KEY TAKEAWAYS
- The study aimed to assess the effectiveness and safety of ningetinib + gefitinib in EGFR-mutant NSCLC patients and determine if MET/AXL levels influence response.
- The primary endpoints were tolerability and ORR.
- The results demonstrated that targeting MET, AXL, and EGFR together shows promise for a specific group of EGFR-mutant NSCLC patients.
Dysregulations of MET and AXL contribute to acquired resistance to EGFR-TKIs in non-small cell lung cancer (NSCLC). However, there is a lack of consensus regarding the ideal definition of MET/AXL dysregulations in EGFR-mutant NSCLC.
Shen Zhao and the team spearheaded the study that aimed to assess the efficacy and tolerability of ningetinib, a MET/AXL inhibitor, in combination with gefitinib for EGFR-mutant NSCLC. Additionally, they aimed to evaluate the clinical significance of MET/AXL dysregulations using various definitions.
The study employed dose-escalation and dose expansion, participants were administered ningetinib at doses of 30 mg, 40 mg, or 60 mg along with gefitinib at 250 mg once daily. The primary endpoints were evaluating tolerability during dose escalation and assessing the objective response rate (ORR) during dose expansion. MET/AXL status was determined through fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).
Among the 108 enrolled patients, the prevalence of MET focal amplification, MET polysomy, MET overexpression, AXL amplification, and AXL overexpression stands at 18.1%, 5.6%, 55.8%, 8.1%, and 45.3%, respectively. 6.8% of patients exhibit concurrent MET amplification and AXL overexpression. Notably, tumors with MET amplification showcase an ORR of 30.8%, while those with MET polysomy register a 0% ORR. The ORR for tumors with MET overexpression, AXL amplification, and AXL overexpression is 24.1%, 20%, and 27.6%, respectively.
For patients with concurrent MET amplification and AXL overexpression, the combination of ningetinib plus gefitinib demonstrates an ORR of 80%, a disease control rate (DCR) of 100%, and a median progression-free survival (PFS) of 4.7 months. Moreover, higher MET copy numbers and elevated AXL expression correlate with an increased likelihood of response. Biomarker analyses revealed that MET focal amplification and overexpression synergistically predict clinical benefit from MET inhibition. Conversely, AXL dysregulations, when defined by an arbitrary threshold, may attenuate the efficacy of AXL blockade.
This study illustrated the viability of employing a combined blockade targeting MET, AXL, and EGFR as a viable strategy for a specific subset of EGFR-mutant NSCLC.
Source: https://www.lungcancerjournal.info/article/S0169-5002(24)00001-1/abstract#%20
Zhao S, Ma Y, Liu L, et al. (2024) ‘’Ningetinib plus gefitinib in EGFR-mutant non-small-cell lung cancer with MET and AXL dysregulations: A phase 1b clinical trial and biomarker analysis.’’ https://doi.org/10.1016/j.lungcan.2024.107468.
