Medical experts at the 2012 Chemotherapy Foundation Symposium presented data on the growing number of targeted treatments for non-small cell lung cancer (NSCLC) with so-called driver mutations—specific genetic mutations that drive tumor growth. Among the drugs showing promise in adenocarcinoma are ridaforolimus for KRAS-mutant tumors, ganetespib for ALK- or KRAS-mutant tumors, and afatinib for EGFR-mutant tumors. For squamous cell carcinoma (SCC), new potential treatments include AZD4547 and BGJ398 (FGFR1-mutant), dasatinib and nilotinib (DDR2 mutant), Tarceva and Iressa (EGFRvIII-mutant), and Yervoy and Cadi-05 (all SCC), while anti–PD-1 antibodies such as BMS-936558 may be effective for both adenocarcinoma and SCC.
Concurrent chemoradiotherapy (CRT), which is radiation treatment delivered at the same time as chemotherapy, has been found to be more effective in locally advanced non-small cell lung cancer (NSCLC) than sequential treatment with chemotherapy before or after irradiation, but also has greater toxic side effects. A retrospective study of patients with stage IIIA/B NSCLC, who had large tumors and/or extensive cancer spread to the lymph nodes, found that large tumors and presence of other illnesses were associated with shorter overall survival after CRT and higher risk of early death during treatment. While NSCLC patients with extensive lymph node involvement, but smaller tumors, may benefit from CRT without excessive risk, patients with large tumors and/or additional illnesses may be better served by alternative treatment approaches.
While adjuvant chemotherapy (ACT) after surgical removal of non-small cell lung cancer (NSCLC) can help prevent cancer recurrence and improve survival, the average benefits are small and the treatment can have serious side effects. A study of patients with adenocarcinoma identified 12 genes that together predicted the likelihood of better (low-risk) or worse (high-risk) long-term outcomes in these patients. Patients with a high-risk “gene signature” benefitted significantly from ACT, while low-risk patients gained no additional benefit, suggesting that the gene set can be used to pinpoint patients for whom ACT treatment would be worth the risk of side effects.
Forty patients with non-small cell lung cancer (NSCLC) with brain metastases (cancer that had spread to the brain) were treated with the EGFR inhibitor Tarceva (erlotinib) and whole-brain radiation therapy (WBRT). Tarceva plus WBRT was relatively well tolerated and resulted in median survival rates (10.9 months) that were higher than in a previous trial of WBRT alone (3.9 months). The fact that many NSCLC patients carry mutations in the EGFR gene may contribute to the beneficial effects of adding Tarceva treatment to WBRT in NSCLC with brain metastases.
A review of recent research discusses EGFR inhibition in the treatment of lung cancer. Scientists have now demonstrated that EGFR-tyrosine kinase inhibitors (TKIs), either by themselves or combined with chemotherapy, are effective first-line treatments for advanced non-small cell lung cancer (NSCLC) with EGFR mutations, and as second-line or maintenance treatments for all advanced NSCLC. TKIs like erlotinib (Tarceva) or gefitinib (Iressa), or anti-EGFR antibodies like cetuximab (Erbitux), may also enhance the effectiveness of radiation therapy for locally advanced NSCLC. Other biomarkers, such as KRAS mutations, may also help predict response to EGFR inhibition therapy.
Erlotinib (Tarceva) was recently approved in the EU as a first-line treatment for advanced non-small cell lung cancer (NSCLC) in patients with mutations in the EGFR gene. In these patients, this recently published guide explains, Tarceva is better tolerated than standard chemotherapy, has higher treatment response rates, and results in longer time periods without the cancer worsening. However, Tarceva does not benefit patients without EGFR mutations, its effect on overall survival has not yet been clearly determined and the risk of serious side effects requires careful patient monitoring.
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.