AB036. Comparison of the effectiveness of gefitinib, erlotinib and afatinib in epidermal growth factor receptor mutated tumors of non-small cell lung cancer

Abstract: The non-small cell lung cancer (NSCLC) accounts approximately 85% of lung cancers and includes predominantly adenocarcinomas, which is the most common type and squamous cell carcinomas. The treatment options include surgery, radiation therapy, and chemotherapy and the decision depends on the patient’s medical status and stage of disease. From 1970 the standard first line treatment for most patients with unresectable NSCLC and good performance status was the use of a combination of chemotherapy regimens and usually cisplatin-based. The most common combination regimens in use at present are platinum based regimens with gemcitabine, with paclitaxel or docetaxel and with vinorelbine combinations. The addition of the recombinant humanized monoclonal antibody bevacizumab that binds to vascular endothelial growth factor (VEGF) to carboplatin and paclitaxel for the treatment of non-squamous advanced NSCLC has demonstrated to increase response rate (RR), progression free survival (PFS) and overall survival (OS) when compared to chemotherapy alone. Despite recent advances with approval of more active chemotherapeutic and anti-angiogenesis agents for stage IV NSCLC, standard therapy can provide only modest clinical benefits with significant toxicities when used in unselected patients. In 2004, the identification of somatic mutations in the epidermal growth factor receptor (EGFR) gene provided the first glimpse of a possible target for a treatment which could maximize clinical outcome in those patients who could benefit from a personalized therapy. Identifying mutations in oncogenes associated with non-squamous NSCLC can help determine which patients are more likely to benefit from a targeted therapy. Such oncogenes include EGFR, KRAS, and ALK. The presence of an EGFR mutation confers a more favorable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. The use of EGFR TKIs is based upon the detection of these mutations. The incidence of EGFR mutations in tumors with non-small-cell histology ranges from ~15% in Caucasians to ~50% in East Asians; 95% of such mutations have been found in adenocarcinomas. Patients bearing EGFR mutations have shown favorable clinical outcomes even with conventional chemotherapy suggesting that EGFR may be a predictive and a prognostic factor. Activation of the EGFR protein stimulates protein tyrosine kinase, which leads to activation of signaling pathways associated with cell growth and survival. Both EGFR overexpression and activating mutations in the tyrosine kinase domain of the EGFR gene lead to tumor growth and progression. Erlotinib, gefitinib and afatinib are examples of EGFR TKIs that can prevent activation of the signaling pathways and improve RRs in selected NSCLC patients. These mutations which are associated with increased sensitivity to EGFR TKIs, predominate in never-smokers, females, and tumors with adenocarcinoma histology. The most common mutations associated with sensitivity to EGFR TKIs include exon 19 deletions and the L858R point mutation and they are associated with RRs of >70%. Other EGFR mutations like T790M and exon 20 insertion, have been associated with much lower response or acquired resistance to TKI’s. The predictive value of EGFR mutations for use of gefitinib has been strengthened by the results of three randomized phase III trials that specifically compared TKIs used as first-line therapy with traditional platinum-based chemotherapy in patients with advanced NSCLC. In 2009 the results of IRESSA Pan-Asia Study were presented. This trial included a big number of Asian ethnicity patients (1,217) who were never smokers or former light smokers with histologic diagnosis of adenocarcinoma. The trial demonstrated an improvement in PFS and RR, with no statistical difference in OS, with the use of gefitinib in EGFR-mutated tumors and better RR and PFS with standard chemotherapy in patients without mutations. The first phase III trial of gefitinib versus chemotherapy as initial treatment of recurrent or advanced NSCLC, based on selection of patients with known activating EGFR mutations was the WJTOG3405 trial, reported in 2010. This trial documented important achievements in RR and PFS with the use of TKIs. Almost the same results were confirmed by another similar Japanese phase III trial, NEJ002, with RR and PFS definitely favoring the use of gefitinib in the first-line setting of metastatic EGFR-mutated NSCLC. Based on the results of the IPASS study, gefitinib was approved for use in Europe for the initial treatment of patients with NSCLC exhibiting EGFR mutations. The positive results of the EURTAC trial, NCT00446225, which was a randomized phase III trial of erlotinib versus standard chemotherapy, suggested that responsiveness in mutation-positive patients was not a function of ethnicity. Afatinib is approved as monotherapy for the treatment of EGFR TKI—naïve adults with locally advanced or metastatic NSCLC with activating EGFR mutations in the EU, and for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test in the US. In two randomized, open-label, multinational phase III trials, progression-free survival was significantly prolonged with afatinib compared with pemetrexed plus cisplatin (LUX-Lung 3) or gemcitabine plus cisplatin (LUX-Lung 6) in treatment-naïve patients with advanced NSCLC with activating EGFR mutations. EGFR-TKIs as a class are generally well tolerated. The two most common toxicities include dermatologic and GI effects, which are mild to moderate, easily managed and reversible. In order to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy, the latest guidelines recommend mutation testing for all patients with advanced NSCLC tumor. The aim of this prospective study is to compare the efficacy of gefitinib, erlotinib and afatinib in patients with advanced NSCLC harboring activating EGFR mutations in first line of treatment. These agents are recommended as first line treatments for NSCLCs with such mutations. The primary endpoint will be the PFS and the secondaries will be the OS and the record of the toxicities. In each of the 3 arms will be participate 20 patients with EGFR mutated tumors. The technique for screening NSCLC patients for driver mutations that it will be used is next-generation sequencing, which overcomes many of the shortcomings of direct sequencing. This massively parallel approach, relying heavily on automation, data storage, and computational processing, allows quantitative analysis of infrequent alleles and simultaneous evaluation of multiple genes or even whole genomes, but is not yet used routinely in clinical practice. In addition, KRAS mutation analysis will be performed in patients with known smoking history in order to determine the correlation of type and mutation frequency with smoking.

Keywords: Non-small cell lung cancer (NSCLC); epidermal growth factor receptor mutations (EGFR mutations); tyrosine kinase inhibitors treatment (TKI treatment)