ΤΑRGETED THERAPIES
Driver mutations with approved targeted therapies
Genes with driver mutations for which approved targeted therapies exist for lung cancer are:
ALK
The ALK (Anaplastic Lymphoma Kinase) biomarker in lung cancer is a rearrangement of a gene in DNA which has a predictive role and indicates people with non-small cell lung cancer likely to benefit from specific targeted therapies.
Studies have shown that 2-5% of patients carry mutations in the ALK gene. It is most commonly found in younger patients (median age of 52 years), non-smokers or light smokers. Clinically, ALK+ tumors have the best prognosis compared to any other lung cancer.
“Curable” mutations in ALK are found in >2-5% of patients with adenocarcinoma, the most common subtype of non-small cell lung cancer.
Next-generation ALK inhibitors play the main role in the therapeutic management of ALK+. The diagnosis of ALK+ requires a molecular analysis of a tumor sample, which is currently reimbursed in Greece.
BRAF V600E
BRAF V600E gene mutations occur in 1%-3% of patients with lung adenocarcinoma. Most of these patients are current or ex- smokers.
EGFR (and mutations not sensitive to tyrosine kinase inhibitors (TKIs))
The EGFR (epidermal growth factor receptor) biomarker in lung cancer is a predictive DNA mutation indicating which people with non-small cell lung cancer are likely to benefit from specific targeted therapies.
Studies link EGFR biomarker positivity, to geographic distribution, gender, race and smoking history.
When the EGFR protein is activated, the tumor becomes more aggressive. In these cases, therapies that target EGFR are more effective than chemotherapy.
“Curable” mutations in EGFR are found in >10-15% of patients with adenocarcinoma, the most common subtype of non-small cell lung cancer. It is most commonly detected in women and in non-smokers.
First, second and third generation EGFR inhibitors and EGFR-targeting bispecific antibodies play an important role in treating EFGR+.
KRAS
The KRAS (Kirsten-Rat Sarcoma 2 viral oncogene) biomarker in lung cancer is a DNA mutation that may serve as a therapeutic target in some patients with advanced non-small cell lung cancer.
A mutation in the KRAS gene is the most common mutation in lung adenocarcinoma in smokers.
A deeper understanding of the molecular mechanisms behind KRAS may in the future lead to alternative therapeutic approach and targeted drugs against the mutated gene.
Mesenchymal-epithelial transition (MET) exon 14 skipping
Approximately 3%-4% of patients with non-small cell lung cancer carry a mutation leading to a mesenchymal-epithelial transition (MET) gene exon 14 skipping. Most of these patients have a history of smoking. There are currently specific, orally administered, molecular inhibitors targeting this mutation.
NTRK
The predictive biomarker NTRK (neurotrophic tyrosine receptor kinase) in lung cancer is a DNA mutation indicating people with NSCLC likely to benefit from targeted therapies.
Studies have shown that less than 1% of patients carry mutations in the NTRK gene.
Specific inhibitors which cause tumor reduction play the main role in treating NTRK+.
The diagnosis of NTRK+ requires an examination of the tumor tissue, which is currently not reimbursed in Greece.
RET
An estimated 2% of lung adenocarcinoma cases – the largest subtype of non-small cell lung cancer (NSCLC) – test positive for RET gene fusion. This means that the normal gene has been ‘fused’ to a part of another gene. The resulting new gene, via the variant RET protein produced, can lead to the conversion of normal cells into cancer cells. RET fusion can be detected by molecular biology methods (decoding the DNA of cancer cells).
At clinical level, RET fusion should be consistently looked for as a driver of cancer growth in lung adenocarcinomas. In many forms, it is a predictive biomarker, thus revealing the therapeutic target. New and innovative drugs, administered orally, have been specifically designed to target and inhibit the RET protein, and by extension cancer growth. Studies to date have shown high response rates in these tumors, and their clinical program is ongoing, both in comparison to established therapies and in earlier stages of cancer, with the prospect of expanding their already established indications.
ROS1
The predictive biomarker ROS-1 (c-ros oncogene 1) in lung cancer is a mutation in DNA indicating people with non-small cell lung cancer likely to benefit from targeted therapies.
Studies have shown that the proportion of patients carrying mutations in the ROS-1 gene is around 1-2% and are generally younger and non-smokers.
The characteristic ROS-1 oncoprotein allows for targeted therapy through new drugs, with highly significant responses and substantial survival.
All current approved targeted therapies fight non-small cell lung cancer (NSCLC). There are no approved targeted therapies for small cell lung cancer (SCLC) yet.
