Tyrosine kinase inhibitors (TKIs) that block EGFR are effective treatments for many cases of advanced non-small cell lung cancer (NSCLC), but are limited by the fact that patients will eventually develop resistance against them. Overexpression of the MET gene may contribute to EGFR-TKI resistance, suggesting that combined inhibition of both EGFR and MET may prevent or overcome this drug resistance. Several MET inhibitors have been developed, including cabozantinib (Cometriq), tivantinib, onartuzumab, and ficlatuzumab, and ongoing trials are investigating the safety and effectiveness of combining them with an EGFR-TKI like erlotinib (Tarceva) or gefitinib (Iressa).
Farletuzumab is an antibody (a type of immune system protein) that inhibits folate receptor α (FOLR1), a protein that is essential for cell proliferation. FOLR1 is overexpressed in a number of tumor types, including non-small cell lung cancer (NSCLC) and, especially, adenocarcinoma. Farletuzumab reduced tumor growth in animal models of cancer, and was well-tolerated in phase I and II studies. An ongoing phase II study is evaluating the effectiveness of combining farletuzumab treatment with chemotherapy in patients with advanced lung adenocarcinoma.
Conatumumab is an antibody (a type of immune system protein) that targets TR-2, a protein that is expressed in tumor tissue in a variety of cancer types. A phase II study of patients with previously untreated advanced non-small cell lung cancer (NSCLC) receiving either conatumumab or placebo in combination with standard paclitaxel (Taxol)–carboplatin (Paraplatin) chemotherapy showed that conatumumab was well tolerated, but did not improve clinical outcomes. However, it is possible that, in patients selected for relevant biomarkers, conatumumab may show effectiveness that is not seen in an unselected patient population.
A review of recent research discusses EGFR inhibition in the treatment of non-small cell lung cancer (NSCLC). Blocking EGFR using drugs called EGFR-tyrosine kinase inhibitors (TKIs) is an effective treatment for advanced NSCLC in patients with mutations in the EGFR gene. However, chemotherapy remains the standard of care for advanced NSCLC without EGFR mutations. Unfortunately, patients commonly develop drug resistance to TKIs like erlotinib (Tarceva) or gefitinib (Iressa). Newer TKIs like afatinib, which target multiple proteins and irreversibly inhibit them, are being explored in clinical trials and may be effective in patients who have become resistant to first-generation TKIs.
In a recent phase I/IIA study, patients with extensive-stage small-cell lung cancer (SCLC) that had not previously been treated were given a drug called pomalidomide. The pomalidomide treatment was combined with standard chemotherapy consisting of cisplatin (Platinol) and etoposide (Etopophos/Toposar). Pomalidomide appeared to be safe, with a maximum tolerated dose of 4 mg per day. However, it did not appear to increase the efficacy or decrease the toxicity of the chemotherapy.
VeriStrat® is a blood test for advanced non-small cell lung cancer (NSCLC) patients intended to determine whether the patients would benefit from erlotinib (Tarceva) treatment. A retrospective analysis of blood samples from elderly patients (age 70+ yr) with advanced NSCLC who had been treated with either Tarceva, gemcitabine (Gemzar), or both found that patients with a “good” VeriStrat result had better outcomes than those with a “poor” result when given Tarceva either alone or in combination with Gemzar, while the benefits of Gemzar alone were unaffected by VeriStrat status. The study authors conclude that elderly patients with poor VeriStrat results should be treated with Gemzar, while first-line Tarceva treatment may be appropriate for patients with good Veristrat results.
Non-small cell lung cancers (NSCLC) with a mutation in the EGFR gene can usually be treated with EGFR-tyrosine kinase inhibitors (TKIs) such as erlotinib (Tarceva), gefitinib (Iressa), afatinib, neratinib, or dacomitinib. However, mutations that are located in a region of the EGFR gene called exon 20 are associated with a lack of response to TKI treatment. A study of tumor tissue from adenocarcinoma (a type of NSCLC) found that such exon 20 mutations are present in approximately 10% of EGFR-mutant adenocarcinoma and 3% of all adenocarcinoma, that they are more common in NSCLC patients who never smoked, and that there are a wide variety of different exon 20 mutations, some of which may be more responsive to TKI treatment than others.
Four phase III studies compared the tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva) or gefitinib (Iressa) to standard chemotherapy as first-line treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). TKI treatment increased progression-free survival (ie, the length of time without the cancer worsening), but did not improve overall survival compared to chemotherapy. In one study, TKI-treated patients maintained a higher quality of life for longer than chemotherapy-treated patients. The findings suggest that TKI treatment should become the standard first-line treatment in advanced NSCLC with mutations in the EGFR gene.
Early-stage non-small cell lung cancer (NSCLC) is usually treated with surgical removal of the tumor. However, in up to 50% of patients, the cancer will return within 5 years. A study of genetic variations that affect the function of microRNAs (small molecules involved in gene expression) found that several of them, including variations in the FAS, FZD4, SP1, and DROSHA genes, were associated with higher or lower probabilities of cancer recurrence and survival. Tests for such microRNA-related genetic variations may eventually help identify high-risk, early-stage NSCLC patients who would benefit from additional treatment after surgery.