MET tyrosine kinase inhibitors in combination with EGFR tyrosine kinase inhibitors in NSCLC patients with EGFR mutations and acquired MET alterations: a systematic review and meta-analysis.

backgroundAcquired MET alterations is one of the resistance mechanisms to advanced NSCLC patients treated with EGFR tyrosine kinase inhibitors (TKIs). Several clinical trials combined MET-TKI (such as capmatinib, tepotinib, savolitinib) with EGFR-TKI to overcome MET alterations resistance. We performed this meta-analysis to determine the efficacy and safety of MET-TKI plus EGFR-TKI combined therapy in NSCLC patients.

methodsPubmed, Embase and the Cochrane Library were searched for relevant studies up to August 19, 2024. Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), median duration of response (mDOR) and adverse events were extracted from the publications and analyzed.

resultsSix studies involving 562 patients were included in this meta-analysis. Our study showed a pooled ORR of 49.2% (95% confidence interval [CI] 0.402-0.582), a pooled DCR of 78.6% (95%CI 0.680-0.893), a mDOR of 6.85 months (95%CI 5.85-7.86), and a mPFS of 5.62 months (95%CI 4.74-6.50) in MET-TKI plus EGFR-TKI combination therapy for NSCLC patients with acquired MET-driven resistance after EGFR-TKI treatment. The pooled efficacy data suggested that combining MET-TKI with a third-generation EGFR-TKI was numerically superior to combining MET-TKI with a first-generation EGFR-TKI in patients who were T790M negative with MET-dependent resistance mechanism (ORR: 56.8% vs. 47.8%, p = 0.15; DCR: 81.6% vs. 75%, p = 0.57; mDOR: 9.08 vs. 7.00 months, p = 0.25; mPFS: 7.45 vs. 4.55 months, p = 0.05). The efficacy data of capmatinib plus EGFR-TKI, savolitinib plus EGFR-TKI and tepotinib plus EGFR-TKI (regardless of generation of EGFR-TKIs) was similar (ORR:47.7% vs. 50.7% vs. 48.8%, p = 0.96; DCR: 71.4% vs. 84.9% vs. 63.3%, p = 0.02; mDOR: NR vs. 8.4 vs. 8.01 months, p = 0.18; mPFS: 5.49 vs. 6.88 vs. 5.48 months, p = 0.56). Capmatinib subgroup seemed to demonstrate lower hepatotoxicity compared with savolitinib and tepotinib subgroups numerically (increased AST level: 12.8% vs. 18.8% vs. 17.4%, p = 0.66; increased ALT level: 14.2% vs. 17.6% vs. 20.1%, p = 0.91). And a lower occurrence rate of ≥ 3 grade TRAEs was observed in the capmatinib subgroup compared to the savolitinib or tepotinib subgroups (30.0% vs. 46.7% vs. 41.2%, p = 0.07).

conclusionThe findings from this meta-analysis suggest that the combination of MET-TKI and EGFR-TKI represents a promising therapeutic approach for NSCLC patients who have acquired MET alterations following EGFR-TKI treatment. Notably, the combination of MET-TKI and a third-generation EGFR-TKI demonstrated enhanced survival benefits compared to the combination with a first-generation EGFR-TKI. Furthermore, different MET-TKIs based combination therapy did not display significant differences in efficacy, while capmatinib based combination therapy showed better safety profile and lower hepatotoxicity.