derive clinical benefit from it. Only 18% of previously untreated BM patients achieved an overall intracranial response rate (ICRR), with an IDCR of 56% (95% CI, 46-66%) at 12 weeks (11) ( Table 1).
Inevitably, the brain is the most common site of PD after resistance to crizotinib because of inadequate central nervous system (CNS) penetration of the drug or the biological change in the tumor (28). Hence, progression of preexisting or development of new intracranial lesions in up to 70% of patients while receiving therapy was a common manifestation of acquired resistance to crizotinib (29). Most systemic cytotoxic chemotherapies and some TKIs seem to cross the intact BBB inefficiently (30).
Limited intracranial response of crizotinib might be related to lower concentrations of the drug in cerebrospinal fluid compared with the plasma concentration (0.616 versus 237 ng/mL, respectively, 5 h after administration of a 250 mg dose) (31).

Ceritinib
Ceritinib is another ALK inhibitor approved for ALK-rearranged NSCLCs that have progressed on crizotinib.
In vitro studies have found that ceritinib has a 20-fold greater potency to inhibit ALK than crizotinib and a 12-fold greater potency than alectinib (32). Ceritinib was found to cross the intact BBB in rats with a brain-to-blood exposure ratio of approximately 15%, although no human data exists (33).
In the phase 1 ASCEND-1 study, ceritinib demonstrated activity in ALK-rearranged locally advanced or metastatic cancer NSCLC patients, including both ALK-naïve and ALK-pretreated patients who had progressed following multiple lines of chemotherapy. Thirty one percent of the ALK inhibitor-naïve patients and 60% of ALK inhibitor-pretreated patients had BM, respectively. There were 94 patients with retrospectively confirmed BM and at least one post-baseline imaging. IDCR was 79% (15 of 19) in ALK inhibitor-naïve patients and 65% (49 of 75) in ALK inhibitor-pretreated patients (14). Overall ICRR was 34.5% (34) ( Table 1).

Alectinib
Alectinib is another powerful ALK inhibitor that has shown activity in crizotinib-resistant patients. A phase 2 study in ALKpositive NSCLC patients observed an objective response rate of 48% (35).
A hurdle in treating BM is achieving a higher rate of drug concentration in the brain because of the BBB. In animal models, alectinib has a high brain-to-plasma ratio (0.63-0.94) and activity in intracranial tumor implantation models (36). Alectinib penetrates into the CNS (2.69 nmol/L) where it is able to exceed the in vitro concentration for ALK inhibition (1.9 nmol/L) (35,37). Alectinib human studies show a 50% CNS distribution, but of a 12-fold lesser potency than ceritinib (33).
Unlike crizotinib and ceritinib, studies also suggest that alectinib is not a substrate of P-glycoprotein (P-gp), a key drug efflux pump typically expressed in the BBB (36), thus allowing for a higher rate of drug penetration through the BBB.
Pooled data analysis of NP28761 and NP28673, two single-arm phase 2 trials, evaluated the CNS effect of alectinib in pretreated ALK-rearranged NSCLC patients (19). NP28761 was limited More recently, J-ALEX, a phase 3 study comparing alectinib and crizotinib in treatment naive patients in Japan, showed an ORR of 85.4% in the alectinib group versus 70.2% in the crizotinib group (20). In patients with BM, the HR for alectinib versus crizotinib was 0.08 (95% CI, 0.01-0.61). The J-ALEX trial enrolled 14 patients with asymptomatic BM in the alectinib arm. Only one of the patients with BM treated with alectinib had progressed by the time of data cut-off (IDCR of 92.9%) (20) ( Table 1). Thus, reducing CNS progression in patients with ALK-positive NSCLC with alectinib could be achievable if alectinib is used in the first-line setting.
The Global ALEX trial is currently ongoing, also comparing alectinib versus crizotinib in first-line ALK-positive NSCLC but on a global scale. If the J-ALEX results are confirmed with this trial, alectinib could likely replace crizotinib as the standard firstline therapy for ALK-positive NSCLC in the future, especially those with BM.

Brigatinib, Lorlatinib, and Others
Brigatinib is an ALK inhibitor with preclinical activity against rearranged ALK and clinically identified crizotinib-resistant mutants. NCT01449461, a phase 1/2 single-arm, open-label, multicenter study in patients with advanced malignancies is ongoing. In a post hoc independent radiological review of patients with baseline BM, 6/12 patients with lesions ≥10 mm had a brain response (≥30% decrease in sum of longest diameters of target lesions) and 8/26 patients with only non-measurable lesions had disappearance of all lesions. ICRR for brigatinib with measureable BM was 50% and the IDCR was 83% (17). In non-measurable BM, the ICRR was 31%, IDCR was 85%, median intracranial PFS was 97 weeks, and median duration of intracranial response 82 weeks ( Table 1). In ALTA, a phase 2 trial of brigatinib, ORR in arm A (90 mg qd) was 46% while ORR in arm B (90 mg qd for 7 days followed by 180 mg qd) was 54%. Seventy-one percent (arm A) and 67% (arm B) had BM (21) ( Table 1).
Since CNS progression is a common site of relapse in NSCLC ALK/ROS1 mutation patients, lorlatinib was developed as a selective brain-penetrant ALK/ROS1 TKI active against most known resistance mutations. The phase 1 portion of the ongoing phase 1/2 study NCT01970865 enrolled patients with ALK+ or ROS1+ NSCLC with or without BM and were treatment naïve or had disease progression after ≥1 TKIs. Preliminary results revealed an objective ICRR of 44% in targetable and non-targetable lesions and 60% in targetable lesion, respectively (22) ( Table 1).
Additional second-generation ALK inhibitors shown to have efficacy in the brain include ASP3026, X396, and entrectinib (38).

First-Generation TKis
Approximately 33% of patients with NSCLC harboring tumors with EGFR-TKI-sensitizing mutations develop BM during treatment (39). Evidence suggests that EGFR TKIs have some limited BBB penetration (40,41). In a pooled analysis including 464 patients from 16 trials to study the efficacy of EGFR TKIs in NSCLC patients with activating EGFR mutations with BM showed that EGFR TKIs produce significant beneficial effects, with a pooled objective ICRR of 51.8%, IDCR of 75.7%, median PFS of 7.4 months, and OS of 11.9 months (23) ( Table 1).
Although erlotinib is effective for EGFR mutant NSCLC, CNS penetration is limited at standard daily dosing. Concentrations in cerebrospinal fluid exceeding the half maximal inhibitory concentration for EGFR mutant lung cancer cells in patients with BM and leptomeningeal metastases (LM) that developed despite standard daily erlotinib or other EGFR TKIs were achieved with weekly intermittent "pulsatile" administration of high-dose (1,500 mg) erlotinib (24). ICRR was 67% ( Table 1). Median time to CNS progression was 2.7 months (range, 0.8-14.5 months), and median OS was 12 months (range, 2.5 months-not reached) (24).
Afatinib These findings perhaps demonstrate a clinical benefit of afatinib in EGFR mutation-positive patients with NSCLC and asymptomatic BM. However, the role of afatinib in active BM remains to be clarified since this was an exclusion criterion in this study. ICRRs were not assessed in this study (Table 1). Therefore, no direct conclusions can be made regarding afatinib's ability to cross the BBB in concentrations sufficient to elicit CNS responses.
Despite limited evidence of EGFR TKIs providing benefit in a few patients with EGFR mutation-positive NSCLC with BM, a clinical need for novel EGFR TKIs with improved efficacy against BM still exists.

Osimertinib in Leptomeningeal Disease
Leptomeningeal metastases are seen in 3-5% of NSCLC (42) and in 9% of EGFR mutation-positive patients (43). Osimertinib is an irreversible EGFR TKI that targets activating mutations (EGFRm) and resistance mutations (T790M). Osimertinib induced sustained tumor regression in an EGFRm PC9 mouse BM model. PET imaging showed higher levels of osimetinib levels in NHP and mouse models, in contrast to rociletinib and gefitinib (39).
In previous trials, osimertinib demonstrated robust systemic activity in patients with EGFRm NSCLC and BM and has shown CNS penetration with sustained tumor regression in BM (44). In the phase 1 BLOOM study, two third-generation EGFR TKIsosimertinib and AZD3759-were studied in patients with EGFR mutation-positive advanced NSCLC (26). Neurological function improved from baseline in 24% (5/21) patients. Radiological improvements in LM were seen in 33% (7/21) patients, and 43% (9/21) had stable disease (SD) ( Table 1). Clearance of tumor

AZD3759 in BM
AZD3759 is a reversible inhibitor of EGFR-activating mutations that was designed to achieve high exposure in the plasma and CNS. AZD3759 has high passive permeability (29.5 × 10 −6 cm/s) and is not a substrate of the efflux transporters Pgp or BCRP at the BBB. In vivo, AZD3759 reached distribution equilibrium in rats, mice, and monkeys (Kpuu,brain and Kpuu,CSF > 0.5), suggesting BBB penetration (45). AZD3759 induced significant tumor regression and dramatically improved animal survival in the BM model (45). The AZD3759 cohort of the BLOOM trial evaluated the safety, tolerability, and early efficacy of AZD3759 in 29 patients with advanced EGFR mutation-positive NSCLC and metastases, including LM (27). Patients with non-LM BM were required to have at least one measurable intracranial or extracranial lesion. Patients with LM had a diagnosis confirmed by positive CSF cytology. All patients received at least one prior line of EGFR TKI therapy and chemotherapy. In addition, 34% of patients underwent prior whole-brain radiotherapy.
AZD3759 demonstrated encouraging intracranial antitumor activity. Among 21 patients with measurable BM, 11 patients demonstrated tumor shrinkage in the target brain lesion at AZD3759 doses of ≥50 mg BID ( Table 1). In this group, there were three confirmed partial responses (PR) and three uncon- iMMUnOTHeRAPY nivolumab Nivolumab, a human IgG4 anti-PD-1 monoclonal antibody is active in the second-line treatment of metastatic NSCLC after progression on a platinum-based chemotherapy. Experience in routine clinical practice may differ from that seen in a controlled clinical trial. In a randomized phase 3 trial (CheckMate 017), the effect of nivolumab was studied in patients with advanced squamous NSCLC and central CNS metastases in a real-world, expanded access program (EAP) in Italy (47). Three hundred seventy-one patients participated in the EAP at 96 centers in Italy. Thirty-seven of 371 (10%) patients had asymptomatic and controlled CNS metastases. The DCR was 49% among patients with CNS metastases, with CR in 1 patient, PR in 6 patients, SD in 11 patients, and PD in 19 patients (  Table 2). These results support further investigation of nivolumab monotherapy in patients with NSCLC and asymptomatic CNS metastases.

Pembrolizumab
Pembrolizumab, a fully human anti-PD-1 monoclonal antibody is approved in first-and second-line treatment of metastatic NSCLC. NCT02085070 is a phase 2 study of pembrolizumab in patients with metastatic melanoma and NSCLC with untreated or progressive BM. The effect of drugs on untreated BM remains unclear because most clinical trials exclude these patients. Early data demonstrated that there was an ICRR of 6/18 (33%) in the NSCLC on pembrolizumab 10 mg/kg arm, similar to the systemic response rate (49) ( Table 2). The median OS was 7.7 months to date.
The available data for the use of anti-PD-1 agents in the treatment of BM do not yet include data on PD-L1 status. These data when available could suggest higher response rates based on the level of PD-L1 positivity.

COnCLUSiOn
Current standard of care for BM that require immediate local intervention (based on symptoms, location, size, or other concerning features) is craniotomy with resection or radiation therapy. There is still a role in integrating locally ablative therapy (LAT) in combination with targeted therapy and immunotherapy in patients with oligometastatic BM that are limited or have low metastatic tumor burden (52).
Prior to the advent of second-generation therapies for BM developing while on crizotinib, the only alternatives were ablation of oligometastatic brain lesion with LAT and continuing crizotinib (28). Using WBRT with concurrent erlotinib (53) was also a viable option rather than changing to traditional chemotherapy.
However, recent data showing dramatic and prolonged responses in BM patients treated with EGFR and ALK TKIs have suggested that delaying LAT and WBRT may be a valid treatment option for patients with asymptomatic BM from NSCLC, especially for those with EGFR-activating mutations or harboring ALK rearrangement.
The challenge will be to determine the optimal sequence of agents and modalities (WBRT and SRS). Perhaps serial genotyping, the degree of BM symptoms, and the toxicity profiles will serve to individualize treatments and determine the role of these targeted therapies in the therapeutic armamentarium of BM.

AUTHOR COnTRiBUTiOnS
The author confirms being the sole contributor of this work and approved it for publication.