Nit-Picking around second line inEGFRwt NSCLC: just an academic effort

Abstract

During the last decade, several new drugs emerged as effective in patients with advanced nonsmall-cell lung cancer (NSCLC). Agents targeting the epidermal growth factor receptor (EGFR), such as gefitinib, erlotinib or afatinib, induced dramatic and durable responses in patients with activating EGFR mutations (EGFRmut+), demonstrating superiority versus platinum-based chemotherapy in front-line setting [1.Mok T.S. Wu Y.L. Thongprasert S. et al.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.N Engl J Med. 2009; 361: 947-957Crossref PubMed Scopus (7025) Google Scholar, 2.Rosell R. Carcereny E. Gervais R. et al.Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.Lancet Oncol. 2012; 13: 239-246Abstract Full Text Full Text PDF PubMed Scopus (4419) Google Scholar, 3.Sequist L.V. Yang J.C. Yamamoto N. et al.Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma withEGFR mutations.J Clin Oncol. 2013; 31: 3327-3334Crossref PubMed Scopus (2547) Google Scholar]. More recently, crizotinib a potent ALK-MET-ROS1 inhibitor demonstrated superiority versus chemotherapy in chemo-naive and in pretreated patients with ALK translocations [4.Shaw A.T. Kim D.W. Nakagawa K. et al.Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.N Engl J Med. 2013; 368: 2385-2394Crossref PubMed Scopus (2831) Google Scholar, 5.Solomon B.J. Mok T. Kim D.W. et al.Firts-line crizotinib versus chemotherapy in ALK-positive lung cancer.N Engl J Med. 2014; 371: 2167-2177Crossref PubMed Scopus (2429) Google Scholar]. The striking superiority of targeted agents versus chemotherapy in molecularly selected patients demonstrated that today, in daily clinical practice, identification of biological characteristics of the tumor is crucial for defining the correct therapeutic strategy. Unfortunately, ∼85% of all NSCLCs are EGFR and ALK wild type and no targeted therapy is available outside clinical trials. In front-line setting, platinum-based chemotherapy remains the best treatment, with regimens including pemetrexed and/or bevacizumab for individuals with nonsquamous histology [6.Reck M. Popat S. Reinmuth N. et al.Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2014; 25: iii27-iii39Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar]. In 2000, docetaxel was the first agent approved for second-line therapy in NSCLC [7.Shepherd F.A. Dancey J. Ramlau R. et al.Prospective randomized trial of docetaxel versus best supportive care in patients with non–small-cell lung cancer previously treated with platinum-based chemotherapy.J Clin Oncol. 2000; 18: 2095-2103Crossref PubMed Scopus (2055) Google Scholar] and few years later two other agents, pemetrexed and erlotinib, reached the approval based on the results of phase III trials showing noninferiority in terms of survival versus docetaxel [8.Hanna N. Shepherd F.A. Fossella F.V. et al.Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy.J Clin Oncol. 2004; 22: 1589-1597Crossref PubMed Scopus (2290) Google Scholar] or superiority versus placebo [9.Shepherd F.A. Rodrigues Pereira J. Ciuleanu T. et al.Erlotinib in previously treated non-small-cell lung cancer.N Engl J Med. 2005; 353: 123-132Crossref PubMed Scopus (5086) Google Scholar]. Additional trials were conducted with the aim of identifying the best second-line therapy [6.Reck M. Popat S. Reinmuth N. et al.Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2014; 25: iii27-iii39Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar]. All trials, conducted in a general and unselected population of pretreated NSCLC, showed only minimal differences in terms of efficacy leading to the conclusion that pemetrexed, docetaxel and erlotinib represent an acceptable option as second-line treatment [6.Reck M. Popat S. Reinmuth N. et al.Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2014; 25: iii27-iii39Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar]. In second-line setting, gefitinib showed superiority versus docetaxel only in EGFRmut+ patients [10.Kim E.S. Hirsh V. Mok T. et al.Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial.Lancet. 2008; 372: 1809-1818Abstract Full Text Full Text PDF PubMed Scopus (1229) Google Scholar], with no survival improvement over placebo in unselected NSCLC [11.Thatcher N. Chang A. Parkikh P. et al.Gefitinib versus best supportive care in previously treated patients with refractory advanced non-small cell lung cancer: results from a randomized, placebo-controlled, multicenter study (Iressa Survival Evaluation in Lung Cancer).Lancet Oncol. 2005; 366: 1527-1537Abstract Full Text Full Text PDF Scopus (2000) Google Scholar]. For such reason, in the UE, gefitinib use is restricted to individuals harboring EGFR mutations. In the present issue, Zhou et al. reported the results of a phase II randomized trial comparing pemetrexed versus gefitinib as second-line therapy in patients with nonsquamous EGFR wild-type (EGFRwt) advanced NSCLC [12.Zhou Q. Cheng Y. Yang J.J. et al.Pemetrexed versus gefitinib as a second-line treatment in advanced non-squamous non-small-cell lung cancer patients harboring wild-type EGFR (CTONG0806): a multicenter randomized trial.Ann Oncol. 2014; 25: 2385-2391Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. The study, conducted in 161 Asiatic patients, showed that pemetrexed is superior to gefitinib in terms of progression-free survival (PFS), with a nonsignificant difference in terms of overall survival (OS). In addition to the clinical end points, authors also re-analyzed the EGFR status using a highly sensitive method, showing that a consistent percentage of the study population, ∼30%, harbored an activating EGFR mutation despite the initial assessment with direct sequencing did not detect any EGFR alteration. Interestingly, in such population of EGFRmut+ patients, no difference in PFS was observed in the two arms. This study raises an important clinical question that is whether chemotherapy should be preferred as second-line treatment in EGFRwt patients. In such population, the efficacy of standard chemotherapy is modest, with a response rate below 10%, a median PFS of 3–4 months and a median OS of 7–8 months [6.Reck M. Popat S. Reinmuth N. et al.Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2014; 25: iii27-iii39Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar]. Even if disappointing, these results seem superior to what achievable with EGFR-TKIs as demonstrated in two phase III trials, the TAILOR and DELTA, and in two meta-analyses [13.Garassino M.C. Martelli O. Broggini M. et al.Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial.Lancet Oncol. 2013; 14: 981-988Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar, 14.Kawaguchi T. Ando M. Asami K. et al.Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA).J Clin Oncol. 2014; 32: 1902-1908Crossref PubMed Scopus (216) Google Scholar, 15.Li N. Yang L. Ou W. et al.Meta-analysis of EGFR tyrosine kinase inhibitors compared with chemotherapy as second-line treatment in pretreated advanced non-small cell lung cancer.PLoS One. 2014; 16: e102777Crossref Scopus (34) Google Scholar, 16.Lee C.K. Brown C. Gralla R.J. et al.Impact of EGFR inhibitor in non–small cell lung cancer on progression-free and overall survival: a meta-analysis.J Natl Cancer Inst. 2013; 105: 595-605Crossref PubMed Scopus (442) Google Scholar]. In addition, both TAILOR and DELTA trials used a highly sensitive method for EGFR mutation test, reducing the risk of including false-negative patients. Nevertheless, ‘pure’ EGFRwt patients did not survive longer with chemotherapy [13.Garassino M.C. Martelli O. Broggini M. et al.Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial.Lancet Oncol. 2013; 14: 981-988Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar, 14.Kawaguchi T. Ando M. Asami K. et al.Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA).J Clin Oncol. 2014; 32: 1902-1908Crossref PubMed Scopus (216) Google Scholar] or, in other words, EGFR-TKIs are not detrimental in pretreated NSCLC irrespective of EGFR status. For such reason, medical oncologists generally based their choice on several factors, including personal experience or familiarity with the drug, toxicity, patient characteristics and preferences, and last but not least, drug costs. Docetaxel is used in pretreated NSCLC since 2000 when the drug was approved based on the results of a phase III study showing superiority versus placebo only in a small subgroup of patients receiving the dose of 75 mg/m2 every 21 days [7.Shepherd F.A. Dancey J. Ramlau R. et al.Prospective randomized trial of docetaxel versus best supportive care in patients with non–small-cell lung cancer previously treated with platinum-based chemotherapy.J Clin Oncol. 2000; 18: 2095-2103Crossref PubMed Scopus (2055) Google Scholar]. All studies comparing docetaxel with gefitinib failed to demonstrate any difference between the two arms in the whole population as well as in the EGFRwt [10.Kim E.S. Hirsh V. Mok T. et al.Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial.Lancet. 2008; 372: 1809-1818Abstract Full Text Full Text PDF PubMed Scopus (1229) Google Scholar, 17.Shepherd F.A. Douillard J. Fukuoka M. et al.Comparison of gefitinib and docetaxel in patients with pretreated advanced non-small cell lung cancer (NSCLC): meta-analysis from four clinical trials.J Clin Oncol. 2009; 27: S15Google Scholar]. Although the cost of the drug is lower than other agents currently approved for second-line therapy, the standard schedule of docetaxel produces considerable toxicity, particularly neutropenia, resulting not cost-effective from the perspective of a variety of payers and health care systems [18.Horgan A.M. Bradbury P.A. Emir A. et al.An economic analysis of the INTEREST trial, a randomized trial of docetaxel versus gefitinib as second/third line therapy in advanced non-small-cell lung cancer.Ann Oncol. 2011; 22: 1805-1811Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. That is the reason why many oncologists prefer a weekly schedule that is probably as effective as the three-weekly schedule but not used as reference arm in any randomized study, with the only exception of the TAILOR trial where investigators had the possibility to choose both schedules [13.Garassino M.C. Martelli O. Broggini M. et al.Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial.Lancet Oncol. 2013; 14: 981-988Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar]. Pemetrexed is not inferior to docetaxel in terms of efficacy [8.Hanna N. Shepherd F.A. Fossella F.V. et al.Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy.J Clin Oncol. 2004; 22: 1589-1597Crossref PubMed Scopus (2290) Google Scholar], with better toxicity profile and higher cost. Only two studies, the TITAN and HORG, compared pemetrexed versus EGFR-TKIs in pretreated NSCLC [19.Ciuleanu T. Stelmakh L. Cicenas S. et al.Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study.Lancet Oncol. 2012; 13: 300-308Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 20.Karampeazis A. Voutsina A. Souglakos J. et al.Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study.Cancer. 2013; 119: 2754-2764Crossref PubMed Scopus (107) Google Scholar] and both showed no difference in survival versus erlotinib even when the analysis was restricted to the EGFRwt population [19.Ciuleanu T. Stelmakh L. Cicenas S. et al.Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study.Lancet Oncol. 2012; 13: 300-308Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar]. Therefore, the whole second-line therapy picture includes different drugs with different cost and toxicity profile and with differences in terms of efficacy, thus animating academic debates marginally influencing the most relevant clinical end point that is patient survival. In such context, it is important to understand how Zhou et al. results compare with previous trials and how they could influence our clinical practice. Comparison with previous studies is difficult for the differences in trial design and patient populations. TITAN and HORG were phase III trials, with TITAN including only chemo-refractory patients [19.Ciuleanu T. Stelmakh L. Cicenas S. et al.Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study.Lancet Oncol. 2012; 13: 300-308Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar] and the HORG including also patients in third line of treatment [20.Karampeazis A. Voutsina A. Souglakos J. et al.Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study.Cancer. 2013; 119: 2754-2764Crossref PubMed Scopus (107) Google Scholar]. In addition, TITAN and HORG used erlotinib as EGFR-TKI and no study formally demonstrated that erlotinib and gefitinib are equivalent in EGFRwt patients. Previous studies showed that erlotinib has some activity even in the wild-type population [9.Shepherd F.A. Rodrigues Pereira J. Ciuleanu T. et al.Erlotinib in previously treated non-small-cell lung cancer.N Engl J Med. 2005; 353: 123-132Crossref PubMed Scopus (5086) Google Scholar, 21.Cappuzzo F. Ciuleanu T. Stelmakh L. et al.Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study.Lancet Oncol. 2010; 11: 521-529Abstract Full Text Full Text PDF PubMed Scopus (1143) Google Scholar], while no study demonstrated any survival effect of gefitinib in absence of EGFR mutations [11.Thatcher N. Chang A. Parkikh P. et al.Gefitinib versus best supportive care in previously treated patients with refractory advanced non-small cell lung cancer: results from a randomized, placebo-controlled, multicenter study (Iressa Survival Evaluation in Lung Cancer).Lancet Oncol. 2005; 366: 1527-1537Abstract Full Text Full Text PDF Scopus (2000) Google Scholar, 22.Zhang L. Ma S. Song X. et al.Gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804): a multicentre, double-blind randomized phase 3 trial.Lancet Oncol. 2012; 13: 466-475Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar]. Therefore, the results of the present study are not surprising considering that the comparison is between an agent, pemetrexed, with demonstrated activity in nonsquamous histology and another agent, gefitinib, with no proven efficacy in EGFRwt. In any case, at least in the UE, the study has limited clinical implications since the vast majority of NSCLC with nonsquamous histology are currently treated in front line or in maintenance setting with pemetrexed and gefitinib is not approved in patients without EGFR mutations. Actually, the heart of the matter remains the choice between erlotinib and docetaxel, also considering that pemetrexed is not indicated for patients with squamous histology [8.Hanna N. Shepherd F.A. Fossella F.V. et al.Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy.J Clin Oncol. 2004; 22: 1589-1597Crossref PubMed Scopus (2290) Google Scholar]. This picture is certainly not exciting because today we are choosing between a cheap but toxic drug and a fancy and expensive targeted agent with modest efficacy in a ‘target-free’ population. Fortunately, the scenario of NSCLC therapy is rapidly evolving and new therapies potentially more effective are emerging. Recent studies showed that adding antiangiogenic agents to chemotherapy modestly but significantly improve survival [23.Garon E.B. Ciuleanu T.E. Arrieta O. et al.Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.Lancet. 2014; 384: 665-673Abstract Full Text Full Text PDF PubMed Scopus (891) Google Scholar] and new checkpoint inhibitors particularly nivolumab and pembrolizumab, are showing promising results even in heavily pretreated patients. We hope that in the next future new options will be available for our patients offering the concrete possibility to extend survival, making disputes on the best second –line treatment of EGFRwt only the memory of an academic effort.