Evolving strategies in the management of non-small cell lung cancer brain metastases: insights from the C-Brain trial

Brain metastases represent a common and serious complication in non-small cell lung cancer (NSCLC), affecting nearly one-third of patients over the course of the disease (1). The risk is particularly high among those with oncogene-driven subtypes, such as epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, where up to half may develop brain involvement (1,2). The prognosis for NSCLC patients with brain metastases is generally poor. In the absence of treatment, median survival can be as short as 1 to 2 months. However, aggressive multimodal strategies including whole-brain radiotherapy (WBRT), surgical resection, and systemic therapy with chemotherapy or targeted agents, can significantly improve outcomes (3). Factors consistently associated with better prognosis include younger age (<65 years), good performance status, effective control of the primary tumor, limited extracranial disease, and use of EGFR tyrosine kinase inhibitors in patients with relevant molecular alterations (4).

In contrast, the management of brain metastases in patients with NSCLC lacking actionable mutations remains limited and challenging. These patients are ineligible for tyrosine kinase inhibitors and are typically treated with standard approaches such as WBRT, chemotherapy, or investigational regimens. While combining chemotherapy with WBRT has demonstrated improved survival over radiotherapy (RT) alone, with response rates reported between 42% and 60% (5,6), the effectiveness of systemic therapies is often limited by the blood-brain barrier (BBB), which impedes drug delivery to intracranial lesions. Recent insights into BBB physiology and tumor-microenvironment interactions have catalyzed the development of novel agents and combination strategies designed to enhance central nervous system (CNS) penetration (7). Nevertheless, patients with EGFR wild-type NSCLC and brain metastases continue to face poor prognoses, with a median overall survival (OS) of around 9 months (1), reinforcing the urgent need for more effective therapeutic options.

To address this clinical gap, Xu et al. conducted the C-Brain trial, a multicenter, single-arm phase 2 study evaluating the combination of brain RT, camrelizumab, and platinum-doublet chemotherapy in patients with newly diagnosed metastatic NSCLC and brain metastases lacking actionable driver mutations. The study enrolled 65 patients across nine tertiary centers in China, the majority of whom had symptomatic brain metastases and non-squamous histology. Treatment involved stereotactic or WBRT alongside camrelizumab and investigator-selected chemotherapy, followed by maintenance therapy in those with disease control. The regimen demonstrated a 6-month progression-free survival (PFS) rate of 71.7%, with manageable toxicity (8).

The findings from the C-Brain study contribute to the growing body of evidence supporting the role of immunotherapy in NSCLC patients with brain metastases. Although prospective data remain limited, some studies suggest that immune checkpoint inhibitor (ICI)-based regimens, including those combined with RT, may offer clinical benefits in this population. Pooled analyses from KEYNOTE-021 (cohort G), KEYNOTE-189, and KEYNOTE-407 showed improved outcomes in patients with stable brain metastases treated with pembrolizumab plus chemotherapy vs. chemotherapy alone, with median OS of 18.8 vs. 7.6 months, and PFS of 6.9 vs. 4.1 months (9). Expanding on this, a pooled analysis of four pembrolizumab monotherapy trials (KEYNOTE-001, -010, -024, -042) included 293 patients (9.2%) with treated, stable brain metastases. Pembrolizumab improved OS vs. chemotherapy in this subgroup [hazard ratio (HR) 0.67 for tumor proportion score (TPS) ≥50%; HR 0.83 for TPS ≥1%] and showed benefits in PFS, response rates, and duration of response. Importantly, treatment-related adverse events were lower with pembrolizumab (66.3% vs. 84.4%) (10). Similarly, the 5-year follow-up of CheckMate 227 Part 1 demonstrated durable OS and intracranial PFS with nivolumab plus ipilimumab, along with a reduction in new brain lesions, regardless of baseline brain metastasis status, with fewer new brain lesions observed in patients receiving dual ICI (11). Furthermore, in a phase 1/2 trial, the combination of dual ICI (nivolumab and ipilimumab) with concurrent stereotactic surgery was found to be safe in patients with active brain metastases from NSCLC, with preliminary evidence of intracranial efficacy (12). Additionally, a single-center, propensity-matched study of 480 patients undergoing craniotomy for brain metastasis resection reported longer OS in those receiving postoperative RT and ICIs (23.0 months) compared to those receiving RT and chemotherapy (11.8 months), indicating a synergistic effect of ICI and RT (13).

Camrelizumab, the programmed cell death 1 (PD-1) inhibitor utilized in the C-Brain trial, is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that restores T cell-mediated antitumor activity by blocking the PD-1/programmed death-ligand 1 (PD-L1) interaction. It has demonstrated clinical benefits across multiple malignancies, including NSCLC (14). In the phase 3 CameL trial, camrelizumab combined with chemotherapy significantly improved OS in advanced non-squamous NSCLC without EGFR or ALK alterations, with a 5-year OS rate of 31.2% vs. 19.3% with chemotherapy alone (HR: 0.62). Among patients who completed 2 years of camrelizumab, the 5-year OS reached 84.3%, with durable responses observed in nearly half. These results supported its approval in China as a first-line treatment when used with platinum-doublet chemotherapy, the same country where the C-Brain trial was conducted (8).

C-Brain represents the first prospective trial to evaluate the combination of brain RT [either stereotactic radiosurgery (SRS) or WBRT], camrelizumab, and platinum-doublet chemotherapy in patients with untreated advanced NSCLC and brain metastases lacking actionable driver mutations. Among the 65 enrolled patients, the majority were male (92%) and of Han Chinese ethnicity, with a median age of 66 years. While this reflects the regional treatment landscape in China, the predominance of male participants and genetically homogeneous population may limit the generalizability of the findings—both across diverse global populations and within more heterogeneous patient groups in the same region (15). Patients eligible for enrollment were adults aged 18 years or older with newly diagnosed brain metastases, no EGFR, ALK, or ROS1 alterations, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. All patients received RT in combination with camrelizumab (200 mg IV every 3 weeks) and investigator-selected platinum-doublet chemotherapy for 4–6 cycles. Those achieving disease control transitioned to maintenance therapy with either camrelizumab alone (for squamous histology) or camrelizumab plus pemetrexed (for non-squamous histology) (8).

Complementing this, the Atezo-Brain and CAP-BRAIN trials were pivotal phase II studies evaluating the efficacy of ICI combined with chemotherapy in patients with advanced nonsquamous NSCLC and untreated brain metastases, historically a population underrepresented in previous clinical trials. The Atezo-Brain trial (16) evaluated atezolizumab in combination with carboplatin and pemetrexed in patients with asymptomatic or minimally symptomatic brain metastases. It demonstrated an intracranial objective response rate (iORR) of 40–45% and a median intracranial PFS (iPFS) of 6.9 months. The regimen was well tolerated, with durable intracranial responses, supporting its use in carefully selected patients without the need for upfront local therapy. However, as a single-arm study, Atezo-Brain’s findings should be interpreted with caution, as the absence of a comparator arm limits definitive conclusions regarding efficacy. Similarly, the CAP-BRAIN trial (17) evaluated camrelizumab with pemetrexed and carboplatin in 45 treatment-naive patients with metastatic nonsquamous NSCLC and bone metastasis who were asymptomatic or had symptoms controlled with dehydration therapy and no previous systemic treatment or local therapy for the target brain lesion. The confirmed iORR was 52.5%, and median iPFS of 7.6 months. The regimen was generally well tolerated. Notably, improvements in cognitive function and quality of life were also observed over time. Although limited by a modest sample size, the findings supported expanding the role of chemoimmunotherapy in this patient population (17).

Building on the concept of chemo-immunotherapy explored in CAP-BRAIN and Atezo-Brain, the C-Brain trial further incorporated local brain RT into the systemic backbone of camrelizumab and platinum-doublet chemotherapy. This combined approach aims to enhance intracranial control by leveraging both immediate cytoreduction and potential immunomodulatory effects of RT, particularly in cases where the BBB may limit drug penetration. Unlike prior studies, C-Brain included a broader and more clinically complex population, enrolling patients with squamous cell NSCLC (23%) and a high proportion (71%) presenting with symptomatic brain metastases at baseline, including 20 requiring dexamethasone and 40 receiving mannitol (8,9,11,16,17). Additionally, 35% of patients presented with more than three brain metastases, and the median size of the largest lesion was 16 mm, indicating a higher overall disease burden. Despite this, the regimen achieved a 6-month PFS rate of 71.7% [95% confidence interval (CI): 58.9–81.1%], highlighting its potential efficacy even in a high-risk population (8).

Notably, the median time to intracranial response was 1.9 months, with a median best percentage reduction in target brain lesions of 68.3%, and the median duration of response was not reached. Subgroup analyses suggested numerically poorer PFS and OS among patients with PD-L1 <1%, more than three brain metastases, liver metastases, or those treated with WBRT. Similarly, a previous retrospective study reported that patients treated with WBRT exhibited low absolute lymphocyte counts (ALC) at 1 month, with ALC <500 associated with worse outcomes (18). The most common grade 3–4 treatment-related adverse events included neutropenia (22%), leukopenia (15%), thrombocytopenia (15%), and lymphopenia (14%). Symptomatically, improvements in tiredness and dizziness were reported by 76% of patients within six weeks of treatment initiation, suggesting potential early quality-of-life benefit alongside clinical efficacy. Radiation necrosis occurred in 5% of patients—two with grade 2 and one with grade 1 toxicity—all of whom recovered with bevacizumab (8). However, compared to systemic-only strategies, the addition of RT raises considerations regarding long-term neurocognitive risks, which must be balanced against its potential for improved local disease control.

Together, these studies illustrate the evolving landscape of treatment for NSCLC patients with brain metastases, highlighting different strategies—ranging from systemic-only regimens to combined local and systemic approaches—tailored to the clinical scenario, symptom burden, and disease extent. Table 1 summarizes these trials and their outcomes. Given the different criteria used for intracranial response assessment [RECIST 1.1 in C-Brain, Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) criteria in Atezo-Brain, and modified RECIST 1.1 criteria in CAP-BRAIN], the cross-trial comparisons should be interpreted with caution (8,16,17).

Another recent study evaluated tislelizumab combined with chemotherapy in patients with untreated, symptomatic, or recently irradiated brain metastases—an even more clinically complex group (19). This study reported iORR of 46.7%, systemic ORR of 43.8%, and a 1-year iPFS rate of 55.8%. Notably, the regimen was well tolerated, with no cases of intracranial pseudoprogression or hyperprogression. Biomarker analysis also identified alterations in cytokine receptor pathways as potential predictors of benefit, independent of PD-L1 or tumor mutational burden (TMB). In addition, prior brain radiation was associated with improved response, suggesting possible synergy with immunochemotherapy as seen in C-Brain trial (19).

However, it is essential to distinguish between two key considerations regarding brain RT: first, whether brain lesions should be treated before the initiation of systemic therapy; and second, whether concurrent administration with systemic therapy provides added benefit. While emerging evidence suggests that early or simultaneous RT may improve outcomes, definitive clinical data remains limited. Ionizing radiation disrupts the BBB, potentially enhancing CNS penetration of systemic agents. Fractionated RT at doses of 20–30 Gy (2 Gy per fraction) has been associated with increased BBB permeability, and preclinical studies demonstrate that it can induce permeability changes as early as 24 hours post-treatment, with effects persisting up to 90 days (20,21). However, the optimal timing to maximize this effect and facilitate drug delivery is still not well defined. A recent meta-analysis further supports the concurrent model—defined as RT administered within 4 weeks before or after starting ICIs as the most favorable approach compared to sequential administration (22).

Beyond BBB modulation, RT has immunostimulatory effects on the tumor microenvironment, including PD-L1 upregulation, increased antigen presentation, cytokine release, and enhanced T-cell infiltration. These changes may potentiate the efficacy of ICIs, even outside the irradiated field via abscopal effects (20-22). The C-Brain trial exemplifies this integrated approach and aligns with the concept of concurrent administration. In this study, camrelizumab was initiated within 7 days of SRS or WBRT. Chemotherapy was introduced alongside the first cycle of camrelizumab in patients receiving SRS, and during the first or second cycle in those receiving WBRT, based on investigator discretion (8). In parallel, advances in molecular testing are shedding light on the biological complexity of NSCLC brain metastases, with important implications for therapy selection and prognostication. Across CAP-BRAIN and C-Brain, PD-L1 positivity was associated with improved outcomes, while no such correlation was observed in Atezo-Brain—highlighting its potential but inconsistent role as a biomarker in NSCLC brain metastases (8,16,17). Next-generation sequencing has revealed substantial clonal heterogeneity, as demonstrated by Paik et al., who identified PI3K pathway aberrations and subclonal diversity in squamous NSCLC brain metastases (23). Liu et al. specifically investigated the genomic and immune landscapes of NSCLC brain metastases, highlighting associations between genetic alterations, neoantigen load, and immunotherapy response in these lesions (24). Additionally, circulating tumor cell (CTC) analyses are beginning to characterize the molecular features of metastasis-initiating cells, offering a potential avenue for earlier detection and therapeutic targeting (25). These emerging insights support the integration of molecular diagnostics into clinical decision-making and trial design for patients with brain metastases from NSCLC.

The C-Brain trial, although promising, has limitations that should be taken into consideration. As a single-arm phase II study with a modest sample size, the findings are hypothesis-generating and require validation in randomized, controlled settings. The study was conducted exclusively in China, with a predominantly male and Han Chinese population, which may limit the generalizability of the results. Additionally, response evaluation was based solely on RECIST 1.1 criteria, rather than CNS-specific tools (RANO-BM or modified RECIST). The relatively short follow-up period may have precluded detection of late-onset toxicities such as radiation necrosis. No validated neurocognitive scales were incorporated to evaluate the cognitive effects of brain RT specifically. Lastly, the absence of biomarker stratification, including PD-L1 expression, TMB, or broader molecular profiling, limits the ability to identify predictors of response.

Despite these limitations, we believe that the C-Brain trial offers early insights that may help guide future treatment strategies for NSCLC patients without actionable mutations, especially those typically excluded from clinical trials due to symptomatic or extensive brain metastases. The use of upfront brain RT in combination with chemoimmunotherapy showed encouraging signs of intracranial control and improvement in symptom burden and health-related quality of life (HRQoL). While these results are of interest, they should be interpreted with caution. Camrelizumab, the ICI used in this regimen, is not approved widely, which limits its immediate applicability. Additionally, as a single-arm phase II study, the findings remain exploratory and require validation through randomized controlled trials (RCTs) before being considered for integration into standard care. Nevertheless, the trial’s structure offers a practical framework that could be further investigated using other ICI available globally.

Looking ahead, advancing the treatment landscape for NSCLC with brain metastases will require rigorously designed RCTs to validate the clinical benefit of emerging strategies such as triplet regimens and combinations of systemic therapy with or without RT. These studies should focus on meaningful endpoints, including OS, intracranial disease control, and HRQoL. In parallel, efforts to identify predictive biomarkers will be critical to refine patient selection and optimize treatment sequencing. Additionally, further studies are needed to determine the optimal timing of RT, whether delivered upfront, concurrently, or deferred. Expanding the therapeutic landscape may also involve novel immune strategies, including dual checkpoint blockade and emerging immunotherapy agents.

In conclusion, the C-Brain trial highlights the potential of integrating chemo-immunotherapy with RT as a promising treatment strategy for NSCLC patients with brain metastases lacking actionable mutations. It reinforces the importance of incorporating CNS-specific endpoints in future trials and calls for the inclusion of patients with active brain metastases, who have been long underrepresented in systemic chemotherapy and immunotherapy research. These findings lay a foundation for future randomized phase III studies aimed at optimizing treatment strategies and improving outcomes in this high-risk population.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-41/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-41/coif). G.L. reports holding stock or other ownership interests in Lucence Diagnostics, Xilis, BioMab Inc., MorphoMetriX, and CDR-Life; receiving honoraria from Boehringer Ingelheim, Blueprint Medicines Corporation, AstraZeneca, Merck & Co. Inc., Janssen Global Services LLC, Rigel Pharmaceuticals Inc., and Dr. Reddy’s Laboratories Ltd.; consulting and/or serving in an advisory role for Pfizer Inc., AstraZeneca, Mirati Therapeutics Inc., Coherus BioSciences Inc., Regeneron Pharmaceuticals Inc., and Dr. Reddy’s Laboratories Ltd.; receiving research funding for himself and his institution from AstraZeneca, Lucence Diagnostics, Xilis, E.R. Squibb & Sons, Merck Sharp & Dohme, EMD Serono, Blueprint Medicines Corporation, Tesaro Inc., Bavarian Nordic A/S, Novartis AG, G1 Therapeutics Inc., Adaptimmune, BMS, GSK, AbbVie Inc., Rgenix, Pfizer Inc., F. Hoffmann-La Roche AG, Genentech Inc., Eli Lilly and Company, and Janssen Global Services LLC, and receiving travel, accommodations, and expenses from Boehringer Ingelheim, Pfizer Inc., E.R. Squibb & Sons, Janssen Global Services Inc., Seagen Inc., Celgene Corporation, Ipsen, Pharmacyclics LLC, Merck & Co. Inc., AstraZeneca, BeiGene Ltd., Coherus BioSciences Inc., and Dr. Reddy’s Laboratories Ltd. Z.H. is a consultant for AZ, and received study drug from Bayer Inc. A.C. is a consultant for Novartis, Tersera, Ipsen, Curium, Exelixis, and Seneca Therapeutics. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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