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Updated: Dec 28, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Recent advances in targeted small-molecule inhibitor therapy for non-small-cell lung cancer-An update
Shubham Atal1, Pravin Asokan1, Ratinder Jhaj1
1Department of Pharmacology, All India Institute of Medical Sciences Bhopal, Bhopal, India.
What Is Known And Objective:
Targeted small molecule EGFR Tyrosine Kinase Inhibitors (TKI's) and the Anaplastic Lymphoma Kinase (ALK) inhibitors have been promising tools for advanced non-small-cell lung cancers (NSCLCs). However, tumours tend to develop subsequent mutations, rendering them drug-resistant. Hence, alternative pathways of therapy need to be explored.
Comment:
Gefitinib, erlotinib and afatinib, once considered as alternatives to platinum-based cytotoxic chemotherapy, have been rendered ineffective in patients with NSCLCs harbouring T790M mutation. Osimertinib is effective in T790M-mutant cancers, but not against those exhibiting the subsequent C797S mutation. ALK gene alterations have rendered tumours insensitive to crizotinib. However, lorlatinib and brigatinib are effective in tumours showing ALK+ mutations. Drugs acting through alternative pathways like the PD-1 pathway, BRAF, VEGFR, EGFR antibodies and NTRK inhibition have been showing promising results.
What Is New And Conclusions:
Osimertinib, brigatinib and allosteric C797S EGFR inhibitors like AI1045, BRAF inhibitors like LXH254 under trials and entrictinib, a recently approved NTRK inhibitor, have all shown improved progression-free survival compared with earlier generations of small molecule inhibitors for NSCLCs.
Insights
Drug resistance in non-small-cell lung cancer (NSCLC) necessitates new therapies. Newer targeted therapies show improved outcomes, but resistance remains a challenge, driving research into alternative treatment pathways.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Targeted small molecule Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) and Anaplastic Lymphoma Kinase (ALK) inhibitors have shown promise for advanced non-small-cell lung cancers (NSCLCs).
- Tumor resistance develops through subsequent mutations, limiting the efficacy of initial targeted therapies.
Purpose of the Study:
- To explore alternative therapeutic pathways for advanced NSCLCs due to acquired drug resistance.
- To review the efficacy of newer generation inhibitors and alternative pathway drugs.
Main Methods:
- Review of current literature on targeted therapies for NSCLC.
- Analysis of drug resistance mechanisms and emerging treatment strategies.
Main Results:
- First-generation EGFR TKIs (gefitinib, erlotinib, afatinib) are ineffective against T790M mutations.
- Osimertinib is effective against T790M but not C797S mutations.
- Brigatinib and lorlatinib are effective against ALK alterations, while newer agents like osimertinib, brigatinib, AI1045, LXH254, and entrectinib show improved progression-free survival.
Conclusions:
- Acquired resistance to EGFR and ALK inhibitors is a significant challenge in NSCLC treatment.
- Emerging therapies targeting specific mutations and alternative pathways (PD-1, BRAF, VEGFR, NTRK) offer improved outcomes for NSCLC patients.
- Continued research into novel therapeutic strategies is crucial for overcoming drug resistance in NSCLC.
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