Efficacy of different therapies for brain metastases of non-small cell lung cancer: a systematic review and meta-analysis

Abstract

Background: As one of the most common causes of death in advanced non-small cell lung cancer (NSCLC), brain metastases (BM) have attracted attention and debate about treatment options, especially for patients with negative driver genes or resistance to targeted agents. Therefore, we conducted a meta-analysis to investigate the potential benefit of different therapeutic regimens for intracranial lesions in non-targeted therapy NSCLC patients.Methods: A comprehensive search was conducted in databases including PubMed, Embase, and the Cochrane Library. The primary endpoints included the intracerebral objective response rate (icORR) and intracerebral progression-free survival (iPFS) in patients with BM.Results: Thirty-six studies involving 1,774 NSCLC patients with baseline BM were included in this metaanalysis. Antitumor agents plus radiotherapy (RT) showed the most significant synergistic effects; the highest pooled icORR that appeared in the combination of immune checkpoint inhibitor (ICI) and RT was 81% [95% confidence interval (CI): 16-100%], and the median iPFS was 7.04 months (95% CI: 2.54-11.55 months).The pooled icORR and median iPFS of RT plus chemotherapy were 46% (95% CI: 34-57%) and 5.7 months (95% CI: 3.90-7.50 months), respectively. The highest median iPFS in nivolumab plus ipilimumab plus chemotherapy was 13.5 months (95% CI: 8.35-18.65 months). ICI plus chemotherapy also showed potent antitumor activity in BM, with a pooled icORR of 56% (95% CI: 29-82%) and a median iPFS of 6.9 months (95% CI: 3.20-10.60 months). Notably, the subgroup analysis indicated that the pooled icORR of patients in programmed cell death-ligand 1 (PD-L1) (≥50%) who received ICI was 54% (95% CI: 30-77%), and that of patients who received first-line ICI was 69.0% (95% CI: 51-85%).Conclusions: ICI-based combination treatment provides a long-term survival benefit for non-targeted therapy patients, with the most significant benefits observed in improving icORR and prolonging overall survival (OS) and iPFS. In particular, patients who received first-line treatment or who were PD-L1-positive had a more significant survival benefit from aggressive ICI-based therapies. For patients with a PD-L1negative status, chemotherapy plus RT led to better clinical outcomes than other treatment regimens. These innovative findings could help clinicians to better select therapeutic strategies for NSCLC patients with BM.

Tackling the challenge of brain involvement in driver-negative non-small cell lung cancer

“…Of course, such an aggressive strategy may also be associated with more side-effects, therefore prospective validation will be necessary before it can be widely recommended. Nonetheless, this concept is certainly plausible and, besides the current meta-analysis by Chen et al ( 6 ), additionally supported by at least two further important arguments: first, a similar strategy combining ipilimumab/nivolumab with upfront brain RT is the treatment of choice for patients with BM from melanoma, another tumor characterized by high tumor mutational burden (TMB) and particular sensitivity to immunotherapy, like NSCLC ( 7 ); second, the Checkmate-9LA trial has shown better efficacy for the combined nivolumab/ipilimumab-based chemoimmunotherapy compared to standard triplet chemoimmunotherapies for NSCLC in the cross-trial comparison with other phase 2 and 3 studies ( Table 1 ) ( 8 - 11 ). Whether the alternative anti-PD-L1/CTLA-4-based chemoimmunotherapy of the POSEIDON study may be equally able to prolong the duration of intracranial responses as the Checkmate 9LA regime, remains unclear at present.…”

“…Thus, continued CTLA-4 blockade appears to be important for the durability of intracranial responses in NSCLC, whereas RT improves their depth, as suggested by the findings of Chen et al ( 6 ). The use of RT to augment ICI efficacy is an area of intense investigation currently: goal is to heat-up the tumor microenvironment (TME) by inducing local inflammation, which may improve priming, trafficking and the effector function of tumor-reactive T cells ( 13 , 14 ).…”

“…Promising in this regard is also the very low frequency of intracranial relapse <10% after durvalumab consolidation in stage III disease ( 17 ), which additionally argues for an exquisite immunotherapeutic sensitivity of BM in NSCLC. While the optimal radiotherapy regimen for boosting the efficacy of ICI remains unclear at present, both stereotactic (SRT) and whole brain radiotherapy (WBRT) have similar efficacy in NSCLC, as shown by Chen et al ( 6 , 9 ). The same had also been reported earlier for TKI-treated EGFR/ALK-mutated tumors, however, SRT is generally preferred nowadays due to its lower neurotoxicity ( 18 ).…”

“…In a recent article of Translational Lung Cancer Research , Chen et al show how use of available immunotherapeutic options could be optimized in order to help in this difficult situation ( 6 ). Through a comprehensive search using PubMed, Embase, the Cochrane Library and other databases, the authors could show considerably higher intracranial overall response rates (icORR) for the combination of ICI with radiotherapy (RT) at 81% vs. 34–56% for ICI monotherapy, chemotherapy, chemoimmunotherapy, or various other combinations.…”

“…At the same time, despite this impressive icORR in the range observed with next-generation EGFR/ALK inhibitors, the duration of responses in driver-negative tumors remain limited with a median intracranial PFS (iPFS) of 7.0 months only. Chen et al provide a possible solution to this problem as well, by showing that the durability of intracranial responses under ICI in NSCLC can be improved by the combined use of checkpoint blockade with dual programmed death 1 (PD-1) cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibition and chemotherapy, which confers an impressive median icPFS of 13.5 vs. 2.3–7.0 months only for other options ( 6 ). These results are of great importance for clinical practice.…”