First-Line EGFR-1 Tyrosine Kinase Inhibition in Patients With NSCLC With Mutant EGFR Gene

Patients with stage IV NSCLC and some patients with advanced locoregional disease (stage III) are in general incurable and have a low probability for long-term survival. Current systemic treatment in good PS patients (PS 0-1) consists of a cisplatin doublet (e.g. cisplatin plus a second drug: vinorelbine, gemcitabine, paclitaxel, docetaxel). The median and one year survival obtained with this treatment ranges between 8-10 months and 25 - 35 % respectively (1,2). Progression-free survival is a median of 5 month or less in randomized studies (3). Response rates obtained are less than 25% in metastatic disease and up to 75% in advanced locoregional disease. Receptor tyrosine kinase inhibitors (RTKI's) are active drugs in patients with NSCLC pre-treated with cisplatin and/or docetaxel containing chemotherapy (2,4). Recently it has been shown that the EGFR1 kinase inhibitor erlotinib added to best supportive care (BSC) prolonged survival compared to BSC alone in patients with advanced NSCLC failing 1st or 2nd line chemotherapy (5). A small number of preliminary reports have indicated that the objective response rate with these RTKI's as first line treatment in some patient populations with advanced NSCLC could be around 20 % (6), The objective (mainly partial) response in the phase II studies with pre-treated patients ranges from 10 - 15 % according to the level of pre-treatment but the control of the disease (stable disease) and improvement of symptoms without demonstrated objective response has been reported to be as high as 40 to 50 % (2,4). The addition of RTKI's or placebo to the current standard doublets (e.g. cisplatin, gemcitabine or taxol/carboplatin) has not been shown to impact on response rate, time to treatment failure or survival in large phase III randomised trials in advanced NSCLC patients not selected for EGFR expression (7,8). Recently, mutations in the intracellular EGFR kinase domain that increase sensitivity of the receptor to RTKI's have been discovered (9,10). These studies suggest that the response/resistance to treatment could be strongly correlated to the presence/absence of such mutations. It is presently unclear whether patients who achieve stable disease under RTKI treatment do have receptor mutations, of which nature such mutations could be or what other biological pathways modulate the responsiveness/resistance. Mutations have been observed in about 10 % or less of the tumours examined. Most mutations in the EGFR kinase domain have been found in adenocarcinoma of non-smokers or minimal smokers. Recent data have established that an EGFR mutation can be found in 30% of adenocarcinoma of the lung if the smoking history is maximally 15 years. The probability of finding a mutation is approximately 50% in never-smokers with adenocarcinoma (11). In contrast to the rather low objective response rate, the clinical benefit rate of treatment with RTKI is around 40 % in a general population of non-small lung cancer (9,10), more than can be accounted for by mutational analysis. EGFR gene amplification might be another determinant for sensitivity, but the biological factors leading to disease stabilisation in some patients with non-activated EGFR are presently unknown. Several humanized monoclonal antibodies (huMoAb) that can inhibit the EGFR-1 receptor have been developed as well. Of these, cetuximab (ErbituxÒ) has been developed most extensively, especially in head and neck (12) and colorectal cancer (13,14), but other, fully humanized antibodies (huMoAb) (ABX-EGF, EMD 72000) are under development. Cetuximab has been assessed in NSCLC, especially in combination with first-line and second-line chemotherapy (15), but no data are currently available with respect to single agent activity. The two types of currently available drugs targeting the EGFR-1, the RTKI's such as gefitinib and erlotinib and huMoAb such as cetuximab and ABX-EGF, are generally well tolerated and devoid of significant grade 3-4 toxicity. While there are strong indications that the major responses obtained with RTKI's could strongly correlate with the presence of tyrosine kinase domain mutations in addition to the known mechanism of action of these drugs (16,17), this is at present yet not so clear for the monoclonal antibodies directed against the extracellular domain of the receptor. Some recent data suggest that EGFR gene amplification might also correlate with response to TKI (18). Patients with Stage IV and some advanced stage III NSCLC are at present incurable and first-line chemotherapy has had only a palliative and a life prolonging effect at a cost of variable toxicity. On the other hand the response rate to TKI in patients with a NSCLC carrying a mutant receptor is probably high as can be inferred from the comparison of the prevalence of such mutations and the response rate to these agents in an unselected population (16). It seems therefore reasonable to explore in a first-line setting the potential of EGFR-1 targeted therapy, as these drugs have a very favourable toxicity profile and might induce prolonged palliation. There are currently no data that would suggest that delaying chemotherapy in this patient population in well controlled conditions and for a limited time period (sufficient to evaluate the efficacy of more novel first-line treatments) might affect the efficacy of subsequent chemotherapy. There are also no data that suggest that prior administration of drugs targeted at the EGFR-1 will induce resistance to subsequent chemotherapy. The distinct respective mechanisms of action of these drugs and chemotherapy also do not suggest this to be likely. In other diseases such as prostate cancer and oestrogen receptor-positive breast cancer, the availability of hormonal treatments permits prolonged and at times long-term disease control with limited discomfort. It is possible that a similar scenario could be obtained with an anti-EGFR treatment in NSCLC carrying a mutant EGFR. Therefore it seems justified to expand previous second-line phase II experience with anti-EGFR strategies to patients with incurable stage III-IV NSCLC without prior therapy and a mutant EGFR. The informed consent towards these patients before entry in the study will clearly state that until now the first-line standard of care has been chemotherapy, which leads to a small overall survival benefit compared to the supportive treatment only and that participation in the current study will delay this treatment within a tightly controlled setting. In the current trial the RTKI erlotinib will be used. Prior experience with this drug has been obtained in phase II and III studies. In the phase II setting, in an unselected pretreated population, a response rate of 12.3% and a median survival of 8.4 months could be obtained (19). In phase III, placebo-controlled studies, combination of erlotinib with concurrent chemotherapy does not provide a survival advantage (gemcitabine and cisplatin in TALENT (20) and paclitaxel and carboplatin in TRIBUTE (21). Several hypotheses can explain these results: lack of selection of patients; antagonism between cytostatic and cytotoxic agents (negative interaction with chemotherapy when given concurrently); chemotherapy and EGFR inhibitors target the same cell population since chemotherapy directly or indirectly affects EGFR function/expression and thereby reducing the effects of EGFR inhibitors. These results are in contrast to the significant survival benefit seen in the phase III randomized placebo-controlled study in NSCLC following failure of 1st or 2nd line chemotherapy (BR21). The response rate was 9% in the erlotinib treated patients, with significant increase in progression free survival (from 8 to 9,7 wks) and increased survival (from 4.7 mth to 6.7 mth, p\< 0.001). In that study the biological parameters that correlate with response (mutation status, EGFR gene amplification and EGFR immunohistochemistry) are still under study. Survival benefit correlated best with the presence of EGFR expression by immunohistochemistry and EGFR gene polysomy (22).