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.

Background: Acquired 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.

Methods: Pubmed, 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.

Results: Six 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).

Conclusions: The 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.