Revolutionizing Lung Cancer Treatment: New Hope for Resistant EGFR-Mutant NSCLC

Study Overview

This study, titled "Ningetinib plus gefitinib in EGFR-mutant non-small-cell lung cancer with MET and AXL dysregulations: A phase 1b clinical trial and biomarker analysis," primarily focuses on the efficacy and tolerability of combining ningetinib (a MET/AXL inhibitor) with gefitinib in treating EGFR-mutant non-small-cell lung cancer (NSCLC) (1). The study design was a phase 1b clinical trial, which included both dose-escalation and dose-expansion phases.

The population under investigation comprised patients with NSCLC who had mutations in the EGFR gene and dysregulations in MET and AXL. These dysregulations are known to contribute to resistance against EGFR tyrosine kinase inhibitors (TKIs). The intervention under investigation was a combination therapy of ningetinib and gefitinib. Patients received varying doses of ningetinib (30 mg, 40 mg, or 60 mg) in combination with a fixed dose of gefitinib (250 mg), administered once daily.

In total, 108 patients were enrolled in the study from March 2017 to January 2021. The study provided detailed results on the proportion of patients with various types of MET and AXL dysregulations, such as MET focal amplification, MET polysomy, MET overexpression, AXL amplification, and AXL overexpression. The objective response rate (ORR) varied depending on the type of dysregulation, with notable responses in certain groups. For instance, patients with concurrent MET amplification and AXL overexpression showed an ORR of 80%, a disease control rate (DCR) of 100%, and a median progression-free survival (PFS) of 4.7 months. The study found that tumors with higher MET copy numbers and AXL expression were more likely to respond to the treatment.

Biomarker analysis indicated that MET focal amplification and overexpression are complementary in predicting the clinical benefit from MET inhibition. However, the arbitrary definition of AXL dysregulations may dilute the efficacy of AXL blockade.

In conclusion, the study demonstrated that a combined blockade of MET, AXL, and EGFR is a viable strategy for treating a subset of patients with EGFR-mutant NSCLC. The trial was registered at Chinadrugtrials.org.cn under the identifier CTR20160875.

Standard Treatment

The current standard treatment for EGFR-mutant non-small-cell lung cancer (NSCLC) typically involves targeted therapies, mainly EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, afatinib, and osimertinib. These drugs have been shown to be effective in patients with NSCLC who have specific mutations in the EGFR gene. Osimertinib, a third-generation EGFR-TKI, is often preferred for patients with EGFR T790M mutation, especially after resistance develops to first or second-generation TKIs.

The results of the study examining the combination of ningetinib (a MET/AXL inhibitor) and gefitinib offer potential advancements in the treatment landscape of EGFR-mutant NSCLC, particularly for patients who develop resistance to EGFR-TKIs due to MET and AXL dysregulations. The findings suggest that the addition of ningetinib to gefitinib can overcome resistance in a subset of patients with specific genetic alterations (MET and AXL dysregulations).

The impact of these findings could be significant:

  1. Targeting Resistance Mechanisms: Since MET and AXL dysregulations are known to contribute to acquired resistance against EGFR-TKIs, this combination therapy could provide a new treatment option for patients who no longer respond to standard EGFR-TKI therapy.

  2. Personalized Medicine: The study emphasizes the importance of genetic profiling in NSCLC treatment. By identifying patients with specific genetic alterations, therapies can be more effectively tailored, which is a key principle of personalized medicine.

  3. Potential New Treatment Option: If further studies, including larger phase 2 and 3 trials, confirm the efficacy and safety of this combination therapy, it could become a new standard treatment option for patients with EGFR-mutant NSCLC who have MET and AXL dysregulations.

  4. Biomarker Research: The study also contributes to the field of biomarker research, highlighting the need for reliable markers to predict response to MET and AXL inhibitors.

In summary, while the current standard of care involves primarily EGFR-TKIs, the results of this study suggest that a combination of ningetinib and gefitinib might offer a more effective treatment strategy for a specific group of patients with EGFR-mutant NSCLC, particularly those who have developed resistance to standard therapies. However, these findings would need to be validated in larger, more definitive trials before they could be integrated into standard clinical practice.

Clinical Impact Potential

The clinical impact potential of this trial can be considered medium. This assessment is based on several factors:

  1. Targeted Population: The trial focuses on a specific subset of patients with EGFR-mutant non-small-cell lung cancer (NSCLC) who have developed resistance to EGFR-TKIs due to MET and AXL dysregulations. This represents a significant but still relatively narrow segment of the NSCLC patient population. The treatment's applicability to a broader patient group remains uncertain.

  2. Phase of the Trial: As a phase 1b trial, the primary focus was on assessing the safety, tolerability, and optimal dosing of the combination therapy of ningetinib and gefitinib. While the trial also provided preliminary efficacy data, these results need to be confirmed in larger phase 2 and 3 trials to establish the true efficacy and safety profile of the treatment.

  3. Innovative Approach: The combination therapy addresses a known mechanism of resistance in EGFR-mutant NSCLC, which is a significant challenge in the current treatment landscape. Therefore, the trial's approach has the potential to address an unmet need in NSCLC treatment.

  4. Biomarker Analysis: The study's emphasis on biomarker analysis to identify patients who would most benefit from the treatment is noteworthy. This approach aligns with the trend towards personalized medicine in oncology, which could improve treatment outcomes.

  5. Preliminary Results: The results showed promising efficacy in certain patient subgroups, particularly those with concurrent MET amplification and AXL overexpression. However, these findings need to be validated in subsequent trials with larger patient cohorts and longer follow-up periods.

In conclusion, while the trial shows promising potential and could lead to a significant improvement in treatment for a targeted group of NSCLC patients, its overall impact is currently medium due to the early phase of the research, the need for further validation, and its applicability to a specific patient subgroup.

Reference

Zhao S, Ma Y, Liu L, Fang J, Ma H, Feng G, Xie B, Zeng S, Chang J, Ren J, Zhang Y, Xi N, Zhuang Y, Jiang Y, Zhang Q, Kang N, Zhang L, Zhao H. Ningetinib plus gefitinib in EGFR-mutant non-small-cell lung cancer with MET and AXL dysregulations: A phase 1b clinical trial and biomarker analysis. Lung Cancer. 2024 Jan 3;188:107468. doi: 10.1016/j.lungcan.2024.107468. Epub ahead of print. PMID: 38181454.