Brain metastases in non-small cell lung cancer

INTRODUCTION — Brain metastases are a common complication in a wide range of cancers, but they are particularly common among patients with lung cancer. Approximately 10 percent of newly diagnosed patients with advanced non-small cell lung cancer (NSCLC) have brain metastases. Of patients with brain metastases, lung cancer is the primary tumor in 40 to 50 percent of cases [1,2].

Though there are well-established management approaches for brain metastases, with local therapies as the cornerstone, treatment options for patients with advanced NSCLC and brain metastases are evolving for several reasons. First, many patients with advanced NSCLC are living several years, allowing more time for brain metastases to develop as well as for adverse effects of prior therapies for brain metastases to emerge. Second, patients with more common driver mutations, specifically activating mutations of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangements, are particularly prone to development of brain metastases. Third, newer targeted therapies against EGFR and ALK have demonstrated far greater intracranial efficacy that permits careful consideration of systemic therapy as a preferred front-line approach over historically favored local therapies. Other novel systemic therapies, including immunotherapy, may also demonstrate sufficient intracranial activity to warrant a revision of historic practices.

These factors lead to evolving management options that are discussed in detail in this topic. An overview of the treatment of brain metastases as well as discussions of the clinical manifestations and diagnosis of brain metastases, management of seizures in patients with brain metastases, and overview of the treatment of advanced NSCLC are found elsewhere. (See "Overview of the treatment of brain metastases" and "Epidemiology, clinical manifestations, and diagnosis of brain metastases" and "Management of vasogenic edema in patients with primary and metastatic brain tumors" and "Seizures in patients with primary and metastatic brain tumors" and "Overview of the initial treatment of advanced non-small cell lung cancer".)

EPIDEMIOLOGY OF BRAIN METASTASES IN NSCLC — Among patients with lung cancer, 16 to 20 percent develop brain metastases. Incidence is higher in patients whose cancers harbor epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement, in whom up to 50 to 60 percent will develop brain metastases over the course of their disease [3-6]. Although some, but not all, data have suggested patients with c-ROS oncogene 1 (ROS1)-positive NSCLC have lower rates of brain metastases than those with ALK rearrangements, the incidence in this subtype is approximately one-third [7,8].

It remains unclear whether this is because these patients have longer survival times and thus, more time to develop brain metastases, whether there is selective pressure and poor central nervous system (CNS) penetration of historically available targeted therapies, or whether these mutation-driven cancers have biologic features that predispose towards progression and growth within the CNS.

PRESENTATION AND DIAGNOSIS — The presenting symptoms and clinical manifestations of brain metastases that develop in the setting of NSCLC are the same as those for brain metastases in other settings. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases".)

GENERAL PRINCIPLES OF MANAGEMENT — In general, the management of patients with advanced NSCLC and brain metastases is comparable to that for patients with brain metastases from other primary tumor sites. The main exception is for patients with a driver mutation, in whom newer-generation targeted systemic therapies have a higher likelihood of success against brain metastases than traditional chemotherapy or older targeted agents. (See 'ALK translocations' below and 'EGFR mutations' below.)

Targeted agents should not be used in the treatment of brain metastases for patients whose NSCLC does not harbor an activating mutation. For example, response to epidermal growth factor receptor (EGFR) inhibitors has been observed primarily in those whose tumors harbor an EGFR mutation rather than those whose tumors do not exhibit an EGFR mutation [9-13]. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'EGFR mutation as a predictor of responsiveness'.)

Monitoring of patients on systemic therapy — Patients with brain metastases receiving systemic therapy should be monitored closely with magnetic resonance imaging (MRI), although the optimal frequency is unknown. We conduct surveillance imaging at an initial two- to three-month interval, and then increase it in patients demonstrating an intracranial response.

Indications for steroids — The role for steroids in the management of brain metastases of patients with advanced NSCLC is identical to that for patients with brain metastases from other primary tumor types. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors".)

Surgical intervention

Severe mass effect or impending herniation — For patients with severe mass effect or the threat of herniation, we favor an initial surgical approach, with subsequent systemic treatment depending on molecular characteristics of the tumor. The surgical management of brain metastases is discussed elsewhere. (See "Overview of the treatment of brain metastases", section on 'Efficacy of surgery'.)

Considerations in oligometastatic disease — Importantly, a subset of patients with an isolated focus of "oligometastatic" disease, typically a single brain or adrenal metastasis, are amenable to resection of the primary chest tumor and local therapies to the solitary metastasis, administered with curative intent [14,15]. (See "Overview of the treatment of brain metastases", section on 'Single brain metastasis'.)

Published series of patients with NSCLC with a solitary "precocious" metastasis to the brain have reported a long-term survival rate of approximately 25 percent [15,16], supporting a unique role for surgery or stereotactic radiosurgery in this setting [16]. A specific benefit of surgical management of a solitary brain metastasis is its diagnostic utility in confirming the diagnosis, tumor histology, and stage of the cancer (if malignancy is confirmed). Surgery should, however, be restricted to patients who are likely to survive the procedure and for whom recovery will not consume the remainder of their anticipated life expectancy.

Notably, because the molecular mutation patterns of brain metastases have been demonstrated to be discordant with those of the primary tumor in many patients [17], additional insights may be offered by obtaining tissue from an isolated brain metastasis. Brain metastases that develop in the setting of a first-generation EGFR tyrosine kinase inhibitor, such as gefitinib or erlotinib, are less likely to be associated with development of acquired resistance mutations such as EGFR T790M than sites of extracranial progression [17]. This is presumably because brain metastases that develop while a patient is on a targeted agent with strong extracranial activity but relatively poor penetration into the central nervous system may be interpreted as having grown in a "sanctuary site" in which the cancer cells are not exposed to effective concentrations of the targeted therapy, in contrast with true acquired resistance to an active dose of that therapy. (See 'Brain metastases upon progression on TKI' below.)

PATIENTS WITH ONCOGENIC DRIVERS

Systemic therapy as initial treatment for ALK and EGFR-positive brain metastases — For many patients with a driver mutation in epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement, systemic therapy may now be utilized as an early intervention rather than the local therapies that have historically been favored. An important exception is for those with severe mass effect or impending herniation, in whom neurosurgical evaluation is indicated as the initial approach. We also note that other experts may reasonably continue to opt for radiation over targeted therapies, given that comparative data are limited and that the cognitive deficits associated with newer radiation modalities such as stereotactic radiation surgery (SRS) are small [18]. Discussion of surgery and radiation for brain metastases is found in other topics. (See "Overview of the treatment of brain metastases", section on 'Efficacy of surgery' and "Overview of the treatment of brain metastases", section on 'Efficacy of SRS alone' and "Overview of the treatment of brain metastases", section on 'Efficacy of WBRT' and "Stereotactic cranial radiosurgery".)

There are several specific reasons why systemic therapy may be particularly favored as an early intervention over local therapies. First, several of the systemic oral therapies directed against these molecular targets have demonstrated far greater intracranial activity than nontargeted therapies against brain metastases from tumors that harbor these driver mutations. Second, as a consequence of the marked efficacy of these targeted therapies, these very patients are increasingly likely to demonstrate a survival in the range of many years rather than only a few months, allowing time for cognitive deficits from previous local therapies, such as whole-brain radiation therapy (WBRT), to manifest [19,20]. Finally, limited observational data suggest similar time to progression and intracranial progression between patients receiving targeted therapy and radiation therapy (RT) versus targeted therapy alone [21].

According to guidelines from the American Society of Clinical Oncology, local therapy may be deferred in favor of targeted therapy in patients with asymptomatic brain metastases from oncogene-driven NSCLC, as part of a multidisciplinary discussion [18]; although we agree with this approach in general, we utilize targeted therapy over radiation even more liberally for those with brain metastases from EGFR, c-ROS oncogene 1 (ROS1), or ALK-mutated NSCLC, offering systemic therapy unless there are surgical indications or the patient experienced intracranial progression on a brain-penetrable inhibitor (algorithm 1 and algorithm 2 and algorithm 3). Multidisciplinary input is critical in optimizing treatment selection for individual patients.

Additional considerations for those who present with an isolated brain metastasis are discussed above. (See 'Considerations in oligometastatic disease' above.)

ALK translocations — For asymptomatic and symptomatic patients, alectinib or other brain-penetrable anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) may be used (algorithm 3). Most patients with brain metastases (either TKI-naϊve or on crizotinib) will frequently respond to these agents [21], and surgery and/or RT may be deferred, thereby potentially reducing patient morbidity associated with these local treatments. However, in the case of severe mass effect or impending herniation, we proceed with surgery as the initial treatment [22,23]. (See "Overview of the treatment of brain metastases", section on 'Efficacy of surgery'.)

Brain metastases at presentation — In the front-line setting, alectinib, brigatinib, lorlatinib, and ceritinib are US Food and Drug Administration (FDA) approved [24-26]. Although ceritinib has demonstrated central nervous system (CNS) activity, it is less CNS penetrant than alectinib, brigatinib, and lorlatinib, and cross-trial comparisons suggest a lower durability of CNS response with ceritinib.

●Alectinib – Support for alectinib over crizotinib as front-line treatment among those with brain metastases comes from phase III trials. In the J-ALEX study, among 43 crizotinib-naïve patients with ALK-positive NSCLC with brain metastases, alectinib demonstrated improved progression-free survival (PFS) relative to crizotinib (hazard ratio [HR] 0.08, 95% CI 0.01-0.61) [27]. Similarly, in the global ALEX study, among those with measurable CNS metastases, alectinib improved PFS relative to crizotinib (HR 0.40 95% CI 0.25-0.64), intracranial response rate (81 [95% CI 58-95] versus 50 [95% 28-72] percent), and duration of intracranial response (17.3 [95% CI 14.8-NR] versus 5.5 months [95% CI 2.1-17.3]). Further results of J-ALEX and ALEX are discussed elsewhere [28]. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Preferred options'.)

●Brigatinib – Brigatinib has demonstrated efficacy over crizotinib in the front-line setting, both systemically and in regards to CNS disease [29]. In the phase III ALTA-1L trial, of 275 patients with treatment-naïve, advanced, ALK-positive NSCLC, 90 had brain metastases at baseline, and 39 had measurable brain metastases (≥10 mm in diameter). The confirmed intracranial response rate among patients with baseline brain metastases was 78 percent with brigatinib versus 26 percent with crizotinib [30]. Brigatinib also improved PFS in this population (HR 0.25, 95% CI 0.14-0.46).

In the entire patient population, brigatinib was associated with a lower rate of intracranial disease progression (9 versus 19 percent, respectively) [29]. Further results are discussed elsewhere. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Brigatinib'.)

●Ceritinib – Ceritinib has been compared with platinum/pemetrexed chemotherapy in the front-line setting but not with crizotinib. Evidence of activity of ceritinib over chemotherapy in the front-line setting comes from the phase III ASCEND-4 trial of 376 treatment-naïve patients with advanced ALK-positive NSCLC, randomly assigned to either a platinum agent plus pemetrexed versus oral ceritinib [31]. Among the 44 patients with measurable brain metastases at baseline, the intracranial response among those receiving ceritinib was 73 (95% CI 49.8-89.3) versus 27 (95% CI 10.7-50.2) percent among those in the chemotherapy group. The median PFS for those with brain metastases receiving ceritinib was 10.7 versus 6.7 months among those receiving chemotherapy (HR 0.70, 95% CI 0.44-1.12). (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Ceritinib'.)

Similarly, in preliminary results of ASCEND-7, which evaluated ceritinib in patients with newly diagnosed or progressive brain metastases, among 44 patients with no prior brain radiation or ALK inhibitor treatment, the whole-body objective response rate (ORR) was 59 percent, and the intracranial response rate was 52 percent, with a median duration of intracranial response of 7.5 months [32].

These ALK inhibitors have not been directly compared in terms of CNS or broader activity. However, based on cross-trial comparisons between ALEX and ASCEND-4, as well as the CNS activity of alectinib in small series of ceritinib-resistant patients [33], our preferred first-line agent for patients with brain metastases is either alectinib or off-label brigatinib, both of which are highly potent in the CNS compared with crizotinib.

●Lorlatinib – In the phase III CROWN trial, 296 treatment-naïve patients with ALK-positive stage IIIB/IV NSCLC were randomly assigned to oral lorlatinib or crizotinib [34]. Among 30 patients with measurable brain metastases, 14 of 17 patients (82 percent) assigned to lorlatinib and 3 of 13 patients (23 percent) in the crizotinib group had an intracranial response; furthermore, 12 patients (71 percent) who received lorlatinib had an intracranial complete response. Lorlatinib was associated with lower 12-month incidence of CNS progression compared with crizotinib, both in patients with (7 versus 72 percent) and without (1 versus 18 percent) brain metastases at baseline [35]. Further results of this trial are discussed elsewhere. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Options under investigation in the first-line setting'.)

Brain metastases upon progression on TKI

Crizotinib-resistant setting — In patients previously treated with crizotinib, either alectinib, ceritinib, or brigatinib are appropriate options [29], and are FDA approved in this setting [24,25,36]. Lorlatinib has been granted FDA approval for the treatment of patients with ALK-positive NSCLC who have progressed on crizotinib and at least one other ALK inhibitor, as well as for those who have progressed on either alectinib or ceritinib as front-line ALK inhibitor therapy for metastatic disease [26].

●Alectinib – Evidence of the intracranial activity of alectinib in the crizotinib resistant setting comes from the phase III ALUR trial, in which 107 patients with advanced ALK-positive NSCLC with progression after both crizotinib and platinum-based chemotherapy were randomly assigned to alectinib or single-agent chemotherapy [37]. Among the 24 patients with measurable baseline CNS disease, CNS ORR was higher with alectinib than chemotherapy (54 versus 0 percent, respectively). Full results from this study are discussed elsewhere.

Further support for alectinib over chemotherapy comes from a pooled analysis of two phase II studies including 136 patients with baseline CNS metastases, 70 percent of whom had prior CNS RT [22]. In this analysis, the CNS ORR, disease control rate, and duration of response for alectinib were 43 percent, 85 percent, and 11.1 months, respectively [22]. Separately, in a retrospective study including 15 patients with large (≥1 cm) or symptomatic CNS metastases that were measurable, alectinib demonstrated a response rate of 72 percent [38]. Finally, alectinib has also demonstrated CNS activity in patients who have developed progressive brain or leptomeningeal metastases on ceritinib [33].

●Brigatinib – Brigatinib is another acceptable option for crizotinib-resistant, ALK-positive patients with brain metastases [39], with the standard 180 mg dose (with lead-in), more active than the 90 mg daily dose [39].

Brigatinib has been tested in a phase I/II trial and a randomized phase II trial (ALTA1) in advanced ALK-positive NSCLC. In the phase I/II trial, which enrolled mostly crizotinib-pretreated patients, the intracranial response rate among 15 patients with measurable CNS metastases at baseline was 53 percent (95% CI 27-79) [40]. The phase II trial randomly assigned 222 crizotinib-pretreated patients to either 90 mg daily or to 180 mg daily (preceded by a one-week lead-in of 90 mg daily) [29,41]. Among 26 patients with measurable brain metastases who received brigatinib at 90 mg daily, the intracranial response rate was 50 percent [41]. Among 18 patients with measurable brain metastases who received brigatinib at 180 mg daily (with lead-in), the intracranial response rate was higher at 67 percent. Median duration of intracranial response was 9.4 and 16.6 months, for the low- and high-dose arms, respectively.

●Lorlatinib – Lorlatinib is a third-generation ALK/ROS1 inhibitor that is effective against ALK resistance mutations and is able to penetrate the blood-brain barrier [26,42,43]. In a phase II trial, among 81 patients who had previously been treated with at least one ALK inhibitor and had baseline brain metastases, the intracranial response rate was 63 percent, and median duration of intracranial response was 14.5 months [26]. In the preceding phase I trial of lorlatinib, the mean ratio of cerebrospinal fluid (CSF) to plasma lorlatinib concentrations was 0.75, confirming the significant CNS penetrability of lorlatinib [42]. In that trial, among 19 ALK-positive patients with measurable CNS disease, most of whom had received crizotinib followed by a second-generation inhibitor such as ceritinib, alectinib, or brigatinib, the intracranial response rate was 42 percent (95% CI 20-67).

●The phase II study of lorlatinib included six different expansion cohorts for ALK-positive patients based on prior treatment [44]. Among 37 patients previously treated with crizotinib and with brain metastases at baseline, the intracranial response rate was 68 percent (95% CI 50-82). Among 83 patients previously treated with two or three ALK inhibitors, including at least one second-generation inhibitor, the intracranial response rate was 48 percent (95% CI 37-59). Activity of lorlatinib in treatment-naïve patients is discussed above. (See 'Brain metastases at presentation' above.)

●Ceritinib – Ceritinib is an acceptable option for those with ALK-positive NSCLC and brain metastases, both in the front-line and crizotinib-resistant settings, although alectinib, brigatinib, and lorlatinib may be preferred. In a study of patients who previously progressed on crizotinib, among 100 patients with baseline brain metastases, the intracranial response rate with ceritinib was 45 percent (95% CI 23-69 percent) [45]. In a separate study of patients with ALK-positive NSCLC and brain metastases, the intracranial response rates to ceritinib among patients with prior ALK inhibitor treatment and brain radiation was 39 percent, and among those with prior ALK inhibitors and no prior brain radiation it was 28 percent [46]. The median duration of response was 9.2 and 10.1 months in these two groups, respectively. (See 'Brain metastases at presentation' above.)

●Other agents – Ensartinib (X-396) has also been reported to have activity against brain metastases. In a phase I/II study that enrolled both crizotinib-naïve and crizotinib-resistant patients, the intracranial response rate among 14 patients with baseline CNS metastases was 64 percent (95% CI 39-84) [47].

Alectinib-resistant setting — Data are evolving regarding management of patients who develop isolated intracranial progression on alectinib (CNS only recurrence with continued extracranial response). In this setting, the options include local therapy if only oligometastatic disease is present (one or a small number of lesions) or a switch to lorlatinib, which has documented CNS activity in patients whose cancer has progressed despite second-generation inhibitors. In the setting of limited data, a choice between these options depends on patient and provider preference as well as the availability of lorlatinib. (See 'Crizotinib-resistant setting' above.)

The management of patients who develop both intracranial and extracranial progression on alectinib is discussed elsewhere. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Treatment after progression on second-generation ALK TKIs'.)

In a case series of two ALK-positive patients who experienced initial improvements in CNS metastases on standard dose alectinib (600 mg twice daily) but who subsequently recurred with symptomatic leptomeningeal metastases, dose escalation to 900 mg twice daily resulted in repeat clinical and radiographic responses [48].

EGFR mutations — The management approach to brain metastases in patients with epidermal growth factor receptor (EGFR) mutation-positive NSCLC is in evolution at the present time. With the demonstrated CNS activity of osimertinib for patients with EGFR-positive NSCLC, more patients may now be able to achieve benefit from systemic therapy alone (algorithm 1).

Brain metastases at presentation

Preference for osimertinib — We favor osimertinib as the initial management for patients presenting with brain metastases from EGFR-mutated NSCLC, except for those with impending herniation or severe mass effect. For patients lacking these indications for surgery, a closely monitored trial of an EGFR inhibitor in lieu of immediate RT is a reasonable approach.

Though this approach has not yet been tested in randomized trials, and retrospective data indicate that deferral of RT may be associated with worse outcomes compared with early RT [49-56], those studies were all conducted with first- or second-generation EGFR TKIs that have not demonstrated the intracranial activity seen thus far with osimertinib. There are only limited data comparing osimertinib with local therapies for the management of brain metastases [21]; however, clinical data with osimertinib reveal encouraging activity against CNS disease, without the neurocognitive defects or postsurgical complications that may arise from brain irradiation or neurosurgery, respectively. Given the lack of data, however, some experts may reasonably opt instead for upfront RT, followed by osimertinib. (See "Delayed complications of cranial irradiation", section on 'Neurocognitive effects' and "Delayed complications of cranial irradiation", section on 'Brain tissue necrosis' and "Overview of the treatment of brain metastases", section on 'Complications of SRS' and "Overview of the treatment of brain metastases", section on 'Early and delayed side effects' and "Overview of the treatment of brain metastases", section on 'Risks and complications'.)

In subset analysis of the FLAURA trial including 116 treatment-naïve patients with EGFR-mutated advanced NSCLC and CNS metastases, the PFS was longer for patients receiving osimertinib compared with those receiving either gefitinib or erlotinib (15.2 versus 9.6 months; HR 0.47, 95% CI 0.30-0.74) [57]. In subsequent reporting, median CNS PFS among patients with measurable and/or non-measurable CNS lesions was not reached with osimertinib and was 13.9 months with standard EGFR TKI (HR 0.48, 95% CI 0.26-0.86) [58]. In addition, irrespective of baseline CNS disease, the rate of CNS progression in the overall study population of 556 patients was also lower with osimertinib (6 versus 15 percent) [57]. Among patients with brain metastases evaluable for response on FLAURA, the intracranial response rate was 91 percent with osimertinib, compared with 68 percent in recipients of a first-generation EGFR TKI.

Though first- and second-generation EGFR TKIs such as erlotinib, gefitinib, and afatinib have antitumor activity in patients with brain metastases, [9,10,13,59-62], these agents are detected in the CSF only at low concentrations, in the 1 to 5 percent range of what is observed in the serum [63-67]. By contrast, osimertinib achieves greater intracranial concentrations [68] and has been demonstrated to have significant intracranial activity against brain metastases at the standard dose of 80 mg daily, and even against leptomeningeal carcinomatosis at 80 to 160 mg daily [69,70]. Discussion of leptomeningeal carcinomatosis is found separately. (See "Treatment of leptomeningeal disease from solid tumors".)

RT as an alternative, over earlier-generation TKIs — Osimertinib achieves higher CSF concentrations and improved outcomes compared with earlier-generation tyrosine kinase inhibitors (TKIs), and therefore it is our preferred initial approach for those with EGFR-mutated NSCLC, even when CNS involvement is present. If osimertinib is not available, we offer radiation therapy (RT) as the initial approach for management for most cases of brain metastases from EGFR-positive NSCLC, with initiation of an earlier-generation TKI upon completion. An alternative option if osimertinib is not available is initiation of an earlier-generation TKI, which is appropriate for patients who either are not candidates for RT, or have asymptomatic, small-volume CNS disease and disseminated systemic disease. Although concurrent brain radiation and/or "pulsed" dosing with a higher dose of EGFR TKI therapy intermittently may achieve higher intracranial concentrations of EGFR TKIs, we do not endorse this approach, given the possibility of greater toxicity and as well as worsened outcomes [56,65,66,71].

Though limited by methodologic problems, a meta-analysis of 12 observational studies including 363 patients with EGFR-positive NSCLC and brain metastases suggested that, compared with initial treatment with a first-generation EGFR TKI, upfront cranial RT resulted in similar intracranial disease ORRs (relative risk [RR] 0.93, 95% CI 0.82-1.06), improved four-month intracranial disease PFS (RR 1.06, 95% CI 1.00-1.12), and improved two-year overall survival (OS; RR 1.33, 95% CI 1.00-1.77) but caused more neurologic toxicities than TKIs [54]. This conclusion is corroborated by a subsequent retrospective analysis of 351 patients with EGFR mutation-positive NSCLC and brain metastases who received initial SRS, WBRT, or EGFR TKI therapy, and experienced a median OS of 46, 30, and 25 months, respectively [53]. Though not a randomized trial and potentially limited by selection bias, multivariate analysis from this study suggested that SRS versus EGFR TKI as well as WBRT versus EGFR TKI were associated with improved survival, results which have also been supported by other studies [51-54].

Although in the absence of osimertinib, we prefer RT as initial therapy for CNS disease, first- and second-generation EGFR TKIs alone have demonstrated some CNS activity. For example, several review papers have aggregated the findings supporting the intracranial activity of earlier-generation EGFR TKIs monotherapy [72,73], and descriptions of a few studies provide examples of the key results:

●A series of 53 evaluable patients with brain metastases from NSCLC included 17 patients with known EGFR mutations who were treated with erlotinib [10]. Eight of nine had an objective partial or complete response after treatment with erlotinib plus WBRT, while six of eight had an objective response to erlotinib alone. The remaining three patients had stable disease. In the entire group, the time to tumor progression in the brain was 11.7 months.

●In a study of 41 Japanese patients with NSCLC with EGFR mutation and brain metastases, gefitinib as monotherapy has demonstrated an ORR of 87.8 percent with OS of 21.9 months [49], supporting the use of EGFR TKIs as monotherapy without radiation.

●Afatinib, a second-generation irreversible EGFR inhibitor, has demonstrated CNS activity in the subgroup analysis of brain metastasis patients in the LUX-Lung 3 and 6 trials with increased intracranial PFS compared with chemotherapy (8.2 versus 5.4 months) [74].

As mentioned above, EGFR inhibitors should not be given in combination with WBRT. In a phase III study by the Radiation Therapy Oncology Group (RTOG 0302) that was stopped early due to slow accrual, 126 patients with NSCLC and one to three brain metastases were treated with WBRT plus SRS, WBRT plus SRS plus temozolomide, or WBRT plus SRS plus erlotinib [56]. OS was worse in each of the drug therapy arms compared with WBRT/SRS alone (13.4 months for WBRT/SRS versus 6.3 and 6.1 months for temozolomide and erlotinib, respectively), and toxicity was significantly higher in patients who received concurrent drug therapy.

In sum, available data suggest that EGFR TKIs demonstrate CNS activity in patients with EGFR mutation-positive NSCLC. However, among EGFR TKIs, osimertinib has demonstrated the greatest consistency in responses of brain metastases and prevention of disease progression within the CNS, making it the preferred treatment option, if available. (See 'Preference for osimertinib' above.)

Brain metastases upon progression on TKI — The approach to progressive intracranial disease is discussed below, with considerations for situations in which progression occurs both systemically and in the CNS, versus intracranially only.

●Intracranial and extracranial progression – For those with progression on a first- or second-generation tyrosine kinase inhibitor (TKI), we obtain a tissue biopsy at progression from the most accessible extracranial site, or plasma for circulating tumor DNA. Further discussion of this methodology is found elsewhere. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Liquid biopsies'.)

However, if urgent neurosurgical indications are present, an intracranial biopsy may be pursued. (See 'Surgical intervention' above.)

•If the T790M resistance mutation is found, we proceed with osimertinib. If a T790M mutation is not found, management occurs in similar fashion as to those lacking an oncogenic driver mutation. (See 'Patients lacking known oncogenic drivers' below.)

A planned subgroup analysis of the AURA3 trial evaluated CNS control with osimertinib versus chemotherapy in those with the acquired T790M resistance mutation [75]. In this trial, patients with T790M mutation-positive advanced NSCLC after progression on a prior EGFR TKI were randomly assigned to either osimertinib or cisplatin/pemetrexed chemotherapy. Among the 46 patients with CNS lesions evaluable for response, the response rate was 70 versus 31 percent for osimertinib versus chemotherapy, respectively (OR 5.13, 95% CI 1.44-20.6). Looking at the preventive effect of these treatments in the full-analysis population of over 400 patients, the CNS PFS was also longer with osimertinib (11.7 versus 5.6 months; HR 0.32; 95% CI 0.15-0.69).

Other evidence supporting use of osimertinib in the setting of T790M-positive NSCLC and brain metastases comes from earlier-phase studies and case reports. For example, pooled results from two phase II trials of osimertinib in EGFR T790M mutation-positive advanced NSCLC demonstrate an ORR and disease control rate of 54 and 92 percent, respectively, among the 50 patients with baseline brain metastases that were evaluable for measurement of response [76]. Intracranial efficacy is also reflected in several case reports that have documented rapid and dramatic responses of brain metastases in patients who have received standard-dose osimertinib [77,78].

Separately, a single-arm study evaluating osimertinib 160 mg in patients with T790M-positive brain metastases described an intracranial ORR and disease control rate of 55 and 78 percent, respectively [79]. Promising activity was also observed among patients with leptomeningeal disease. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Patients with non-small cell lung cancer'.)

•For patients who develop progression on osimertinib, we treat along similar lines as for those without an oncogenic driver mutation. (See 'Patients lacking known oncogenic drivers' below.)

●Isolated intracranial progression – In the setting where patients exhibit good extracranial disease control but intracranial progression, it is unclear whether the intracranial disease represents true acquired resistance versus a "sanctuary" site, with inadequate exposure to the EGFR TKI. The fact that brain metastases are significantly less likely than extracranial sites of progression to harbor the T790M acquired resistance mutation suggests the interpretation of inadequate CNS penetration. This is particularly true for first- and second-generation EGFR TKIs, such as gefitinib, erlotinib, and afatinib.

•For patients who develop isolated intracranial progression on a first- or second-generation EGFR TKI, we transition to osimertinib. Switching to osimertinib may obviate the need for local therapy and significantly reduce the risk of further CNS progression compared with continuation of the original earlier-generation EGFR TKI.

However, osimertinib is FDA approved in the second-line setting only for patients with the acquired resistance mutation T790M (which is less commonly seen in the setting of intracranial versus extracranial progression [17]). As such, some experts may prefer to continue systemic treatment with an earlier-generation TKI for patients with isolated intracranial progression on such an agent, reserving osimertinib for possible later treatment of T790M-mediated resistance. In such cases or when osimertinib is not available, it is acceptable to use local therapy for the brain metastases and continue the current EGFR TKI. If this option is chosen, the original TKI may be continued until either progression of extracranial disease, or progression of intracranial disease after local therapies have been applied.

As a second alternative strategy, one may pursue brain biopsy, with subsequent transition to osimertinib if T790M is uncovered, versus local therapy to the brain metastases and continuation of the original TKI if T790M is not found.

•For patients who develop isolated intracranial progression on osimertinib and continue to demonstrate good extracranial disease control, we favor management of the brain metastases with local therapy as indicated, with no change in systemic therapy from osimertinib.

Other oncogenic drivers — Targeted agents have shown promising activity for other oncogenic drivers as well, although data are more limited than for EGFR and ALK, and as such, we typically suggest local treatment strategies in addition to systemic therapy, rather than systemic therapy alone.

ROS1 translocations — For patients with c-ROS oncogene 1 (ROS1)-rearranged NSCLC and brain metastases, the optimal first-line treatment has not been established. For patients with small, asymptomatic brain metastases, we proceed with systemic therapy using entrectinib, or, if unavailable, crizotinib (algorithm 2) [80], with close surveillance of symptoms and brain imaging. For patients with larger or symptomatic brain metastases, we favor either local approaches (RT or surgery) followed by systemic therapy, or referral to a clinical trial of a next-generation, CNS-penetrant ROS1 inhibitor. If RT is being considered, we prefer, if possible, stereotactic radiosurgery (SRS) over WBRT. (See "Stereotactic cranial radiosurgery", section on 'SRS versus conventional RT' and "Overview of the treatment of brain metastases", section on 'Efficacy of SRS alone'.)

Entrectinib, a potent ROS1/tropomyosin receptor kinase (TRK) inhibitor, has demonstrated CNS activity in crizotinib-naïve, ROS1-positive patients [81]. In a pooled analysis of three studies including 24 patients with measurable baseline CNS metastases, the intracranial ORR was 79 percent, the median intracranial PFS was 12.0 months, and the median intracranial duration of response was 12.9 months [82]. Earlier data from these trials have led to the approval of entrectinib for patients with ROS1-translocated NSCLC (irrespective of line of treatment or presence of intracranial disease) [81,83]. Based on its excellent overall efficacy and superior activity within the CNS, it is our preferred first-line option for patients with ROS1-positive NSCLC and brain metastases. For those with ROS1-positive NSCLC without brain metastases, either entrectinib or crizotinib are appropriate options, although CNS relapses on crizotinib may be seen due to its poor CNS penetration [8]. Ceritinib also appears to be effective for those with intracranial disease from ROS1-positive NSCLC. In a phase II study of ceritinib in crizotinib-naïve, ROS1-positive NSCLC, two patients had measurable CNS disease at baseline, and one of the two demonstrated an intracranial response to ceritinib [84]. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'ROS1 rearrangements'.)

For patients who have relapsed on front-line crizotinib (intracranially and/or extracranially), the third-generation ALK/ROS1 inhibitor lorlatinib is appropriate, in the absence of severe mass effect or risk of herniation (although lorlatinib is off-label in this setting). Overall, though studies are limited by small numbers and even smaller subsets of patients with brain metastases, available data support a high degree of intracranial activity with lorlatinib. In the phase I study of lorlatinib, three of five patients (60 percent) had intracranial objective responses, two of whom had experienced disease progression on prior crizotinib [42]. Similarly, in the phase II study of lorlatinib, among 11 ROS1-positive patients with baseline brain metastases who were crizotinib naïve, the intracranial response rate was 63 percent [85]; among 24 patients with baseline brain metastases who had been treated with crizotinib as their only previous ROS1 TKI, intracranial response rate was 51 percent.

The investigational agent repotrectinib is promising for patients with ROS1-positive NSCLC. In preliminary data, among three TKI-naϊve patients with measurable baseline CNS disease, the intracranial ORR was 100 percent (three of three); among four patients with measurable baseline CNS disease who had previously received treatment with a TKI, the ORR was 50 percent (two of four) [86]. In both groups, the median duration of response was 5.5 months.

In the event of CNS progression despite systemic therapies, we proceed to radiation or, less commonly, surgery, if clinically appropriate.

MET exon-14-skipping mutations — For those with a MET exon-14-skipping mutation and brain metastases from NSCLC, we suggest capmatinib, which is approved by the FDA [87]. Capmatinib is a highly selective and potent MET inhibitor that crosses the blood-brain barrier. Tepotinib is another FDA-approved agent for patients with MET exon-14-skipping mutations [88]. Though intracranial activity is not well characterized, it demonstrates intracranial activity in patients with brain metastases [89].

However, for patients with tumors that are MET amplified only, we proceed with local therapies and immunotherapy/chemotherapy first, rather than a MET inhibitor, given fewer supporting data for these agents in such cancers.

In preliminary results of the GEOMETRY-mono-1 trial including 97 patients with advanced NSCLC associated with a MET exon-14-skipping mutation, there were 13 patients with evaluable baseline brain metastases, per independent review committee [90]. Upon treatment with capmatinib, 7 of the 13 patients (54 percent) had intracranial response, four of whom had complete resolution of all brain lesions. Three of the seven responders had prior brain radiotherapy; five of the seven responders had either signs of progression in the existing brain lesion(s) or new brain metastases at study entry. Intracranial disease control (stable or responding disease) was achieved in 12 of 13 patients.

Tepotinib is an alternative option in this setting. In the VISION trial, among the 11 patients with brain metastases (all of which were nontarget tumors), the response rate to tepotinib was 55 percent, with a median duration of response of 9.5 months [89].

RET fusions — For patients with advanced NSCLC with a RET rearrangement and brain metastases, we suggest either selpercatinib or pralsetinib, both of which are approved by the FDA [91,92].

In a randomized phase III trial including 29 patients with measurable brain metastases at baseline that were either asymptomatic or had been neurologically stable for at least two weeks, selpercatinib resulted in an intracranial response that occurred in 82 versus 58 percent in the control group (platinum-based chemotherapy, with or without pembrolizumab, at the investigator's discretion) [93]. At 12 months 76 percent continued to have a response with selpercatinib, versus 63 percent in the control group. Further results of this trial are discussed elsewhere. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'RET rearrangements'.)

Similarly, in the previous multicohort, open-label, phase I/II LIBRETTO-001 study, responses in intracranial lesions were observed in 85 percent of the patients with measurable disease [94,95]. Objective responses were observed regardless of whether patients had received prior systemic therapy and/or radiotherapy. Among the 22 patients with CNS response, median duration of CNS response was 9.4 months.

Pralsetinib is another FDA-approved RET inhibitor with intracranial activity, with intracranial response rate of 80 percent (7 of 9 patients) in those with baseline measurable intracranial metastases in an early-phase clinical study [96].

KRAS G12C — For patients with advanced NSCLC with a KRAS G12C rearrangement and brain metastases, we suggest adagrasib or sotorasib as an initial systemic treatment strategy. Examples of available data are below:

●Adagrasib – In a single arm trial (KRYSTAL-1) in 19 patients with KRAS^G12C-mutated NSCLC and untreated measurable CNS disease, adagrasib was associated with an intracranial objective response rate of 42 percent, PFS of 5.4 months, and median OS of 11.4 months [97]. Grade 3 treatment related events occurred in 10 patients (40 percent), with one grade 4 event (4 percent), and no grade 5 events. The most common CNS-specific treatment related adverse events were dysgeusia (24 percent) and dizziness (20 percent).

●Sotorasib – In a presented abstract of a phase I/II study including 40 patients with stable brain metastases, 65 percent of had received prior radiotherapy and 20 percent had prior brain surgery [98]. Among 16 patients with baseline and at least one scan on treatment, intracranial disease control (stable or responding disease) was achieved in 88 percent. Sotorasib was associated with a median PFS and OS of 5.3 and 8.3 months in NSCLC patients with stable BM previously treated with radiation or surgery.

Given these results, these targeted agents are our suggested initial strategy for most patients with intracranial disease lacking indications for neurosurgical intervention; however, initial radiation followed by adagrasib is an acceptable alternative, as there are no randomized trials comparing these strategies in this setting. (See 'Systemic therapy as initial treatment for ALK and EGFR-positive brain metastases' above.)

Sequencing of TKI with local therapies — For those with intracranial involvement treated with initial targeted therapy only (ie, no initial local therapy), we continue the targeted agent until evidence of progression, either systemically or intracranially. At that point, we proceed with local management of intracranial disease, with choice between radiation and surgery dependent on extent of the disease. (See 'Surgical intervention' above.)

However, for patients who are undergoing local therapy as part of the initial management strategy for intracranial disease, consideration must be given to timing of TKIs in relation to local treatment. For patients who undergo neurosurgery for brain metastases, it is reasonable to start or resume a tyrosine kinase inhibitor (TKI) as early as one to two days after surgery, presuming that oral medications can be tolerated.

For patients who will receive radiation, we routinely favor holding the TKI until completion of therapy, unless a patient has such extensive tumor burden and cancer-related symptoms that withholding systemic therapy for one to several weeks risks significant deterioration. This is to decrease the risk of cognitive complications. For example, although some evidence suggests that erlotinib can be safely administered with concurrent WBRT [55], other data suggest a potentially greater risk of cognitive complications with concurrent EGFR TKI and WBRT [99]. Similarly, for those treated with SRS, we typically recommend holding the TKI and resuming the day after SRS is completed, given an absence of data to speak to the safety of TKI therapy with concurrent SRS.

PATIENTS LACKING KNOWN ONCOGENIC DRIVERS

Preference for initial RT, followed by systemic therapy — In our practice, our approach is as follows (algorithm 4):

●We offer local therapy with radiation therapy (RT) for most patients with good performance status and brain metastases. Subsequent to local management of brain metastases, we proceed with systemic therapy. There are some patients, however, in whom RT is not the optimal initial management:

•For patients who present with disseminated lung cancer and asymptomatic brain metastases, chemotherapy rather than RT has been proposed as an alternative, using a regimen specific for lung cancer. (See 'Chemotherapy, with or without immunotherapy' below.)

•For those with poor performance status, best supportive care (BSC), including steroids, is an appropriate option. (See 'Best supportive care' below.)

•For those with severe mass effect or impending herniation, a surgical approach is indicated. (See "Overview of the treatment of brain metastases", section on 'Efficacy of surgery'.)

●Chemotherapy also appears to be less effective than RT for brain metastases that have been previously irradiated, and therefore we prefer repeat RT for most patients in this setting, if felt to be safe and feasible.

In general, practice has shifted away from routine whole-brain radiation therapy (WBRT) and toward stereotactic radiosurgery (SRS) for patients with a limited number of brain metastases. This broad topic is reviewed elsewhere. (See "Overview of the treatment of brain metastases", section on 'Patients with good performance status'.)

For patients in whom whole brain radiation therapy is indicated, however, approaches to minimize cognitive decline such as use of memantine or hippocampal sparing may be appropriate for some. Indications for WBRT and use of interventions to decrease associated cognitive decline are discussed elsewhere. (See "Overview of the treatment of brain metastases", section on 'High tumor burden or multiple large tumors' and "Overview of the treatment of brain metastases", section on 'Hippocampal avoidance and memantine'.)

Alternatives

Chemotherapy, with or without immunotherapy — NSCLC lacking a driver mutation is less responsive to systemic therapy than oncogene addicted cancers. As such, for most patients lacking a targetable driver mutation, we treat intracranial disease initially with RT, followed by systemic therapy. However, an exception is for those with disseminated NSCLC and asymptomatic brain metastases, whom we treat with a lung cancer-specific chemoimmunotherapy regimen, rather than with RT, in efforts to control systemic progression while potentially managing intracranial disease. In such cases, RT may be reserved as a later option in the event of subsequent progression of brain metastases. (See "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation".)

For patients with nonsquamous cancers with untreated, asymptomatic brain metastases, the combination of atezolizumab plus carboplatin and pemetrexed is an acceptable alternative to radiation. In a single-arm phase II trial in 40 patients with advanced nonsquamous NSCLC with asymptomatic brain metastases, atezolizumab plus carboplatin and pemetrexed was associated with an intracranial median PFS of 6.9 months and response rate of 43 percent [100]. Systemic median PFS was 8.9 months and response rate was 45 percent. The median overall survival (OS) was 11.8 months, and the two-year OS rate was 28 percent. While these results are promising, this strategy has not been compared with upfront radiation.

Chemotherapy alone has also been evaluated in patients with brain metastases. In a randomized pilot trial involving 48 neurologically asymptomatic patients, no significant differences in response rate or survival were observed when patients were treated with chemotherapy (vinorelbine plus gemcitabine) followed by RT rather than with RT followed by chemotherapy [101].

Response rates of brain metastases to chemotherapy are highest in patients who had not received prior systemic treatment or RT. In a series of 43 previously untreated patients with NSCLC, the objective response rate to the combination of cisplatin and etoposide was 30 percent, and the median survival was 32 weeks [102]. Other platinum-based regimens have given similar response rates in previously untreated patients [103-105]. Topotecan and pemetrexed also have single-agent activity [106,107]. Temozolomide is an option for further-line therapy, though data have been mixed regarding its activity, with response rates ranging from 0 to 20 percent [108-113].

Immunotherapy monotherapy — Treatment with immune checkpoint inhibitors such as the programmed cell death protein 1 (PD-1) antibody pembrolizumab is now routinely administered as first-line treatment with chemotherapy to patients with nonsquamous NSCLC, or as monotherapy for squamous or nonsquamous NSCLC in patients whose tumors express high-level expression of programmed cell death ligand 1 (PD-L1). In addition, several immune checkpoint inhibitors directed against PD-1 or PD-L1 (including nivolumab, pembrolizumab, and atezolizumab) are approved for the majority of patients with advanced NSCLC previously treated with conventional chemotherapy. Accordingly, most patients with advanced NSCLC and brain metastases are eligible to receive an immune checkpoint inhibitor in the first-line or later setting, either alone or potentially concurrent with chemotherapy. These indications are discussed in detail elsewhere. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation".)

Although rapidly evolving, present data are limited with immune checkpoint inhibitors for brain metastases from advanced NSCLC. Therefore, other treatments directed against intracranial disease should be pursued in most patients. For patients receiving intracranial RT for brain metastases and on immunotherapy for extracranial disease, we continue immunotherapy concurrently with radiation, though we recognize supporting data are retrospective [114-116], and that prospective studies are required to confirm that there are no increased toxicities associated with this approach. Alternatively, some experts may opt to delay RT and treat patients with small-volume, asymptomatic brain metastases with immunotherapy (with or without conventional chemotherapy), particularly if predictive markers such as PD-L1 expression indicate a higher probability of response.

Patients with active CNS disease have largely been excluded from most trials with checkpoint inhibitors. However, available evidence provides a proof of principle that PD-1 or PD-L1 immune checkpoint inhibitors as monotherapy can induce objective intracranial responses in patients with brain metastases from advanced NSCLC, on the order of approximately 30 percent [117-119], with greater levels of PD-L1 expression correlating with higher likelihood of response. Responses appear to be durable to the extent of the limited follow-up thus completed and typically concordant with extracranial responses to immunotherapy, with one retrospective study of 255 patients with brain metastases on immune checkpoint inhibitors reporting discordant cranial-extracranial response in 13 percent [117]. However, the extracranial efficacy of such agents remains confined to a minority of patients with advanced NSCLC overall, in particular the roughly 30 percent of patients whose tumors have high-level PD-L1 expression. Representative data are summarized:

●Pembrolizumab – An open-label, phase II trial of patients with NSCLC with untreated brain metastases demonstrated activity of pembrolizumab, with 11 of 37 (30 percent) patients with PD-L1-positive tumors experiencing objective CNS responses, and 0 of 5 (0 percent) of those with PD-L1-negative tumors experiencing CNS responses [119]. Patients were not permitted to have neurologic symptoms or require steroids, and those whose tumors expressed oncogenic variants previously associated with low response rates to checkpoint inhibitor therapy (eg, epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], or human epidermal growth factor receptor 2 [HER2] mutations) were excluded. In the PD-L1-positive cohort, responses were concordant with extracranial objective responses in nearly 80 percent of cases that were evaluable for both CNS and systemic responses. CNS responses were durable over the limited interval of follow-up (one-third of patients with CNS responses were progression free in the CNS at one year).

●Nivolumab – Analysis of the nivolumab expanded-access program in Italy identified 372 squamous NSCLC patients, of whom 38 had asymptomatic brain metastases [120]. The disease control rate was 39 percent. Median progression-free survival and OS in brain metastasis patients were 5.5 and 6.5 months, respectively [121]. A small series of five patients with NSCLC brain metastases treated with nivolumab has demonstrated activity in three of the cases [122].

●Atezolizumab – Preliminary presentation of pooled data of patients enrolled in one of five treatment studies with the PD-L1 inhibitor atezolizumab suggests that atezolizumab is well tolerated and active in NSCLC patients with brain metastases [123]. No treatment-related grade 4 or 5 neurologic adverse events were seen in patients with brain metastases (n = 79). In one of the trials included in this analysis, among patients with baseline brain metastases, there was a nonsignificant trend towards reduction in the risk of developing new CNS lesions with atezolizumab compared with docetaxel (hazard ratio [HR] 0.42, 95% CI 0.15-1.18).

Although initial data are promising, we await further studies to determine whether patients with brain metastases from NSCLC who lack an oncogenic driver mutation can safely defer local therapies in favor of immune checkpoint inhibitor therapy.

Best supportive care — A leading concern about WBRT has been the potential cognitive toxicity and other morbidities of this approach, along with the limited survival of patients who have undergone WBRT, even with modern techniques [124]. For patients with baseline poor performance status, BSC and steroids are an appropriate alternative to RT.

The QUARTZ trial, which randomized patients with advanced NSCLC and brain metastases to dexamethasone and BSC with or without WBRT, has raised particular questions about the role of WBRT in this setting [125]. The trial revealed no significant difference in OS or quality of life (QOL) between the two groups.

Though these results failed to demonstrate a clear clinical benefit with WBRT, the shortcomings of the study are profound and limit the generalizability of the conclusions. Specifically, the median OS was only approximately two months in both arms, only a few weeks longer than the duration of treatment, suggesting that a large proportion of the patients were too debilitated to benefit from significant interventions. In addition, a very prolonged duration of enrollment suggests that participating centers exercised significant selection bias, specifically favoring for referral to the QUARTZ trial a limited subset of patients in whom the investigators felt it appropriate to potentially randomize to steroids and supportive care alone. Subset analysis of the QUARTZ trial revealed an improved survival with WBRT in younger patients, specifically those under the age of 60, along with a trend toward more favorable outcomes in patients with a Karnofsky performance status of 70 or higher and NSCLC with controlled primary disease.

The results of the QUARTZ trial highlight that WBRT does not confer a significant benefit in either OS or QOL in patients who are older and/or have a compromised performance status. Concerns about selection bias, combined with the overall remarkably poor outcomes of patients on both arms of this trial, however, lead many to feel that these conclusions are not generalizable. In particular, they may not apply to patients with a better performance status, younger age, and/or better control of extracranial disease.

SPECIAL CONSIDERATIONS

Medically frail — In general, the management approach for frail patients with advanced NSCLC and brain metastases is reviewed elsewhere. (See "Overview of the treatment of brain metastases", section on 'Patients with poor performance status'.)

As noted above, patients with a driver mutation, such as an anaplastic lymphoma kinase (ALK) rearrangement or epidermal growth factor receptor (EGFR) mutation, can demonstrate dramatic and prolonged responses of both extracranial and intracranial tumor burden to newer tyrosine kinase inhibitors (TKIs) directed against these targets, often with favorable tolerability. Accordingly, medically frail patients with brain metastases in whom one of these driver mutations is detected may be strong candidates for initial treatment with one of these targeted therapies, particularly if brain metastases are asymptomatic. (See 'Patients with oncogenic drivers' above.)

For frail patients without a driver mutation, stereotactic radiosurgery (SRS) may be feasible. While whole-brain radiation therapy (WBRT) remains an option, the results of the QUARTZ trial suggest that patients with NSCLC and brain metastases may realize little or no benefit from WBRT, a finding that is likely particularly relevant for patients with a marginal or poor performance status [125]. (See 'Best supportive care' above.)

Leptomeningeal disease — The general approach to patients with leptomeningeal disease is discussed in detail elsewhere. (See "Treatment of leptomeningeal disease from solid tumors".)

Many targeted agents have shown efficacy in patients with leptomeningeal disease, for example, lorlatinib and alectinib for ALK-positive cancers [126,127] and selpercatinib in RET-fusion cancers [128]. For those with EGFR-mutated tumors and leptomeningeal disease, osimertinib has demonstrated significant intracranial activity against brain metastases at 80 to 160 mg daily [69,70,129]. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Patients with non-small cell lung cancer'.)

Considerations during the COVID-19 pandemic — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)

SUMMARY AND RECOMMENDATIONS

●Introduction – Brain metastases are a common complication in a wide range of cancers, but they are particularly common among patients with lung cancer. Approximately 10 percent of newly diagnosed patients with advanced non-small cell lung cancer (NSCLC) have brain metastases. (See 'Introduction' above.)

●Patients with severe mass effect or risk of herniation – For patients with severe mass effect or the threat of herniation, we favor a surgical approach initially, with subsequent systemic treatment depending on molecular characteristics of the tumor. The surgical management of brain metastases is discussed elsewhere. (See "Overview of the treatment of brain metastases", section on 'Efficacy of surgery'.)

●Patients with oncogenic drivers, lacking surgical indications – For patients without severe mass effect or the threat of herniation, the initial approach depends upon whether an oncogenic driver mutation is present and whether a central nervous system (CNS)-penetrant tyrosine kinase inhibitor (TKI) is available (algorithm 3 and algorithm 2 and algorithm 1 and algorithm 4).

•Targetable driver mutations – For those with brain metastases from advanced NSCLC associated with the targetable driver mutations discussed above (anaplastic lymphoma kinase [ALK] or epidermal growth factor receptor [EGFR] mutations, we suggest targeted therapy as an initial approach, rather than radiation or surgery (Grade 2C), given evidence of high intracranial activity in trials. However, these therapies have not been compared directly with radiation therapy (RT) or surgery, and RT therefore remains an appropriate alternative. (See 'Patients with oncogenic drivers' above.)

For those with brain metastases from c-ROS oncogene 1 [ROS1] translocations, MET exon-14-skipping mutations, RET fusions, or KRAS G12C, we typically suggest multimodal treatment including radiation followed by systemic therapy rather than systemic therapy alone (Grade 2C).

Specific systemic treatment strategies for those with brain metastases from oncogenic driver-mutated NSCLC (without severe mass effect or the threat of herniation) are as follows:

•ALK – For patients with ALK-translocated NSCLC, we recommend front-line treatment with a next-generation ALK inhibitor over both crizotinib and chemotherapy (Grade 1B). Appropriate options include alectinib, brigatinib, or lorlatinib. In the front-line setting, if these agents are unavailable, ceritinib is an acceptable alternative.

In the crizotinib-resistant setting, we recommend alectinib, lorlatinib, or brigatinib over chemotherapy (Grade 1B), but ceritinib is an acceptable alternative (algorithm 3). (See 'ALK translocations' above.)

•ROS1 – For patients with ROS1-mutated tumors, we suggest entrectinib over crizotinib (algorithm 2) (Grade 2C). (See 'ROS1 translocations' above.)

•EGFR – For patients with EGFR-mutated tumors (algorithm 1):

-Who present with brain metastases, we recommend initial treatment with osimertinib over earlier-generation TKIs or chemotherapy (Grade 1B). (See 'EGFR mutations' above.)

-Who develop both intracranial and extracranial progression on a first- or second-generation EGFR TKI, we obtain biopsy of the most accessible site. For those with a T790M resistance mutation, we recommend osimertinib over chemotherapy (Grade 1B). For those lacking a T790M resistance mutation, we treat with RT followed by systemic chemotherapy, along the lines of treatment for those lacking driver mutations. (See 'Brain metastases upon progression on TKI' above.)

-Who develop isolated intracranial progression on a first- or second-generation EGFR TKI, we suggest a transition to osimertinib (Grade 2C). Switching to osimertinib may obviate the need for local therapy and reduce the risk of further CNS progression compared with continuation of the original EGFR TKI. In the setting of limited data, however, one may alternatively use local therapies for the brain metastases and continue the original TKI; or obtain a biopsy, with approach dictated by the results. (See 'Brain metastases upon progression on TKI' above.)

•MET – For patients with MET exon-14-skipping mutations, we suggest capmatinib rather than chemotherapy or immunotherapy (Grade 2C). Tepotinib is a reasonable alternative. (See 'MET exon-14-skipping mutations' above.)

•RET – For patients with a RET rearrangement, we suggest the RET inhibitor selpercatinib or pralsetinib rather than chemotherapy or immunotherapy (Grade 2C). (See 'RET fusions' above.)

●Patients without targetable oncogenic drivers, lacking surgical indications – For patients lacking a driver mutation and without indication for neurosurgical management, we suggest RT (algorithm 4) (Grade 2C), although systemic therapy is a reasonable alternative initial management strategy, particularly for those with asymptomatic brain metastases. Additionally, for those with poor performance status, best supportive care may be used instead. (See 'Chemotherapy, with or without immunotherapy' above and 'Best supportive care' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledges Alice T Shaw, MD, PhD, and Howard (Jack) West, MD, who contributed to earlier versions of this topic review.