1. Introduction
The majority of lung cancers are non-small cell lung cancer (NSCLC), of which lung adenocarcinoma and squamous cell carcinoma are the most common histological subtypes [1]. NSCLC, especially lung adenocarcinoma, is characterized by a high frequency of driver mutations in oncogenes including EGFR, KRAS, STK11, MET, ALK, ERBB2/3, FGFR1/2/3, ROS, and RET [1]. Patients with NSCLC with oncogene driver mutations have rates of brain metastases (BrMs) in the range of 30–40% and up to 60% of these patients will develop BrMs [2,3,4,5]. Small cell lung cancer (SCLC), which makes up approximately 15% of lung cancer diagnoses, is characterized by a propensity for early metastasis with only one-third of patients presenting with early-stage disease [6]. SCLC tumors are characterized by frequent inactivating mutations in TP53 and RB1 and significant intratumoral heterogeneity, which contributes to metastasis and resistance [6]. SCLC is associated with a high propensity to develop BrMs; 10–25% of patients present with BrMs, and up to 60% of patients will develop BrMs [7,8]. Substantial advances have been made in the management of BrMs for lung cancer. We review the advances in radiation therapy, which continues to be a mainstay in the management of BrMs in lung cancer patients. Clinical trials have expanded the application of stereotactic radiosurgery (SRS), and evaluated strategies for preserving neurocognition with whole-brain radiotherapy (WBRT), including in prophylactic cranial irradiation (PCI) [9]. In addition, we also discuss emerging systemic therapies that have been found to have intracranial efficacy, albeit predominantly in post hoc and retrospective analyses.
2. Radiotherapy
WBRT [10] and SRS [11] were first described in the 1950s for targeting lesions in the brain. Given that the majority of BrMs result from the hematogenous spread of tumor cells, it was thought that the brain could be seeded with micrometastases at the diagnosis of BrMs [12,13]. Thus, WBRT was preferred for the management of single or multiple BrMs to prevent neurologic compromise from uncontrolled brain tumors [13]. Indeed, WBRT was shown to provide clinical improvement [10,14] as well as a possible survival benefit in select patients [15], leading to its adoption as standard practice for the management of brain metastases in NSCLC. Randomized prospective trials subsequently evaluated the addition of surgery [16,17] or SRS [18,19] to WBRT in patients with three or fewer BrMs and found improved survival and local control with the addition of either modality to WBRT relative to WBRT alone. Given the neurocognitive toxicity associated with WBRT, subsequent phase III clinical trials challenged WBRT as the standard of care for patients with 1–3 or 4 BrMs by comparing SRS with or without WBRT [20,21,22,23]. These trials have demonstrated improved central nervous system (CNS) disease control with the addition of WBRT, but improved quality of life and cognitive preservation with SRS alone, and no difference in overall survival, thus establishing SRS as the standard of care for limited BrMs, often defined historically as up to four lesions based on the inclusion criteria of these trials [20,21,22,23,24]. In a prospective study of 1194 patients, both the OS and rate of adverse events were comparable between patients with 2–4 lesions and those with 5–10 [25]. These results expanded the use of SRS for higher numbers of BrMs and decreased the reliance on a strict cutoff of four or less BrMs in guidelines and clinical practice. A subsequent metanalysis of 54 trials of 11,898 patients demonstrated that the combination of SRS and WBRT was superior to WBRT alone for local control while WBRT and SRS exhibited improved distant brain control over SRS alone [26]. No differences were found in the overall survival and the addition of WBRT was associated with worse neurocognitive outcomes [26]. It is important to note that the clinical trials evaluating radiotherapy in BrMs comprised 40–100% NSCLC patients, but also included additional cancer types, including breast, prostate, kidney, and colorectal cancer. Nonetheless, these trials have guided clinical practice recommendations in NSCLC [27]. In NSCLC, current emerging advancements in WBRT aim to preserve cognitive function whereas efforts to improve SRS are evaluating an increasing number of target lesions, fractionation, neoadjuvant vs. adjuvant approaches when combined with surgery, and optimal integration with emerging systemic therapies including immunotherapy and target therapies.
SCLC has high rate of metastasis to the brain, with 40–60% of patients developing BrMs during the course of their disease [28,29,30]. Given the propensity of SCLC to develop metastases and the poor prognosis of SCLC BrMs, prophylactic cranial irradiation (PCI) (which functionally entails the prophylactic administration of WBRT for the goal of eliminating potential subclinical, microscopic disease in the brain) has been the standard since studies established a local control and survival benefit in the 1990s and 2000s [31,32,33]. Due to the high propensity of SCLC to develop BrMs, concerns for diffuse, multicentric brain lesions, management has favored WBRT for the treatment of possible micrometastases. For SCLC patients with BrMs, WBRT thus continues to be a mainstay in the treatment of SCLC patients, who were excluded from the landmark prospective trials establishing SRS for limited BrMs. However, restrospective studies have found similar survival rates between SRS and WBRT; ongoing phase II and III trials are investigating if SRS is comparable to WBRT in SCLC patients with BrMs. For PCI, randomized studies of SCLC are currently elucidating if active surveillance and PCI are comparable and if hippocampal avoidance (HA) can reduce the cognitive decline from PCI. Table 1 includes relevant clinical trials leading to advances in radiotherapy for the management of BrMs and the current standard of care.
2.1. Whole-Brain Radiotherapy
WBRT was a mainstay for the treatment of NSCLC BrMs after it was described to provide symptomatic improvement in the 1950s and 1960s [10,14]. Prior to the era of routine imaging for monitoring tumor growth, dose escalation trials established regimens of 20–30 gray (Gy) in 5–10 fractions for achieving clinical remission in patients with BrMs, including those with lung cancer [34,35]. However, the role of WBRT has been decreasing in more recent years due to concerns regarding toxicity, the lack of a clear OS benefit with WBRT for most patients, and the emergence of alternative treatment options for patients with increasing numbers of BrMs [36]. Indeed, the Alliance N0574 trial, which showed a difference in the overall survival between SRS with WBRT vs. SRS alone, found that the addition of WBRT to SRS led to worsened cognitive deterioration at 3 months compared to that with SRS alone (91.7% vs. 63.5%, p < 0.001) and a decreased QoL score (−10.9 vs. −1.3 mean change from baseline, p = 0.002) [23]. The QUARTZ trial randomized 538 patients with NSCLC who were determined by a multidisciplinary team of neurosurgeons and radiation oncologists to be poor candidates for surgery or SRS to WBRT or best supportive care, including dexamethasone [37]. The trial did not demonstrate significant improvements with WBRT in the overall survival, quality of life, or quality-adjusted life-years. The overall survival was comparable between the two groups, with a median survival of approximately 9 weeks. The subgroup analysis of the QUARTZ trial demonstrated a survival benefit for patients less than 60 years of age and a trend towards improved survival in patients with a Karnofsky performance score (KPS) of 70 or greater and controlled extracranial disease [37], suggesting that certain populations may benefit from WBRT.
In NSCLC patients who have a good performance status, but present with BrMs that are too extensive for targeting with SRS, WBRT remains a reasonable option for local control and palliation. Various strategies have been developed for improving cognitive preservation with WBRT [9]. The phase III RTOG 0614 trial evaluated the potential neurocognitive protective effect of memantine, an NMDA receptor antagonist, in the context of WBRT [38]. Memantine was associated with a significantly longer time to cognitive decline (HR 0.78; 95% CI 0.62–0.99, p = 0.01) and a trend towards less decline in the primary endpoint of delayed recall (0 vs. −0.90, p = 0.059) relative to WBRT alone [38]. To determine if HA using intensity-modulated radiotherapy (IMRT) could preserve cognition, the phase III NRG CC001 trial compared HA-WBRT to WBRT, with both arms receiving memantine [39]. The time to cognitive failure was significantly reduced in HA-WBRT with memantine relative to WBRT with memantine (adjusted HR 0.75, 95% CI 0.58–0.95, p = 0.02), establishing HA-WBRT with memantine as the standard of care for patients with no metastases in the hippocampal region. In addition, The National Taiwan University Hospital conducted a phase II randomized trial to investigate if hippocampal avoidance (HA) could preserve neurocognition in WBRT [40]. With no difference in the PFS or OS, HA yielded an improved recognition–discrimination index and memory although there were no significant differences in the total recall or delayed recall.
In SCLC, the recognition of high rates of CNS progression led to the development of PCI as a strategy to mitigate BrMs. Although PCI was effective in reducing the rates of BrMs, concerns emerged regarding the potential toxicity to cognitive function and QOL [41]. PCI became the standard of care for LS-SCLC following a 1999 meta-analysis of PCI in patients predominantly with LS-SCLC in remission, demonstrating a reduced incidence of BrMs from 58.6% to 33.3% with PCI, associated with an OS benefit of 5.4% at 3 years [32]. In 2007, a phase III EORTC trial randomized patients with ES-SCLC to PCI or no further therapy and identified a 14% benefit in the OS at 1 year after randomization [33]. As a result, PCI became the standard of care for both LS and ES-SCLC. However, a pooled analysis of the PCI RTOG 0212 and 0214 trials has shown cognitive decline with PCI [42].
In an effort to reduce the deleterious cognitive effects of PCI, the PREMER trial randomized patients with SCLC to PCI or PCI with hippocampal avoidance (HA-PCI) [43]. HA-PCI was protective against cognitive decline compared to standard PCI with no differences in the OS or quality of life. A separate trial sponsored by the Netherlands Cancer Institute (NKI) randomized SCLC patients to PCI or HA-PCI and found the decline in the Hopkins verbal learning test score to be comparable between the two groups [44]. The NRG CC003 (NCT02635009) phase III trial evaluating intracranial response and rates of neurocognitive failure with PCI vs. HA-PCI was recently reported [45]. The addition of HA to PCI led to reduced neurocognitive failure (adjusted HR 0.77, 95% CI 0.61–0.98, p = 0.03) with a non-inferior 12-month intracranial response rate [45].
Other trials have sought to improve QOL outcomes in SCLC by re-examining the role of PCI altogether in the era of brain MRI surveillance. In a Japanese randomized trial, patients with ES-SCLC without BrMs on MRI were randomized to prophylactic cranial radiation at 25 Gy in 10 fractions or observation, with all patients undergoing routine MR brain imaging, and observation was found to yield a non-inferior OS compared to that with PCI (13.7 months vs. 11.6 months, p = 0.094) [46]. The ongoing phase III Maverick (NCT04155034) and EORTC PRIMALung trials [47] are randomizing patients with LS-SCLC and ES-SCLC to MR surveillance with or without PCI.
2.2. Stereotactic Radiosurgery
After it was demonstrated that SRS yielded reduced neurocognitive toxicity with no difference in the overall survival for patients with up to 4 BrMs [20,21,22,23] and subsequently in patients with 5–10 BrMs [25], research efforts have sought to advance SRS technology for multicentric BrMs and elucidate optimal fractionation and combination with surgery and systemic therapies. With the advent of volumetric modulated arc therapy, it became feasible to target multiple lesions using a single isocenter, which can reduce the treatment time of SRS for BrMs [48,49]. A retrospective study of 173 patients with 1014 BrMs showed a median beam-on time of 4.1 min and a median brain dose of 2.19 Gy; the local control at 1 year was 99%, while grade 2 or higher radionecrosis at 1 year was 1.4% [50]. These findings suggest that single-isocenter multicentric SRS technology is both effective and safe, expanding the feasibility of targeting higher numbers of BrMs in a reasonable amount of time for patients.
To mitigate the potential late side effect of radiation necrosis, a number of studies have evaluated the potential benefits of fractionating SRS over multiple treatments. Retrospective and dose-escalation studies suggest 27 Gy in three fractions to be associated with improved local control, with rates of radionecrosis at around 10% (95% CI 0–29%) [51,52]. However, for small lesions (≤2 cm), 15–24 Gy in one fraction is a reasonable approach based on the RTOG 90-05 trial, with doses varying by patient-specific and tumor-specific factors [27,53]. A meta-analysis of 24 studies of single-fraction vs. multifraction SRS revealed multiple fractions were associated with decreased rates of radionecrosis for tumor size 4–14 cc and 2–3 cm diameter [54]. An NRG phase III trial is examining one or three fractions of SRS in patients with one to eight lesions with a maximum diameter between 1.0 cm and 3.0 cm (NCT06500455).
An active area of research with respect to SRS is characterizing the safety and efficacy of SRS for an increasing number of lesions. A phase III trial, which was closed early due to slow accrual, randomized 72 patients with 4–15 BrMs to SRS or WBRT and demonstrated that SRS preserved cognitive function with no differences in the local control or OS between the two groups [55]. A retrospective analysis of patients with EGFR-mutated and ALK-rearranged NSCLC receiving SRS for four or more BrMs found that the mean hippocampal (1.2 Gy) and whole-brain (0.8 Gy) doses remained low with SRS for more than ten lesions [56]. Another retrospective study of patients treated with SRS for 10 or more lesions without concurrent WBRT found freedom from progression at 12 months of 96.8% for upfront treatment and 83.6% for salvage treatment with a mean hippocampal dose of 1.5 Gy [57]. In addition, a prospective cohort of 70 patients with 1174 BrMs in which 73% of the patients received a single fraction of 20–24 Gy found a median OS of 19.2 months, with local control in 97.3% of the lesions and a cumulative incidence of radionecrosis in 2.1% of the lesions [58]. These findings together suggest that SRS for many BrMs may achieve higher hippocampal sparing than in HA-WBRT. Ongoing randomized clinical trials are currently evaluating SRS for up to 20–30 BrMs, comparing SRS to HA-WBRT (NCT03550391, NCT03075072, NCT04277403) or comparing SRS with or without WBRT (NCT03775330).
In an effort to improve CNS disease control without WBRT, the phase 3 METIS trial examined tumor treating fields (electric fields that disrupt cancer cell division) in addition to SRS. In patients with mutation-negative NSCLC, tumor treating fields (TTFs) led to a doubling of the intracranial PFS (median of 21.9 vs. 11.3 months, p = 0.02) without impairing cognition [59]. These findings suggest that TTFs could be an alternative to WBRT with less cognitive toxicity in patients with extensive BrMs, although this has not been explored in the clinical trial setting.
In SCLC, due to the high rate of CNS metastasis in SCLC and concerns for diffuse or multifocal BrMs, as well as the prevalence of PCI as a component of first-line therapy, patients with BrMs were excluded from the randomized trials that established SRS as the first line for BrMs [60]. Consequently, WBRT remained the standard of care, even in the context of limited or solitary BrMs [60]. To evaluate the potential role of SRS alone in SCLC, the FIRE-SCLC cohort study compared 710 SCLC patients treated with first-line SRS between 1994 and 2008 to a cohort of patients receiving first-line WBRT [31]. Although WBRT was associated with an improved time to CNS progression (HR 0.38, 95% CI 0.26–0.55, p < 0.001), this did not translate into an improvement in the OS with WBRT (6.5 months for SRS, 5.2 months for WBRT, p = 0.003) [31]. Subsequently, a systematic review and meta-analysis of retrospective studies comparing SRS and WBRT in SCLC patients with BrMs found a similar OS between the two groups [61]. Together, these data suggest that SRS may be an appropriate first-line therapy in some patients [60]. The phase II ENCEPHALON (NCT03297788) randomized 56 patients with SCLC, up to 10 BrMs, and a KPS greater than 50 to WBRT or stereotactic radiotherapy (SRT, SRS for small lesions 20 G or 18 Gy, and hypofractionated SRT to 30 Gy in five fractions for lesions > 3 cm). The primary endpoint of neurocognition after cerebral irradiation was 7.7% in the SRT group and 24% in the WBRT group (p = 0.0723), whereas there were no differences in the overall survival between the two groups [62]. An additional phase II prospective single-arm trial of 100 patients across four centers evaluated SRS/SRT in SCLC patients with up to 10 BrMs; 66% of the patients were treated with SRS alone and 32% underwent SRT for at least one site. The rate of neurologic death at 1 year was 11.0% (95% CI 4.8–17.2%), which is comparable to the authors’ historical institutional rate of 17.5% for neurologic death with WBRT at 1 year [63]. The phase III trials NRG CC009 (NCT04804644) and NCT06457906 comparing WBRT to SRS for patients with SCLC and up to 10 BrMs are ongoing and will likely provide a definitive answer if SRS and/or SRT is a safe therapeutic approach for SCLC patients with BrMs.
2.3. Surgery and Radiotherapy
Surgery remains an important component in the local management of large and/or symptomatic BrMs for the management of mass effect or symptoms and for diagnostic information [27]. Recurrence at the resection bed 1 year after surgery alone is relatively common, with rates of approximately 50–60% in clinical trials [22,64]. Adjuvant WBRT and SRS have been demonstrated to significantly improve local control at the resected site [17,22,64], although, as expected, WBRT but not SRS has been shown to improve intracranial recurrence [64,65]. The EORTC 22952-26001 trial demonstrated that after SRS or surgery, adjuvant WBRT improved the local control and time to neurologic death without improving the performance status [22]. A phase III trial of 194 patients comparing post-operative WBRT to SRS showed decreased cognitive deterioration with SRS relative to WBRT (52% vs. 85% at 6 months, p < 0.00031), while WBRT was associated with improved intracranial disease control (55% vs. 81% at 6 months) [65,66]. In addition, a retrospective cohort study of 558 patients with resected BrMs and adjuvant hypofractionated SRS found a durable local control of 71% at 3 years with grade 3 or higher neurologic toxicity of 4.1% more than 6 months after treatment, supporting effective local control with post-operative SRS [67]. Active areas of investigation include optimal fractionation as well as timing relative to surgery. The ongoing ALLIANCE trial A071801 (NCT04114981) is evaluating one or multiple fractions of SRS to the surgical bed. A phase II trial (NCT05871307 is investigating the treatment response and local tumor control of neoadjuvant SRS, intraoperative RT, or adjuvant SRS in the treatment of BrMs. In addition, three ongoing phase III trials are comparing local and distal brain recurrence, including the development of leptomeningeal disease, following pre-operative or post-operative SRS and surgery for BrMs (NCT03741673, NCT03750227, NCT05438212). In contrast to NSCLC, the data on SCLC regarding efficacy and timing are limited and, thus, surgery is reserved in these patients for the management of mass effect or symptoms [27].
2.4. Re-Irradiation
Given the increasing efficacy of targeted therapies and combinatorial strategies leading to increased survival, lung cancer patients are increasingly needing multiple courses of radiation for BrMs. The data on re-irradiation in the context of BrMs are limited, although initial clinical trials on SRS included WBRT followed by SRS or SRS followed by WBRT (Andrews et al., 2004; Aoyama et al., 2006; Brown et al., 2016; Chang et al., 2009; Kocher et al., 2011). SRS followed by WBRT or vice versa has been demonstrated to be safe, although WBRT has been associated with significant neurocognitive decline. Limitations of re-irradiation with SRS include the dose to organs at risk and the volume of normal brain tissue receiving certain dose levels. For SRS, the volume of brain tissue receiving 18 Gy (V18) has been shown to be predictive of radionecrosis and for V18 > 30.2 mm2, the rate of radionecrosis was 14% [51]. Additional studies are needed to further characterize the limitations of re-irradiation with SRS, although it appears to be safe within acceptable dose constraints.
Table 1Key clinical trials defining radiation therapy for brain metastases.
| Comparison | Trial Name or 1st Author | No. of BrM | Arms | No. of Patients | % Lung Cancer | Primary Endpoint | Additional Outcomes | Note | Citation |
|---|---|---|---|---|---|---|---|---|---|
| WBRT dose escalation | Borgelt et al. | Not specified | 1st study | 1st study: n = 233 (30 Gy/2 wks) | 60% | Overall rate of improvement in neurologic function 47% in 1st study, 52% in 2nd study | Median OS 18 weeks in the 1st study and 15 weeks in the 2nd study. | Patients with higher neurologic function at presentation had higher rate of improvement in neurologic function | [33] |
| WBRT vs. best supportive care | QUARTZ | Not specified | WBRT vs. optimal supportive care (OSC) | n = 269 (WBRT) | 100%, NSCLC | 46.4 vs. 41.7 days of QALYs (90% CI −12.7 to 3.3 days) | OS comparable between WBRT and OSC (HR 1.06, 95% CI 0.90–1.26, p = 0.8084) | 20 Gy in 5 fractions lower than what is used at some institutions; improved OS with WBRT for age < 60. | [37] |
| WBRT + | RTOG 0614 | Not specified | WBRT + placebo vs. | n = 252 (placebo) | 70% | Trend towards less decline in delayed recall (0 vs. −0.90, p = 0.059) with memantine relative to WBRT alone | Longer time to cognitive decline with memantine (HR 0.78; 95% CI 0.62–0.99, p = 0.01) | [38] | |
| Hippocampal avoidance (HA) WBRT | NRG CC001 | Not specified | WBRT + memantine vs. | n = 257 (WBRT) | 59% | Cognitive failure (measured as decline in reliable change index on at least one cognitive test) lower with HA-WBRT vs. WBRT (HR 0.74, 95% CI 0.58–0.95, p = 0.02) | Reduced deterioration in executive function at 4 months (40.4% vs. 23.3%, p = 0.01) and in learning/memory at 6 months (24.7% vs. 11.5%, p = 0.049); OS 7.6 vs. 6.3 months, p = 0.31; intracranial PFS 5.3 vs. 5.0 months, p = 0.21 | [39] | |
| WBRT +/− SRS | RTOG 9508 | 1–3 | WBRT vs. | n = 164 (WBRT) | 64% | Median OS 6.5 vs. 5.7 months (p = 0.1356) | Improved control of treated lesions at 1 year in WBRT + SRS group (82% vs. 71% p = 0.01) | [18] | |
| SRS +/− WBRT | Aoyama et al. | 1–4 | WBRT + SRS vs. | n = 65 (WBRT + SRS) | 67% | Medians OS 7.5 vs. 8.0 months (p = 0.42) | 12-month brain tumor recurrence rate 46.8% vs. 76.4% (p < 0.001). | Salvage brain treatment less frequent in the WBRT + SRS group (n = 10) vs. SRS alone (n = 29) (p < 0.001); SCLC excluded | [20] |
| Chang et al. | 1–3 | SRS +WBRT vs. | n = 28 (SRS + WBRT) | 55% | Mean probability of 5 point decline in HVLT-R-TR at 4 months 52% vs. 24% (96% confidence) | Median OS (actuarial) 5.7 vs. 15.2 months (p = 0.003) | Terminated early due to difference in primary outcome; SCLC excluded. | [21] | |
| EORTC 22952–26001 | 1–3 | surgery or SRS -> | n = 179 (SRS or surgery alone) | 53% | Median time to WHO performance status deterioration to more than 2 was 10.0 vs. 9.5 months (p = 0.89) | Median OS 10.9 vs. 10.7 months (p = 0.89). | SCLC excluded | [22] | |
| Alliance NCCTG N0574 | 1–3 | SRS + WBRT vs. | n = 102 (SRS + WBRT) | 69% | Cognitive deterioration (decline > 1 standard deviation from baseline on.1 cognitive test) 91.7% vs. 63.5% (p < 0.001) | Quality of life −12.0 vs. −1.0 pts p = 0.001 at 3 months. | SCLC excluded | [23] | |
| SRS dose | RTOG 90-05 | 1 | ≤20 mm 18–24 Gy | n = 156 patients | 43% NSCLC or breast | For ≤20 mm, grade 3–5 neurotoxicity in 11% of pts with 21 Gy and 10% with 24 Gy. For 21–30 mm, grade 3–5 neurotoxicity in 20% of pts with 18 Gy, 38% with 21 Gy, and 58% with 24 Gy. For 21–40 mm, grade 3–5 neurotoxicity in 14% of pts with 15 Gy, 50% with 18 Gy. | The actuarial radionecrosis incidence was 5%, 8%, 9%, and 11% at 6, 12, 18, and 24 months after SRS, respectively | For tumors < 20 mm, 24 Gy dose determined by investigator preference not to escalate to 27 Gy, rather than excessive toxicity | [53] |
| Kim et al. | 1–3 | 24 Gy in 3 fractions | n = 15 (24 Gy/3 fx) | 72% | The 6-month cumulative incidence of radiation necrosis was 0% with 24 Gy/3 fx, 13% (95% CI 0–29%) with 27 Gy/3 fx, and 37% (95% CI 1–58%) with 30 Gy/3 fx. | 12-month PFS 65% with 24 Gy/3 fx, 80% with 27 Gy/3 fx, and 75% with 30 Gy/3 fx. 24 Gy/3 fx significantly associated with local treatment failure (p = 0.037) | [52] | ||
| NRG-BN013 | 1–8 | SRS in 1 fraction vs. | n = 269 (estimated enrollment) | Not yet reported | Time to local failure; not yet reported | Intracranial PFS, overall survival, differences in failure patterns, rates of radiation necrosis, time to salvage WBRT, post-treatment adverse events | maximum diameter ≥ 1.0 cm and ≤3.0 cm | NA | |
| SRS to an | Yamamoto (JLGK0901) | 1–10 | NA | n = 455 (1 BrM) | 76% (included SCLC) | Non-inferior OS for 2–4 tumors vs. 5–10 HR 0.97, 95% CI 0.81–1.18, p < 0.0001 for non-inferiority | Proportion of SRS-induced grade 3–4 adverse events: 2% of pts with 1 tumor, 2% of pts with 2–4 tumors, and 3% of pts with 5–10 tumors | [25] | |
| Li et al. (NCT01592968) | 4–15 | SRS vs. | n = 50 (SRS) | Not yet reported | HVLT_R_TR (memory function) at 4 months Z-score decreased by 0.21 vs. 0.74 (p = 0.041) | Median OS 7.8 vs. 8.9 months (p = 0.59) | Early termination due to NRG CC001 | [55] | |
| NCT03075072 | 5–20 | SRS vs. | n = 196 (estimated enrollment) | Not yet reported | Quality of life (MDASI-BT) | Overall survival, neurologic survival, incidence/time to detection of new BrM, incidence/time to LR of treated BrM, development of radionecrosis, development of LMD, incidence/time to salvage surgery or WBRT, time to neurologic decline | SCLC excluded | NA | |
| NCT03550391 | 5–15 | SRS vs. | n = 206 (estimated enrollment) | Not yet reported | Overall survival, neurocognitive PFS | Time to CNS failure, differences in CNS failure patterns, number of salvage procedures, time to (re)initiation of systemic therapy, estimated cost, quality of life | SCLC excluded; Will collect plasma/serum samples, imaging features on MRI that may predict tumor control/neurocognitive outcomes, and dosimetry | NA | |
| NCT04277403 | 4–15 | SRS vs. | n = 150 (estimated enrollment) | Not yet reported | Intracranial progression free survival | Neurocognitive function (VLMT, COWAT, TMT), local control rate (MRI/FET-PET), survival, quality of life | SCLC excluded; simuntaneously integrated boost to each metastasis of 51 Gy to 95% of PTV in 12 fractions 4.25 Gy/fraction | NA | |
| NCT03775330 | 5–30 | SRS vs. | n = 126 (estimated enrollment) | Not yet reported | HLVT-R-TR 2 months post treatment | Additional neurocognitive tests including HLVT-R, TMT, COWA, and CTB COMP; local control, distant brain failure, overall CNS response, overall survival, and quality of life | SCLC excluded | NA | |
| SRS + tumor treating fields (TTF) | METIS (EF-25) | 1–10 | SRS vs. | n = 298 | 100%, NSCLC | Time to first intracranial progression 11.3 vs. 21.9 months with the addition of TTF (HR 0.67, 95% CI 0.48–0.93, p = 0.02) | Adverse events with TTF mainly dermatological; TTF | no prior WBRT | [59] |
| Surgery + | “Patchell I” | 1 | Surgery + WBRT vs. | n = 25 (surgery +WBRT), | 77% | Median OS 40 vs. 15 weeks | Functional independence 38 vs. 8 weeks p < 0.005 | [16] | |
| “Patchell II” | 1 | Surgery + WBRT vs. | n = 49 (WBRT), | 60% | Intracranial recurrence 18% vs. 70% p < 0.001 | DBC 86% vs. 63% p < 0.01 | RT dose 50.4 Gy/28 fractions higher than standard of care | [17] | |
| Mahajan et al. | 1–3 | Surgery + SRS vs. | n = 64 (SRS) | 10% | 12-month local tumor free recurrence rate was 72% (95% CI 60–87%) vs. 43% (95% CI 31–59%) with a HR 0.46 (95% CI 0.24–0.88, p = 0.015) | Median OS 17 vs. 18 months (p = 0.24). The probability of being free of distant BrM at 12 months was 42% vs. 33% (p = 0.35) | 46% of patients in the observation arm underwent WBRT compared to 38% in the SRS arm | [64] | |
| NCCTG N107C/CEC·3 | 1–4 | SRS to cavity vs. | n = 98 (SRS), | 59% | Cognitive-deterioration free survival 3.7 vs. 3.0 mo. p < 0.0001 | LC 61.8% vs. 87.1% at 1 y p = 0.00016 | After post-hoc central review, no diffference in LC between SRS and WBRT | [65,66] | |
| SRS vs. WBRT | ENCEPHALON | 1–10 | SRS or SRT (for >3 cm) vs. WBRT | n = 26 (SRS or SRT) | 100%, SCLC | Drop of at least 5 points from baseline in HVLT-R 7.7% vs. 24% (p = 0.0723) | median OS 124 vs. 131 days (p = 0.36), QoL | inclusion criteria included KPS > 50, which is lower than trials for NSCLC | [62] |
| Ayal Aizer et al. | 1–10 | SRS or SRT (for >2 cm) vs. | n = 66 (SRS) | 100%, SCLC | Rate of neurologic death at 1 year 11.0% (95% CI 4.8–17.2%) | Median OS 10.3 months | Compared to their WBRT outcomes indirectly, which showed 1-year rate of neurologic death in 17.5% of pts | [63] | |
| NCT06457906 | 1–10 | SRS or SRS vs. | n = 340 (estimated enrollment) | 100%, SCLC | Cognitive function (HVLT-R-TR at 6 months), median overall survival | MoCA score at 3, 6, 9, and 12 months, quality of life scores, neurological PFS, intracranial PFS, PFS, treatment-related toxicities | NA | ||
| NRG CC009 | 1–10 | SRS vs. | n = 200 (estimated enrollment) | 100%, SCLC | Cognitive function failure (cognitive decline measured on HVLT-R, COWA, or TMT) | Perceived difficulties in cognitive abilities, symptom burden (MDASI-BT), intracranial PFS, overall survival, incidence of neurologic death, adverse effects, radionecrosis | NA | ||
| PCI | Auperin et al. (meta-analysis of 7 trials) | NA | PCI vs. | n = 987 | 100%, SCLC | OS at 3 years 20.2% with PCI vs. 15.3% without (HR 0.84, 95% CI 0.73–0.97, p = 0.01). | Decreased incidence of BrM with PCI (RR 0.46, 95% CI 0.38–0.57, p < 0.001) | [32] | |
| Slotman | NA | PCI vs. | n = 143 (PCI) | 100%, SCLC | PCI associated with decreased risk of symptomatic BrM (HR 0.27, 95% CI 0.16–0.44, p < 0.001) | Median DFS 12.0 vs. 14.7 weeks (p = 0.02), median OS 5.4 vs. 6.7 months (p = 0.003) | [33] | ||
| Takahashi et al. | NA | MRI surveillance vs. | n = 111 (observation) | 100%, SCLC (ES) | Median overall survival 11.6 vs. 13.7 months (p = 0.094) | Most frequent grade 3 or worse adverse events were anorexia (2% vs. 6%), malaise (1% vs. 3%), and weakness in a lower limb (5% vs. 1%) | Terminated at interim analysis due to PCI being superior to observation | [46] | |
| MAVERICK (SWOG S1827) | NA | MRI surveillance vs. | n = 668 (estimated enrollment) | 100%, SCLC | Overall survival; not yet reported | Cognitive failure free survival, brain-metastasis-free survival, frequency/severity of toxicities | NA | ||
| EORTC PRIMALung | NA | MRI surveillance vs. | n = 600 (estimated enrollment) | 100%, SCLC | Overall survival; not yet reported | Cognitive failure-free survival, quality of life, and acute/late toxicities | [47] | ||
| HA-PCI | PREMER | NA | PCI vs. | n = 75 (PCI) | 100%, SCLC | Decline in delayed free recall on the FCSRT at 3 months was 23.5% vs. 5.8% p = 0.003 | Quality of life, incidence of BrM, and OS not significantly different between the 2 groups | [43] | |
| Belderos et al. | NA | PCI vs. | n = 84 (PCI) | 100%, SCLC | HVLT-R-TR decrease of 5 points or more in 29% (PCI) vs. 28% (HA-PCI) p = 1.00. | No significant differences on any cognitive tests between the groups | [44] | ||
| NRG CC003 | NA | PCI vs. | n = 392 patients total | 100%, SCLC | Non-inferior 12-month intracranial response rate (14.8% PCI vs. 14.2% HA-PCI, p < 0.0001 non-inferiority) | No significant difference in OS (adjusted HR 0.83, 95% CI 0.63–1.09, p = 0.19) | HA-PCI arm had lower COWA scores at bseline and showed greater deterioration in COWA over time (−0.259, p = 0.042) | [45] |
3. Systemic Therapy
3.1. Targeted Therapies
In NSCLC, especially adenocarcinoma, personalized therapeutic approaches have led to the development of increasingly efficacious targeted inhibitors for patients with actionable alterations, including in EGFR, ALK, KRAS, BRAF, RET, ROS1, MET, and NTRK [68]. There are increasing data for the CNS efficacy of newer-generation tyrosine kinase inhibitors (TKIs), although much of the data still come from secondary analyses of subsets of prospective trials (Table 2).
In NSCLC patients with canonical EGFR mutations, osimertinib is a third-generation TKI developed to overcome resistance to the EGFR T790M mutation [69], shown to exhibit penetrance of the blood–brain barrier in non-human primate studies [70]. In pre-planned analyses of patients with measurable and/or nonmeasurable CNS lesions in the phase III trials AURA3 [71] and FLAURA [72], osimertinib monotherapy led to a 40% CNS ORR in patients with EGFR T790M and resistance to previous TKI treatment and a 66% CNS ORR in the first-line setting; higher CNS ORRs were seen in patients with ≥1 measurable CNS lesion (Table 2). A phase II cohort study of 160 mg osimertinib NSCLC patients with EGFR T790M and BrMs or LM demonstrated an intracranial ORR of 55% in the BrM patients and intracranial progression was observed in 18.5% of the LM patients [73], suggesting that doubling the dose could be a reasonable strategy for the local control of BrMs and LM. In patients without CNS metastases, the ADAURA study of 682 stage IB-IIIA NSCLC patients showed that the CNS DFS HR was 0.36 (95% CI 0.23 to 0.57) for adjuvant osimertinib relative to placebo, suggesting a role for osimertinib in CNS prophylaxis [74]. In contrast to typical EGFR mutations, data on the intracranial efficacy of inhibitors targeting EGFR/ERBB2 exon 20 insertions in NSCLC have been limited [75,76] (Table 2).
Second- and third-generation ALK inhibitors have also shown promising intracranial control in patients with ALK fusion-positive NSCLC [77,78,79,80,81,82] (Table 2). A post hoc analysis of the phase III ALEX trial randomizing treatment-naïve patients with ALK mutations to alectinib or crizotinib demonstrated that the intracranial ORR was 85.7% with alectinib (n = 25) vs. 71.4% with crizotinib (n = 21) in patients who had received prior radiotherapy and 78.6% (n = 21) versus 40.0% (n = 22) in patients with previously untreated BrMs [78]. In addition, the CROWN trial randomized 296 treatment-naïve patients with ALK-mutated NSCLC to lorlatinib or crizotinib, and a post hoc analysis demonstrated that in the patients with baseline BrMs (n = 37 lorlatinib, n = 39 crizotinib), the intracranial ORR was 65% vs. 18% favoring lorlatinib [81]. Importantly, the median time to intracranial progression with lorlatinib was not reached versus 16.4 months with crizotinib, suggesting durable responses were achieved with lorlatinib. Moreover, a phase II trial evaluated lorlatinib in patients who had previously received one to three prior ALK TKIs; among 57 patients with BrMs at baseline, the intracranial ORR was 56.1% [77].
In the Ras-Raf pathway, inhibitors of KRAS G12C have demonstrated modest local control for intracranial metastasis, while data on BRAF V600E in NSCLC patients are limited [83,84] (Table 2). The phase II CodeBreaK100 trial demonstrated an ORR of 37.1% and a median duration of response (DoR) of 11.1 months for sotorasib in KRAS G12C-mutated NSCLC, although intracranial outcomes were not assessed [85]. Adagrasib exhibited an intracranial ORR of 33.3% (94% CI 18.0–51.8) among 33 patients with NSCLC with KRAS G12C mutations with previously treated stable BrMs [86]. In the phase I/II trial of garsorasib in KRAS G12C-mutated NSCLC, 11 of 79 patients had stable BrMs and exhibited an intracranial ORR of 17% [87].
RET, ROS1, MET, and NTRK encode receptor tyrosine kinases that are mutated in a small proportion of lung adenocarcinomad and for which selective and multi-kinase inhibitors have recently been developed with CNS activity (Table 2). In the phase I/II ARROW, LIBRETTO-001, and LIBRETTO-321 trials assessing selective RET inhibitors in patients with RET fusion-positive NSCLC, a small portion of patients had measurable BrMs at baseline and exhibited intracranial response rates of 56–91% [88,89,90]. In addition, a post hoc analysis of the LIBRETTO-001 and LIBRETTO-201 trials of selpercatinib in RET fusion-positive NSCLC found that the incidence of BrMs remained at 0% for up to 36 months in 30 patients without BrMs at baseline [91].
Similarly, potent and selective ROS1 inhibitors were shown to have high rates of intracranial ORR (79–89%) in phase I/II clinical trials in patients with NSCLC positive for ROS fusions [92,93] (Table 2). In patients with MET exon 14 skipping mutations, which act as oncogenic drivers in 3–4% of NSCLC [68], selective MET inhibitors were found to cause intracranial responses in 7 of 13 (53.8%) and 5 of 7 (71.4%) patients with measurable BrMs at baseline in the GEOMETRY mono-1 ad VISION trials, respectively [94,95]. In patients with NRTK1/2/3 gene fusions, the tropomyosin receptor kinase inhibitor entrectinib demonstrated an intracranial response in 6 of 11 patients with NRTK1/2/3 fusion-positive NSCLC and BrMs at baseline [91].
The antibody–drug conjugate trastuzumab-deruxtecan (T-DXd) has demonstrated efficacy in HER2-mutated NSCLC metastatic to the brain. In the phase II DESTINY-Lung-01 trial of T-DXd in unresectable and/or metastatic HER2-expressing NSCLC, the HER2-mutated cohort included 33 patients with stable BrMs and showed an intracranial ORR of 54.5% [96], while a intracranial response was not reported in the HER2-overexpressng cohort [97]. Similarly, the phase II DESTINY-Lung-02 trial evaluating the dosing of T-DXd in HER2-mutated metastatic NSCLC demonstrated CNS response rates of 45–60% [98]. In patients with EGFR-mutated NSCLC, the HERTHENA-Lung01 phase II trial evaluated patritumab deruxtecan (HER3-DXd) in patients who progressed with EGFR TKI therapy and platinum chemotherapy. In 30 patients with baseline BrMs (no prior radiotherapy), the intracranial ORR was 33.3% (95% CI 17.3–52.8) [99]. The ongoing HERTHENA-Lung02 phase III trial is randomizing patients with progression on third-generation EGFR TKIs to HER3-DXd or platinum chemotherapy and will evaluate the intracranial PFS along with secondary endpoints (NCT05338970) [100].
Bispecific antibodies can inhibit ligand binding for signaling pathways as well as lead to the activation of the anti-tumor immune response and increasingly are being tested in lung cancer [101]. The PAPILLON trial examined the addition of amivantamab, a bispecific antibody targeting EGFR and c-MET that can activate monocytes/macrophages and NK cells through its Fc domain, to chemotherapy in patients with NSCLC with EGFR exon 20 insertions [102]. Although the addition of amivantamab led to an ORR of 73% compared to 47% with chemotherapy alone, the CNS efficacy was not evaluated and patients with untreated BrMs were excluded. In the phase III MARIPOSA trial, patients with EGFR-mutated NSCLC were randomized to the first-line treatment of osimertinib or amivantamab with lazertinib, which demonstrated a benefit on the PFS in patients with a history of BrMs with amivantamab and lazertinib (HR 0.69, 95% CI 0.53–0.92), although the intracranial ORR and PFS were not described [103]. The MARIPOSA-2 trial examined the intracranial response rates in patients with EGFR-mutated NSCLC treated with amivantamab with carboplatin-pemetrexed with or without lazertinib and found that amivantamab with chemotherapy led to prolonged median intracranial PFS relative to chemotherapy alone (12.5 versus 8.3 months) [104]. The majority of trials of bispecific antibodies in lung cancer to date have excluded symptomatic and/or active BrMs [102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118] (Table 3). Randomized studies evaluating the impact on CNS efficacy and prevention of BrMs of bispecific antibodies are needed to elucidate if they are effective in achieving an intracranial response or preventing the formation of new BrMs.
Collectively, the findings from these trials demonstrate that targeted inhibitors with CNS penetrance offer the potential for CNS disease control in NSCLC. Further randomized trials with an emphasis on the degree and duration of the intracranial response and long-term CNS PFS are needed to evaluate the durability of CNS responses in NSCLC with targetable mutations and BrMs. The combination of targeted inhibitors with platinum chemotherapy is also being evaluated as a strategy for achieving higher rates of local control for BrMs and preventing the development of new CNS lesions. The GAP-BRAIN trial randomized patients with untreated EGFR-mutant NSCLC BrMs to gefitinib alone or gefitinib with pemetrexed and platinum chemotherapy [119]. Gefinitib and chemotherapy improved the intracranial PFS (15.6 months (95% CI, 14.3–16.9 months) vs. 9.1 months (95% CI, 8.0–10.2 months)) compared with gefitinib alone. The intracranial ORR was 85% with gefinitib and chemotherapy vs. 63% with gefitinib alone (p = 0.002), although grade 3 and higher adverse events were common [119]. The phase III FLAURA2 trial randomized patients to osimertinib monotherapy or osimertinib with platinum-pemetrexed and included brain scans of all patients at baseline and progression [120]. The CNS ORR was 73% in the combination-treated versus 69% in the monotherapy group. The intracranial PFS was 20.1 (0–33.3) months in the combination arm and 13.9 (0–33.1) months in the monotherapy arm. A critical limitation of osimertinib with platinum chemotherapy was a doubling of the incidence of grade 3–5 adverse events as well as a doubling of fatal events in the combination treatment arm compared to those with osimertinib alone [120,121].
3.2. Chemotherapy and Immunotherapy
First-line platinum-based chemotherapy has been shown to yield an intracranial ORR of 20–30% in patients with stage IV NSCLC with BrMs [122] and cisplatin and pemetrexed can achieve CNS response rates up to 40% in lung adenocarcinoma [123]. Immune checkpoint inhibitors (ICIs) are an established strategy in the management of metastatic NSCLC, especially in patients without oncogene driver mutations (NCCN guidelines). However, data on the efficacy of ICIs in BrMs are limited. A prospective study of NSCLC patients treated with programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) blockade with or without anti–cytotoxic T-lymphocyte antigen 4 (CTLA4) included 255 patients with BrMs, of which 39.2% were active, 14.3% were symptomatic, and 27.4% were treated with steroids, demonstrating an intracranial ORR of 27.3% in the active BrMs [124]. In a phase 2 trial evaluating pembrolizumab in patients with NSCLC or melanoma and untreated BrMs (5–20 mm in size, not previously treated or with progression after prior radiotherapy), intracranial responses were observed in 29.7% of the cohort with at least 1% PD-L1 expression (n = 37); no intracranial responses occurred in the patients with less than 1% or unevaluable PD-L1 expression (n = 5) [125]. A post hoc analysis of the Checkmate 227 trial part 1 examined intracranial outcomes in NSCLC patients with tumor PD-L1 expression 1% or greater treated with nivolumab plus ipilimumab or chemotherapy [126]. The intracranial progression-free survival at 5 years was 16% (95% CI: 5–33) with nivolumab plus ipilimumab and 6% (95% CI: 1–22) with chemotherapy. In the patients with baseline BrMs, 4% developed new brain lesions with nivolumab plus ipilimumab compared to 20% with chemotherapy, while the rates of new BrMs in the patients without baseline BrMs were comparable [126].
Although the blood–brain barrier [127] and relatively immune-privileged status of the CNS [128] were thought to limit the access of systemic therapies to the brain, these studies suggested that chemotherapy and ICIs have some intracranial efficacy against BrMs. Given the low intracranial response rates to either modality, ongoing trials are evaluating the efficacy of combining PD-1/PD-L1 blockade and chemotherapy in treatment-naïve NSCLC with BrMs. The phase II CAP-BRAIN trial has revealed an intracranial ORR of 52.5% in treatment-naïve patients with nonsquamous NSCLC without EGFR mutations or ALK translocations and at least three BrMs treated with camrelizumab and carboplatin/pemetrexed [129]. Similarly, the phase II Atezo-Brain trial evaluated atezolizumab with carboplatin/pemetrexed in EGFR- and ALK-negative nonsquamous NSCLC with untreated asymptomatic or symptomatically controlled BrMs [130]. The median intracranial PFS was 6.9 months and the intracranial ORR was 42.7%; an exploratory analysis showed a comparable intracranial response in the patients receiving steroids (50%) compared to those who were not (39%), suggesting corticosteroid use did not impair the intracranial responses in the context of ICIs and chemotherapy in this trial [130].
Targeting the signaling of vascular endothelial growth factor (VEGF) has also been proposed to prevent BrM formation in lung adenocarcinoma [131]. A phase II trial examined ramucirumab (anti-VEGFR-2) and docetaxel in stage IV NSCLC after progression on prior chemotherapy [132]. In 25 patients, the median intracranial PFS was 4.6 months and the intracranial ORR was 20%. The phase III Impower150 study randomized patients with chemotherapy-naïve stage IV nonsquamous NSCLC to atezolizumab plus carboplatin/paclitaxel (ACP), bevacizumab (anti-VEGF) plus carboplatin/paclitaxel (BCP), or atezolizumab plus bevacizumab plus carboplatin/paclitaxel (ABCP) [133]. Although patients with untreated BrMs were excluded, CNS imaging was performed at baseline and as clinically indicated. New BrMs developed in 11.9% of the patients treated with ACP, 6.0% of the patients treated with BCP, and 7.0% of the patients treated with ABCP; the median time to development of new BrMs was not met. Randomized studies examining VEGF/VEGFR inhibition in patients with BrMs are needed to further evaluate if targeting this pathway is efficacious in preventing the development of BrMs in nonsquamous NSCLC [133].
In SCLC, objective intracranial responses to chemotherapy have been reported in the range of 30%, including in the case of symptomatic BrMs [134,135]. In a large retrospective study, first-line combination chemotherapy achieved a systemic response rate of 73% and an intracranial response rate of 27%; however, the time to symptom progression was comparable between the intracranial responders and non-responders [136]. In a randomized trial from the EORTC, the addition of WBRT to teniposide increased the intracranial response rate to 57% [137]. In these patients, the survival was poor (the median was approximately 3 months) and WBRT offered no significant improvement in survival over teniposide therapy alone.
Immune checkpoint blockade was shown to produce systemic response rates up to 33% in patients with ES-SCLC [138,139]. Recent clinical trials have shown CNS efficacy in SCLC with the addition of PD-1/PD-L1 blockade to chemotherapy. The IMPower133 trial evaluated the addition of atezolizumab to carboplatin and etoposide, with 11% of patients receiving PCI in both arms. In a secondary analysis of the trial, atezolizumab led to a doubling of the time to intracranial progression in both patients who had received PCI and in those who had not [140]. In addition, the bispecific antibody tarlatamab targeting delta-like ligand 3 (DLL3) and the CD3 T-cell co-receptor has shown systemic efficacy in previously treated SCLC; patients with stable, treated BrMs were allowed, although the intracranial efficacy outcomes have not been reported [141].
Table 2Intracranial efficacy of selected targeted therapies in lung cancer.
| Drug Class | Target(s) | Trial Name | Arms | Phase | Patient Characteristics | No. of Pts with BrM | CNS Disease Inclusion Criteria | Measurement of CNS Response | CNS Outcomes | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| Targeted inhibitor (e.g., tyrosine kinase inhibitors, inhibitors of MAPK pathway) | Typical EGFR (L858R, Ex19del, T790M) | AURA3 | Osimertinib | III | Progression on 1st line EGFR TKI treatment and | Any BrM: | Asymptomatic, stable CNS metastases not requiring steroids at least 4 weeks before study entry | RECIST 1.1 | CNS ORR | [71] |
| FLAURA | Osimertinib vs. | III | Stage IIIB-IV | Any BrM: | Asymptomatic, stable CNS metastases included; if symptomatic, neurologic status stable ≥2 weeks after completion of definitive therapy and steroids | RECIST 1.1 | CNS ORR | [72] | ||
| ADAURA | Osimertinib | III | Stage IB-IIIA NSCLC | Not reported | Not specified | NA | CNS recurrence in 6% (osimertinib) vs. 11% (placebo) | [74] | ||
| FLAURA 2 | Osimertinib vs. | III | Stage IIIB-IV | Any BrM: | Asymptomatic, stable CNS metastases included; if symptomatic, neurologic status stable ≥2 weeks after completion of definitive therapy and steroids | RECIST 1.1 | CNS ORR | [120] | ||
| GAP-BRAIN | Gefitinib vs. | III | Stage IV | n = 81 (gefitinib) | At least 3 BrM or patients with 1–2 intracranial lesions who were not suitable for or refused radiotherapy | Modified RECIST 1.1 | CNS ORR 63% (95% CI 52–74%) vs. 85% (95% CI 77–93%) p = 0.002 | [105] | ||
| EGFR/ERBB2 Ex20ins | ZENITH20 | Poziotinib | II | Stage IIIB-IV | n = 36 (EGFR Ex20 insertion) | BrM allowed if asymptomatic or previously treated (must be stable on post-radiation MRI) | Modified RECIST 1.1 | CNS ORR 8.3% (CR) | [75] | |
| NCT02716116 | Mobocertinib | I/II | Stage IIIb-IV NSCLC or other solid tumors | n = 12 | Active BrM allowed | NA | CNS ORR not reported | [76] | ||
| ALK | NCT01970865 | Lorlatinib | II | Stage IV NSCLC | n = 95 (n = 67 with prior brain-directed RT) | Asymptomatic treated or untreated CNS metastases were allowed; Excluded if SRS or partial brain RT within 2 weeks prior to randomization or WBRT within 4 weeks prior to randomization | Modified RECIST 1.1 | Intracranial ORR 56.1% (95% CI 42.4–69.3%); median intracranial duration of response 12.4 months (95% CI 6.0–37.1) | [77] | |
| ALEX | Alectinib vs. | III | Stage IIIB-IV | Any BrM: | BrM or LMD allowed if asymptomatic | RECIST 1.1 | CNS ORR | [78] | ||
| J-ALEX | Alectinib vs. | III | Stage IIIB-IV | Any BrM: | BrM or LMD allowed if asymptomatic (>2 weeks since last dose of steroids prior to enrollment) | RECIST 1.1 | CNS progression longer with alectinib than crizotinib (HR 0.22, 95% CI 0.10–0.48, p < 0.0001) | [79] | ||
| ALTA-1L | Brigatinib vs. | III | Stage IIIB-IV | Any BrM: | Asymptomatic or stable BrM allowed (no increased dose of steroids or anticonvulsants for 7 d prior to randomization) | RECIST 1.1 | Measurable BrM: CNS ORR 78% (95% CI 52–94%) vs. 26% (95% CI 10–48%) | [80] | ||
| CROWN | Lorlatinib vs. | III | Stage IIIB-IV | Baseline BrM: | BrM allowed if asymptomatic and not currently requiring steroid treatment; Excluded if SRS or partial brain RT within 2 weeks prior to randomization or WBRT within 4 weeks prior to randomization | Modified RECIST 1.1 | Measurable BrM: CNS ORR 82% vs. 23% | [81] | ||
| NCT04009317 | Envonalkib vs. | III | Stage IIIB-IV | Baseline BrM: | BrM allowed if asymptomatic; patients stratified by presence of BrM at baseline | RECIST 1.1 | CNS ORR 79% (95% CIwith envonalkib, 5% with crizotinib | [82] | ||
| BRAF V600E | NCT01336634 | Dabrafenib + trametinib | II | BRAF V600E NSCLC | Cohort C: n = 2 (nonmeasurable, previously treated) | Asymptomatic, untreated BrM (<1 cm in the largest dimension) or treated BrM stable for 3 weeks allowed | RECIST 1.1 | Both patients had non-CR and non-PD | [83] | |
| NCT03915951 | Encorafenib + binimetinib | II | BRAF V600E NSCLC | n = 4 (treatment-naïve) | Excluded if symptomatic or active BrM or LMD | RECIST 1.1 | One patient from each group experienced intracranial progression. | [84] | ||
| KRAS G12C | CodeBreak100 | sotorasib | II | Stage I-IV | n = 26 | BrM excluded if active and/or untreated | NA | Not reported | [85] | |
| KRYSTAL-1 | adagrasib | I/II | Stage III-IV NSCLC | n = 42 | BrM allowed if adequately treated and neurologically stable | NA | CNS ORR 33.3% (95% CI 18–51.8%); median CNS PFS 5.4 months | [86] | ||
| NCT05383898 | garsorasib | I | Stage III-IV NSCLC | n = 11 (n = 6 with measurable BrM at baseline) | BrM excluded if unstable or progressive | RECIST 1.1 | CNS ORR 17%; CNS disease control rate of 100% (note: median overall follow-up 8.8 months) | [87] | ||
| RET | ARROW | pralsetinib | I/II | Treatment-naïve and previously treated | n = 9 (measurable BrM) | Excluded if BrM associated with progressive neurologic symptoms | RECIST 1.1 | CNS ORR 56% (5 of 9 pts had CR) | [88] | |
| LIBRETTO-001 | selpercatinib | I/II | Treatment-naïve and previously treated | n = 22 (measurable BrM) | Allowed if neurologically stable with stable steroid dose for 14 days before enrollment; no surgery or RT w/in 28 days and no SRS within 14 days allowed | RECIST 1.1 | CNS ORR 82% (86% without prior RT, 75% with prior RT) | [89,91] | ||
| LIBRETTO-321 | selpercatinib | II | Treatment-naïve and previously treated | n = 5 (measurable BrM) | Allowed if asymptomatic or previously treated and stable disease for ≥2 weeks | RECIST 1.1 | CNS ORR 80% | [90] | ||
| ROS1 | ALKA-371-001 | entrectinib | I/II | Treatment-naïve and previously treated | n = 46 (any BrM) | Allowed if asymptomatic or previously treated and stable disease | RECIST 1.1 | Measurable BrM: CNS ORR 79.2%, CNS median PFS 12.0 months | [92] | |
| TRIDENT-1 | repotrectinib | II | Treatment-naïve and previously treated | n = 3 (TKI-naïve) | Allowed if asymptomatic; asymptomatic LMD allowed | RECIST 1.1 | TKI-naïve: CNS ORR 100% | [93] | ||
| MET ex14 alteration | GEOMETRY mono-1 | capmatinib | II | Treatment-naïve and previously treated | n = 13 | BrM allowed if no increase in steroid dose within 2 weeks before enrollment | RECIST 1.1 | CNS ORR 54%; 3 of 7 patients with a CNS response received RT | [94] | |
| VISION | tepotinib | II | Treatment-naïve and previously treated | n = 15 (BrM) | Asymptomatic BrM were allowed. | RANO-BM | Measurable BrM: CNS ORR 71%; CNS disease control rate 87% | [95] | ||
| Antibody-drug conjugate | HER2 | DESTINY-Lung01 | trastuzumab deruxtecan | II | Stage III-IV NSCLC | n = 29 (Cohort 1) | Active BrM excluded (defined as untreated and symptomatic or requiring therapy with steroids or anticonvulsants) | NA | Only systemic activity in pts with BrM was analyzed | [96,97] |
| DESTINY-Lung-02 | trastuzumab deruxtecan | II | Metastatic NSCLC with activating HER2 mutation | n = 57 | Active BrM excluded (defined as untreated and symptomatic or requiring therapy with steroids or anticonvulsants) | NA | Only systemic activity in pts with BrM was analyzed | [98] | ||
| HER3 | HERTHENA-Lung01 | HER3-DXd | II | EGFR L858R or Ex19del NSCLC | n = 30 (no prior RT) | Excluded if symptomatic/untreated or requiring therapy with corticosteroids or anticonvulsants | RECIST 1.1 | CNS ORR 33.3% (95% CI 17.3–52.8%) | [99] | |
| HERTHENA-Lung02 | HER3-DXd | III | EGFR L858R or Ex19del NSCLC | Not reported | Active BrM allowed although excluded if active treatment with steroids; LMD excluded | RECIST 1.1 | Not reported | [100] |
Selected clinical trials of immunotherapy agents in lung cancer.
| Drug Class | Target(s) | Trial Name/Number | Arms | Phase | Patient Characteristics | No. of Pts with BrM | CNS Disease Inclusion Criteria | CNS Response | CNS Outcomes | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| Immune checkpoint inhibitors | PD-1 | NCT02085070 | Cohort 1: PD-L1 ≥1% + pembrolizumab | II | NSCLC cohort | n = 42 | Untreated or progressing BrM allowed; 5–20 mm | Modified RECIST 1.1 | Cohort 1: 88% CNS ORR | [125] |
| CAP-BRAIN | Camrelizumab + | II | NSCLC with no prior systemic therapy | n = 45 | BrM allowed if asymptomatic or symptoms controlled with dehydration therapy | Modified RECIST 1.1 | Measureable BrM: CNS ORR 52.5% (95% CI 36.1–68.5%) | [129] | ||
| PD-L1 | Atezo-BRAIN | Atezolizumab + pemetrexed/carboplatin | II | NSCLC with no prior systemic therapy | n = 40 | BrM allowed if asymptomatic or symptoms controlled with medical therapy | RANO-BM | 12-week PFS 62.2% | [130] | |
| PD-1/ | CheckMate 227 | Nivolumab + ipilimumab vs. nivolumab + chemotherapy | III | Stage IV or recurrent NSCLC | n = 202 | BrM allowed if previously treated and asymptomatic | Not reported | Intracranial PFS 16% (95% CI: 5–33) vs. 6% (95% CI: 1–22%) | [126] | |
| Bispecific antibodies | MET/ | PAPILLON | Amivantimab +carboplatin/ | III | NSCLC | Not reported | BrM allowed if stable, asymptomatic, and not requiring steroids or anti-convulsants for ≥14 d | Not reported | Not reported | [102] |
| MARIPOSA | Amivantimab | III | Stage III-IV NSCLC | Not reported | BrM allowed if stable and asymptomatic | Not reported | Not reported | [103] | ||
| MARIPOSA-2 | chemotherapy vs. | III | Stage III-IV NSCLC | n = 120 (chemo) | BrM allowed if stable and asymptomatic | Not reported | Not reported | [104] | ||
| CHRYSALIS | Amivantimab | I | Stage III–IV | n = 18 | BrM allowed if previously treated and asymptomatic at time of screening | NA | No report of CNS responses; no difference in ORR in patients with BrM vs. patients without | [105] | ||
| PALOMA-3 | Amivantimab IV vs. subcutaneous | III | NSCLC | n = 34 (i.v.) | BrM excluded if symptomatic or progressive; LMD excluded | Not reported | Not reported | [106] | ||
| CHRYSALIS-2 | Amivantimab + lazertinib | I/IB | EGFR-mutated NSCLC with progression on 1st line therapy | n = 8 | BrM allowed if previously treated and asymptomatic at time of screening | Not reported | Not reported | [107] | ||
| HER2/ | NCT02912949 | Zenocutuzumab | I/II | Documented NRG1 gene fusion | Not reported | BrM allowed if previously treated and asymptomatic | Not reported | Not reported | [108] | |
| HER2/ | NCT04521179 | KN026 + KN046 | II | HER2-positive (IHC 3+ or HER2 gene amplification) solid tumors | Not reported | BrM allowed if previously treated and asymptomatic | Not reported | Not reported | [109] | |
| PD-1/ | COMPASSION-01 | Cadonilimab | I | Metastatic solid tumors refractory to standard therapies or no standard therapy | Not reported | Not specified although patients receiving steroids within 14 d of drug administration were excluded | Not reported | Not reported | [110] | |
| NCT04172454 | Cadonilimab | Ib/II | NSCLC that had previously failed platinum-based doublet chemotherapy | Not reported | Not specified although patients receiving steroids within 14 d of drug administration were excluded | Not reported | Not reported | [111] | ||
| NCT04646330 | Cadonilimab + anlotinib | Ib/II | Stage IIIB-IV NSCLC | Not reported | Active BrM excluded | Not reported | Not reported | [112] | ||
| MAGELLAN | Multi-arm study | Ib | Stage III NSCLC with progression on prior treatment | Not reported | Untreated BrM excluded | Not reported | Not reported | [113] | ||
| PD-L1/ | ENREACH-L-01 | KN046 + carboplatin/paclitaxel vs. | III | Stage IV squamous NSCLC | NA | BrM and LMD allowed if treated or asymptomatic | NA | NA | NA | |
| NCT03838848 | KN046 | II | NSCLC, failure on platinum-based chemotherapy | n = 3 | BrM excluded if untreated or active | Not reported | Not reported | [114] | ||
| NCT04054531 | KN046 + pemetrexed (non-squamous) | II | Stage IV NSCLC, treatment-naïve | n = 15 | BrM excluded if untreated or symptomatic | Not reported | Not reported | [115] | ||
| PD-1/ | NCT04931654 | AZD7789 | I/II | Stage IIIB-IV NSCLC (Part A) | Not reported | Symptomatic BrM or LMD excluded | NA | NA | NA | |
| PD-1/ | ARTEMIDE-01 | Rilvegostomig | I/II | Stage III-IV NSCLC | 22.5% | Symptomatic BrM excluded | Not reported | Not reported | [116] | |
| PD1/ | HARMONi-5 | Ivonescimab | 1b | Stage IIIB-IV NSCLC | Not reported | Active BrM excluded; note: also excluded pateints receiving steroids in the past 2 years | Not reported | Not reported | [117] | |
| CD3/ | NCT02324257 | RO6958688 | I | Confirmed CEA expression in tissue (non-CRC patients) | Not reported | BrM allowed if previously treated, asymptomatic, and not requiring steroids or anti-convulsants for ≥14 d | NA | NA | NA | |
| NCT026501713 | RO6958688 + atezolizumab | Ib | Confirmed CEA expression in tissue (non-CRC patients) | Not reported | BrM excluded if active or untreated, including if identified on CT/MRI during screening | NA | NA | NA | ||
| Morpheus-Lung | Numerous arms, including: | I/II | NSCLC | Not reported | BrM excluded if symptomatic, untreated, or actively progressing; LMD excluded | NA | NA | [118] | ||
| CD3/ | NCT04496674 | Ab CC-1 + toczilizumab | I/II | Lung SCC | NA | BrM and LMD excluded | NA | NA | NA | |
| NCT04822298 | AMG 160 | Ib | NSCLC | Not reported | BrM and LMD allowed if treated or asymptomatic | NA | NA | NA |
4. Combinatorial Strategies
In EGFR-mutated NSCLC, Magnuson et al. performed a multi-institutional analysis to evaluate multidisciplinary optimal management options for patients with BrMs managed with the first-generation TKI erlotinib [142]. The patients were treated with SRS or WBRT followed by EGFR-TKI or an upfront EGFR-TKI alone, reserving SRS or WBRT for subsequent intracranial progression. The upfront SRS followed by TKI was associated with a prolonged OS (46 months) relative to the upfront WBRT (30 months) or TKI alone (26 months, p = 0.001). Retrospective studies in the era of newer-generation TKIs with enhanced CNS activity have exhibited varying results. One study comparing a CNS-penetrant TKI alone to a CNS-penetrant TKI with CNS radiation therapy (RT) in EGFR- and ALK-mutated NSCLC found no significant differences in the time to progression or time to intracranial progression between the TKI alone or with CNS RT [143]. In contrast, a Japanese study investigated osimertinib alone or with upfront CNS RT for BrMs from EGFR-mutated NSCLC and reported that both the OS and intracranial PFS were significantly longer with upfront RT compared to with osimertinib alone [144]. The TURBO-NSCLC retrospective study of patients treated at seven US centers examined CNS-penetrant TKIs with or without upfront SRS in patients with EGFR or ALK alterations [145]. The patients receiving upfront SRS were more likely to have at least one BrM measuring 1 cm or larger (p < 0.001) and neurologic symptoms (p < 0.001) at initial presentation. The upfront SRS was associated with improvements in the local CNS control (HR 0.30 [95% CI 0.16 to 0.55], p < 0.001) and time to CNS progression ([HR], 0.63 [95% CI, 0.42 to 0.96]; p = 0.033), whereas there were no differences in the OS. The patients with larger BrMs (≥1 cm) had higher rates of CNS progression, and the subgroup analyses suggested that these patients may benefit more from upfront SRS [145].
A strategy of an upfront TKI to reduce the burden of CNS disease and avoid WBRT, potentially followed by SRS, termed “CNS downstaging”, has also being examined as a strategy for EGFR-, ALK-, or ROS1-driven NSCLC patients with extensive BrMs (>10) at presentation [146]. In an initial study from the University of Colorado, 12 patients with a median of 49 BrMs at presentation were treated with upfront CNS-penetrant TKI, resulting in a median 97% reduction in the CNS tumor volume per patient and a median of five residual BrMs at the best CNS response. All the patients avoided WBRT and seven patients subsequently received SRS. This case series suggests that the upfront administration of CNS-active TKIs could represent a promising strategy to downstage extensive CNS presentations and to convert some patients into SRS candidates. Phase II trials are ongoing investigating Osimertinib with or without upfront SRS (NCT03497767, NCT03769103), which have recently been reported in abstract. At 12 months, the intracranial PFS was 70% (95% CI 52–93%) for upfront SRS and 53% (95% CI 34–81%) for upfront osimertinib in LUOSICNS (NCT03769103) and 67% (95% CI 49–93%) with upfront SRS vs. 67% (95% CI 49–90%) for upfront osimertinib in OUTRUN (NCT03497767) [147]. There was no statistically significant difference between the two arms in the intracranial PFS or overall survival. Prospective trials are evaluating outcomes following the randomization of patients with oncogene-mutated NSCLC and asymptomatic BrMs to upfront or delayed cranial RT (SRS or WBRT) (NCT05236946, ICON-RT) and will provide more insight into the timing of SRS in the context of systemic osimertinib.
Given the potential modulating effects of radiation on the anti-tumor immune response [148], there are numerous ongoing studies evaluating the safety and efficacy of combining RT and ICIs. One retrospective analysis examined the activity and toxicity profile of pembrolizumab in patients who had received previous RT (extracranial or thoracic) in the KEYNOTE-001 phase I trial [149]. In the patients who had previously received any RT, pembrolizumab led to an improved median survival compared to that in patients without prior RT (10.7 vs. 5.3 months, p = 0.026). Moreover, the PACIFIC trial demonstrated significantly longer survival in stage III NSCLC patients with the addition of durvalumab to chemoradiotherapy with a lower incidence of new BrMs with durvalumab (5.5% vs. 11.0%) [150]. In regard to the safety of CNS-directed therapies, a retrospective study of patients with newly diagnosed BrMs treated with SRS, including 294 NSCLC patients, found symptomatic radiation necrosis in 20% of patients who had received ICIs compared to 6.8% of patients who had not received ICIs [151]. Phase I/II trials have demonstrated that SRS given with nivolumab/ipilimumab or pembrolizumab has an acceptable safety profile and favorable outcomes [152,153,154]. However, a systematic review of 16 studies found a trend towards increased incidence of radionecrosis with SRS and ICIs compared to SRS alone (16.0% vs. 6.5%, p = 0.065) [155]. An IRRF study of 395 patients with 2540 BrMs found that the risk of any-grade radionecrosis and symptomatic radionecrosis following single-fraction SRS increased as V12 Gy exceeds 10 cm3 and was comparable between concurrent and non-concurrent SRS and ICIs [156]. These results suggest that the combination of SRS and ICIs may lead to the increased incidence of radionecrosis, and prospective studies are needed to elucidate the safety and efficacy of combining these modalities [157]. Prospective trials examining the combination of SRS and ICIs are ongoing (NCT03340129, NCT04889066, NCT05522660, NCT06501391) and will elucidate if this combinatorial strategy can yield durable outcomes in NSCLC patients with BrMs.
5. Leptomeningeal Metastases
Leptomeningeal metastasis (LM), or the spread of cancer to the cerebrospinal fluid (CSF) and leptomeninges, harbors a very poor prognosis. In addition to systemic therapy strategies, LM has historically been treated with radiation for symptomatic disease, WBRT, or, in highly selective cases, cerebrospinal irradiation (CSI). LM presentations are heterogeneous and treatments may be highly individualized. Both WBRT and involved field radiation of symptomatic sites in the brain or spine are commonly used in clinical practice [9]. Photon-based CSI using three-dimensional conformal radiation therapy (3D CRT) has demonstrated improved neurologic function and survival in patients with LM, but also led to significant toxicity to the esophagus, bowel, and bone marrow [158]. Given the toxicity with photon CSI, hypofractionated proton CSI (pCSI) was evaluated in patients with LM and dose-limiting toxicities were found of lymphopenia, thrombocytopenia and fatigue and durable control in 4 of 21 patients, who were free of CNS progression for more than 12 months [159]. A phase II trial subsequently randomized patients with NSCLC or breast cancer and LM 2:1 to pCSI or photon IFRT and found the primary endpoint of CNS PFS to be significantly improved with pCSI versus IFRT (median 7.3 months vs. 2.3 months, p < 0.001) [160]. The NRG phase III RADIATE-LM trial is ongoing to investigate outcomes with pCSI compared to IFRT in breast and NSCLC patients with LM using IMRT (NCT06500481).
Recent developments in systemic therapies have contributed to improved outcomes in LM. A retrospective review of pemetrexed in the treatment of LM in patients with EGFR-mutated NSCLC demonstrated prolonged survival with pemetrexed use after the development of LM relative to no pemetrexed use (median 13.7 months vs. 4.0 months, p = 0.008). However, prospective studies are needed to investigate if systemic chemotherapy can indeed prolong survival in NSCLC patients with LM. CNS-penetrant TKIs have demonstrated activity in LM in patients with oncogene-driven NSCLC, including alectinib in ALK fusion-positive [161], selpercatinib in RET-rearranged [162], and osimertinib in EGFR-mutated [163,164]. In prospective trials of osimertinib in LM in patients with EGFR-mutated NSCLC that had progressed with prior EGFR-directed TKI, the LM ORR was 41% with 160 mg daily [163] and 51.6% with 80 mg daily [164]. A retrospective multi-institutional study of patients with LM treated with osimertinib 160 mg daily found that among patients with CNS progression on 80 mg daily, dose escalation to 160 mg led to a median CNS control of 3.8 months, which was increased to 5.1 months with concurrent chemotherapy and/or radiation [165]. A prospective trial treated patients with EGFR-mutated NSCLC and LM with osimertinib and bevacizumab, achieving an ORR of 50% and a median OS of 12.6 months [166]. Thus, combinatorial strategies with osimertinib represent a promising strategy for the management of LM.
Intrathecal chemotherapy (ITC) has recently been evaluated in NSCLC patients with LM. A pooled analysis was performed of four prospective and five retrospective studies comprising 552 patients; 37 patients received ITC only and achieved a median survival of 7.5 months. The majority of the patients received a multimodal approach (e.g., ITC and SRS) with a median survival of 3.0 to 5.0 months; which could possibly reflect the higher toxicity of combining therapeutic approaches in patients with LM [167]. A phase II trial of intrathecal pemetrexed in patients with EGFR-mutated NSCLC who had progressed on TKIs demonstrated a response rate of 80.3% with acceptable side effects [168]. Further studies are needed to assess the optimal multi-intervention approach to LM.
6. Concluding Remarks
In conclusion, the management of brain metastasis in lung cancer is increasingly personalized. Stereotactic radiosurgery is preferred for up to 10 brain metastases and should be considered for up to 20–30 at the discretion of the treating radiation oncologist [27]. For patients with actionable mutations with CNS-active therapies, multidisciplinary decision making should guide the timing of systemic therapies with SRS or WBRT as appropriate [27]. Increasing systemic therapies are available with CNS activity that can be leveraged to reduce the radiation volume in patients with BrMs. In the case of extensive BrMs, our institutional experience has been to use several approaches depending on the systemic disease, patient factors, and patient preference, including WBRT, WBRT followed by SRS to non-responding lesions, and SRS to larger lesions when patients are on CNS-active therapy (Figure 1). Further prospective randomized trials are needed to guide multidisciplinary management in these various contexts.
7. Future Directions
Collectively, the management of BrMs centers around balancing individual patient factors, e.g., performance status and preference, with preserving neurocognition both by curbing tumor progression as well as sparing healthy brain tissue. The emergence of CNS-penetrant targeted therapies shows promise for providing local control. In addition, the FLAURA2 [120] and CAP-BRAIN [129] trials suggest that combinatorial strategies could overcome drug resistance mechanisms to yield durable intracranial responses and prevent morbid CNS failures. However, the durability of local control from targeted therapies is unclear and the anti-tumor efficacy must be balanced against adverse side effects. The optimal integration of radiotherapy with systemic approaches thus represents an evolving question in the management of BrMs in lung cancer. Studies evaluating the biologic mechanisms of radiation and systemic therapies are needed to elucidate possible synergistic effects, for example, between the immunogenicity of radiation and immune checkpoint inhibitors [156].
It will be crucial to determine through prospective randomized trials which patients may benefit from the combination of SRS and systemic agents vs. de-intensification strategies. Ongoing research regarding predictors of synergistic toxicities between emerging systemic therapies and CNS-directed RT are essential to individualizing patient management. For patients with BrMs from NSCLC with targetable mutations, the ICON-RT trial will investigate a strategy of using upfront CNS-active drug therapy to debulk (or downstage) intracranial disease followed by individualized treatment only to residual or progressive lesions with SRS. This trial will evaluate whether patients with high-risk lesions harboring drug resistance mechanisms might benefit from therapeutic intensification with radiation.
Additionally, advances in radiotherapy, including increasingly targeted radiation techniques, e.g., IMRT over 3D CRT, in combination with approaches to preserve cognitive function, e.g., memantine or hippocampal avoidance, can be leveraged to balance the local control afforded by radiotherapy with the possibility of cognitive decline or radionecrosis. Clinical trials are needed to determine if strategies such as TTFs or the integration of RT with systemic therapies may avoid WBRT in patients with extensive BrMs at baseline.
Another integral aspect of the management of lung cancer BrMs includes predicting which patients will develop BrMs to guide clinical decision making. Radiomics have recently been described as a strategy to predict BrMs in T1 or curatively resected lung adenocarcinoma [170,171]. Cerebrospinal fluid (CSF) circulating tumor cells (CTCs) have been found to be useful both in diagnosing LM [172] as well as in predicting response to pCSI [173]. Cell-free DNA (cfDNA) has been detected in the CSF and has been proposed as a liquid biopsy for monitoring CNS metastases [174]. In addition, cfDNA signatures were found to have a high negative predictive value (85%) and specificity (93%) in excluding BrM development in breast cancer. In lung cancer, unique profiles of circulating tumor DNA (ctDNA) were associated with the development of BrMs and changes in the ctDNA within the CSF could predict intracranial responses [175]. Prospective studies are needed to inform if CSF or peripheral biomarkers can guide the treatment of BrMs. Indeed, prospective studies are underway to sample CSF for CTCs and cfDNA (NCT04343573).
Another approach is evaluating the genomic or histological features of the primary tumor. CDKN2A/B deletions and alterations in the cell cycle pathway have been found to be associated with BrMs while MYC amplifications have been found to be associated with multifocal BrMs [176]. Given that MYC alterations are common in SCLC [6], it is possible that MYC mutations are associated with the pattern of BrMs in SCLC and this warrants further investigation. In addition, the expression of ASCL1 or NEUROD1 on immunohistochemistry, as biomarkers associated with BrMs, was associated with worse CNS outcomes in BrM-free SCLC patients at diagnosis [177]. As biomarkers associated with BrMs are increasingly identified, prospective studies are needed to guide personalized approaches leveraging these findings.
Efforts to predict response have attempted to integrate various features such as imaging, clinical features, and genomic information. A CoxCC model for progression risk stratification of EGFR TKI treatment integrated MR radiomics, clinical features, and a “prognostic index” using molecular markers (lung-molGPA), and the modified lung-molGPA achieved an AUC of 0.88, 0.73, 0.92, and 0.90 for predicting the PFS at 3, 6, 9, and 12 months, respectively [178]. Given the advances in supervised and unsupervised machine learning, further studies to develop predictive models for BrMs in both NSCLC and SCLC patients are needed to guide therapeutic approaches.
Collectively, as advances are made in CNS-penetrant systemic therapies, the integration of radiation with multimodality regimens, and the identification of predictive biomarkers, the management of BrMs will become increasingly personalized. It will be critical to leverage level I evidence to define how best to optimize management. The selection of a multidisciplinary treatment should take into account the CNS disease, overall clinical picture, and patient preference regarding therapeutic tradeoffs, such as intracranial disease control and quality of life.
Conceptualization, L.R.G.P. and C.G.R.; data curation, K.G.H.; writing—original draft preparation, K.G.H.; writing—review and editing, L.R.G.P., C.G.R. and K.G.H.; supervision, L.R.G.P. All authors have read and agreed to the published version of the manuscript.
L.R.G.P has stock or ownership in Clovis Oncology, Schrodinger, and Novavax. L.R.G.P. has a consulting or advisory role in Aviko, Monograph Capital, Galera Therapeutics, Monte Rosa Therapeutics, Best Doctors/Teladoc Inc., Turnstone Biologics, Genece Health, and DxCover Rx. C.G.R and K.G.H. declare no conflicts of interest.
Footnotes
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![View Image - Figure 1. Towards personalized therapeutic strategies in lung cancer patients with BrMs. Due to the hematogenous nature of the dissemination of BrMs, patients historically received WBRT for the treatment of multiple BrMs (left). However, due to clinical trials demonstrating neurocognitive toxicity with WBRT and efficacy of SRS for numerous BrMs, SRS has become the standard of care for up to 10 BrMs and ongoing trials are evaluating the efficacy of SRS up to 30 BrMs (center). In the era of novel targeted therapies and combinatorial strategies with intracranial efficacy, the treatment of BrMs is becoming increasingly personalized (right), with the use of SRS to target persistent metastases or those with poor response to systemic therapies. Images adapted from Figure 3a of Suh et al. [169].](https://media.proquest.com/media/hms/THUM/2/07Jia?_a=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&_s=%2FHiLHwz1MzMtTyhIospzuhUuXUE%3D "View Image - Figure 1. Towards personalized therapeutic strategies in lung cancer patients with BrMs. Due to the hematogenous nature of the dissemination of BrMs, patients historically received WBRT for the treatment of multiple BrMs (left). However, due to clinical trials demonstrating neurocognitive toxicity with WBRT and efficacy of SRS for numerous BrMs, SRS has become the standard of care for up to 10 BrMs and ongoing trials are evaluating the efficacy of SRS up to 30 BrMs (center). In the era of novel targeted therapies and combinatorial strategies with intracranial efficacy, the treatment of BrMs is becoming increasingly personalized (right), with the use of SRS to target persistent metastases or those with poor response to systemic therapies. Images adapted from Figure 3a of Suh et al. [169].")
Enlarge this image.Figure 1. Towards personalized therapeutic strategies in lung cancer patients with BrMs. Due to the hematogenous nature of the dissemination of BrMs, patients historically received WBRT for the treatment of multiple BrMs (left). However, due to clinical trials demonstrating neurocognitive toxicity with WBRT and efficacy of SRS for numerous BrMs, SRS has become the standard of care for up to 10 BrMs and ongoing trials are evaluating the efficacy of SRS up to 30 BrMs (center). In the era of novel targeted therapies and combinatorial strategies with intracranial efficacy, the treatment of BrMs is becoming increasingly personalized (right), with the use of SRS to target persistent metastases or those with poor response to systemic therapies. Images adapted from Figure 3a of Suh et al. [169].
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