Bevacizumab + EGFR-TKI improves OS in EGFR-mutated NSCLC with leptomeningeal metastases

Adding bevacizumab to an EGFR tyrosine kinase inhibitor (TKI) improves overall survival (OS) in adult patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and leptomeningeal metastases (LMs), according to a single-centre, retrospective, real-world study in China. OS was, however, similar between patients on chemotherapy plus EGFR-TKI and those on EGFR-TKI monotherapy. 

LM is a serious complication in advanced NSCLC, especially in patients with EGFR mutations. [Lancet 2018;19:e43-e55] To investigate prognostic factors associated with LM in EGFR-mutated NSCLC, the researchers analyzed clinical data from 123 patients aged >18 years who were treated at Henan Cancer Hospital between January 2016 and December 2020. Of these patients (median age, 56 years; female, 69.9 percent; smoking history, 34.1 percent; adenocarcinoma, 99.2 percent; brain metastasis [BM], 56.1 percent), 88.6 percent exhibited classical EGFR mutations, including exon 19 deletion (39.0 percent) and exon 21 L858R mutation (49.6 percent), while the remaining 11.4 percent had nonclassical EGFR mutations. [Clin Lung Cancer 2024;doi:10.1016/j.cllc.2024.02.001]

Overall, 16.3 percent of patients (n=20) were concurrently diagnosed with NSCLC and LM (primary LM), while 83.7 percent of patients (n=103) developed LM during treatment (secondary LM). Before LM diagnosis (n=111), 36.9 percent of patients received first- or second-generation (G1/2) EGFR-TKI monotherapy (gefitinib, icotinib, erlotinib, dacomitinib), 29.7 percent received bevacizumab plus G1/2 EGFR-TKI, and 23.4 percent received chemotherapy plus G1/2 EGFR-TKI. After LM diagnosis (n=123), 31.7 percent of patients received third-generation (G3) EGFR-TKI monotherapy (osimertinib, almonertinib), 30.1 percent received bevacizumab plus G3 EGFR-TKI, and 27.6 percent received chemotherapy plus G3 EGFR-TKI.

Results showed that in the classical EGFR mutation subgroup, exon 19 deletion was associated with significantly longer OS vs exon 21 L858R mutation (median, 30.1 months vs 26.0 months; p=0.024). There was no statistically significant difference in OS between the classical EGFR mutation and nonclassical EGFR mutation subgroups (median, 28.0 months vs 24.2 months; p=0.484).

Additionally, patients with BMs had significantly shorter OS than those without BMs (median, 25.4 months vs 33.4 months; p<0.001), as did patients with primary LM vs those with secondary LM (median, 21.2 months vs 28.3 months; p=0.005).

Among patients with secondary LM, combined therapy with bevacizumab plus G1/2 EGFR-TKI before LM diagnosis was associated with delayed LM onset vs G1/2 EGFR-TKI monotherapy (median, 19.4 months vs 13.9 months; p=0.038). After LM diagnosis, treatment with bevacizumab plus G3 EGFR-TKI was associated with significant OS improvement vs EGFR-TKI monotherapy (median, 14.5 months vs 10.0 months; p=0.036). No clinical benefits were observed with chemotherapy plus EGFR-TKI vs EGFR-TKI monotherapy before LM diagnosis (median, 16.6 months vs 13.9 months; p=0.185) or after LM diagnosis (median, 9.2 months vs 10.0 months; p=0.867).

Multivariate analysis showed an association between poor OS and presence of BMs (hazard ratio [HR], 0.445; 95 percent confidence interval [CI], 0.285–0.697; p<0.001), while no significant association was found with primary LM (p=0.305). Conversely, favourable OS was associated with combined therapy with bevacizumab plus EGFR-TKI both prior to LM diagnosis (HR, 2.038; 95 percent CI, 1.130–3.678; p=0.018) and after LM diagnosis (HR, 1.815; 95 percent CI, 1.075–3.064; p=0.026).

“Large-scale prospective studies are needed to validate the prognostic factors [in EGFR-mutated NSCLC],” the researchers noted.