Tyrosine kinase inhibitors and monoclonal antibodies in EGFR expressing lung cancer
Lung cancer is considered as the second most common cancer in both men and women worldwide.
It is a leading cause of death from cancer, with 1 in 4 people succumbing to the disease. Hence, the early diagnosis and treatment of lung cancers is a hot bed for cancer researchers. The most common (~80%) type of lung cancer is the non-small cell lung cancer (NSCLC), as opposed to the small cell lung cancer which is treated with chemotherapy drugs and novel cyto-toxics that have now been identified.
The treatment of NSCLC is based on molecular research, which is greatly advanced ─ NSCLC is now understood to consist of multiple pathologies each with a unique molecular basis for which a tailored treatment has now become possible. A targeted pharmacotherapy is planned by oncologist resulting in a better clinical outcome for the individual patient (personalized medicine). Each patient gets subjected to various biomarkers that can predict the outcome of a specific drug for the cancer and the eventual prognosis of the patient.
Epidermal growth factor receptor (EGFR) is responsible for cell growth and proliferation. Increased EGFR expression, through mutations had been observed in 40-80% of NSCLCS leading to abnormal cell growth and proliferation. The first line EGFR inhibitors, tyrosine kinase inhibitors (TKIs), were Gefitinib and Erlotinib.
Gefitinib showed superior response, survival rates, and quality of life with EGFR mutant lung adenocarcinomas in an East Asian population. TKIs in non-mutant EGFR (wild type) do not have a similar response so it is better for patients with NSCLC to be screened for the presence of EGFR mutation. In fact, even in mutant EGFR, resistance to TKIs is possible, and continuous monitoring of response through regular biopsies after tumor progression is advised. Second line Afatanib, has shown better response and survival rates and third generation targeted therapies are being explored to overcome the resistant mechanisms.
Some NCLCS (3-7% ) possess an ALK gene fused to a protein, the (Echinoderm Microtubule-associated protein-like protein 4 (EML4). Although these tumors, common among younger lung cancer patients with a “no/light smoking” history, do not have a good prognosis, Crizotinib has shown to have a survival advantage in this subset of lung cancer patients.
EGFR activation can also be inhibited by monoclonal antibodies (mAbs). Anti-EGFR mAbs now include Cetuximab, Necitumumab, Panitumumab and Matuzumab. A combination of Cetuximab with platinum doublet chemotherapy has been examined in patients with advanced NSCLC. Results of the other mAbs combinations are awaited.
Essentially, lung cancer therapy is not just restricted to the histological type, but also rests on the molecular level of the tumor type. The treating oncologist is thus guided by rationally choosing either a single targeted agent or combinations depending on the individual genetic make-up and response of the patient with lung cancer.