REVIEW URRENT C OPINION
Novel drugs against non-small-cell lung cancer Robert Pirker
Purpose of review Important therapeutic advances for patients with advanced non-small-cell lung cancer (NSCLC) with focus on individualized therapy have recently occurred and are summarized in this review. Recent findings Cetuximab added to first-line chemotherapy has been shown to improve survival in patients with high epidermal growth factor receptor (EGFR) expression in their tumors. Afatinib has shown improved progression-free survival and better quality of life compared to chemotherapy in patients with EGFRmutation-positive adenocarcinomas. Several other EGFR-directed agents are in clinical development. Crizotinib improved progression-free survival compared to second-line chemotherapy with docetaxel or pemetrexed in patients with advanced anaplastic lymphoma kinase-positive NSCLC. Selumetinib added to docetaxel has improved outcome compared with docetaxel in a randomized phase II trial in patients with advanced KRAS-mutant NSCLC and this combination is currently studied in a phase III trial. Nintedanib added to docetaxel improved progression-free survival in the second-line therapy of patients with advanced NSCLC but many other angiogenesis inhibitors failed to improve clinical outcome in phase III trials. Several other targeted therapies are currently evaluated in phase III trials in patients with advanced NSCLC. Summary Recent trials have led to the approval of afatinib and crizotinib for subsets of patients with advanced NSCLC. Keywords afatinib, cetuximab, crizotinib, selumetinib, targeted therapy
INTRODUCTION Chemotherapy of non-small-cell lung cancer (NSCLC) with a platinum-based doublet containing a third generation anticancer drug has been well established. Advances in the systemic treatment can be achieved through better understanding of the molecular pathogenesis of lung cancer and the molecular mechanisms of action of anticancer drugs. In particular, identification of driver mutations may offer novel therapeutic opportunities [1,2]. Targeted therapies based on molecular changes of tumor cells may offer higher efficacy and greater specificity. Many targeted agents have been studied in lung cancer. Bevacizumab has been approved in combination with first-line chemotherapy for patients with nonsquamous NSCLC. In the European Union (EU), erlotinib has been approved for patients with advanced NSCLC who had previously been treated with chemotherapy and as a maintenance therapy in patients with stable disease under first-line chemotherapy. This article summarizes novel agents that have been or are currently studied in phase III trials.
EPIDERMAL GROWTH FACTOR RECEPTORDIRECTED MONOCLONAL ANTIBODIES Targeting the epidermal growth factor receptor (EGFR) is an important therapeutic strategy in patients with NSCLC [3]. Several EGFR-directed monoclonal antibodies have been evaluated within clinical trials [3–5]. These antibodies block receptor signaling through competitively binding to EGFR on the surface of tumor cells but may act also via antibody-dependent cellular cytotoxicity or other immunological mechanisms [3,6].
Cetuximab Cetuximab has been studied in combination with first-line chemotherapy in two phase III trials [7,8]. Department of Medicine I, Medical University of Vienna, Vienna, Austria Correspondence to Robert Pirker, MD, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel: +43 1 40400 4422; fax: +43 1 40400 4461; e-mail: [email protected] Curr Opin Oncol 2014, 26:145–151 DOI:10.1097/CCO.0000000000000056
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KEY POINTS High EGFR expression based on an IHC score appears to be a predictive biomarker for cetuximab when added to first-line chemotherapy. Afatinib increases progression-free survival and quality of life compared with cisplatin and pemetrexed in patients with advanced EGFR-mutant NSCLC. Crizotinib is superior to second-line chemotherapy in patients with advanced ALK-positive NSCLC. Selumetinib is a promising agent for the treatment of KRAS-mutant NSCLC.
The FLEX trial evaluated cisplatin and vinorelbine with and without cetuximab in 1125 patients with advanced NSCLC and enriched for EGFR expression [7]. The trial demonstrated an improvement in overall survival (OS) for chemotherapy and cetuximab with a hazard ratio of 0.87 (P ¼ 0.044). Median survival times were 11.3 and 10.1 months, respectively. The BMS099 trial phase III trial failed to demonstrate an improvement in progression-free survival for cetuximab added to carboplatin and a taxane (paclitaxel or docetaxel) in patients (n ¼ 676) with advanced NSCLC but unselected for EGFR expression [8]. A meta-analysis based on 2018 patients with advanced NSCLC from four randomized trials confirmed the benefit of chemotherapy and cetuximab compared with chemotherapy alone in terms of OS, progression-free survival and response rates [9]. The hazard ratio for death was 0.878 (95% confidence interval, CI 0.795–0.969; P ¼ 0.01) in favor of chemotherapy and cetuximab.
Characterization of predictive biomarkers First-cycle rash was shown to be associated with better prognosis [10]. KRAS wildtype, EGFR copy numbers and EGFR-activating mutations did not predict benefit from cetuximab [11,12]. EGFR expression based on an immunohistochemistry (IHC) score was then shown to predict benefit from cetuximab in patients of the FLEX trial [13 ]. Immunohistochemical EGFR expression was assessed by means of the pharmDx kit (Dako, Glostrup, Denmark). Membrane staining intensity was divided into no staining, weak, intermediate and strong staining. The percentages of cells at the various staining intensities were determined and an IHC score was calculated as described [13 ]. For further analysis, patients were grouped into those with high (IHC score 200) and low (score < 200) &&
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EGFR expression. High EGFR expression was detected in 31% of patients. Among these patients, the hazard ratio for death was 0.73 (95% CI 0.58–0.93; P ¼ 0.011) in favor of chemotherapy and cetuximab compared with chemotherapy alone. Median survival times were 12.0 (95% CI 10.2–15.2) and 9.6 months (95% CI 7.6–10.6), and 1-year survival rates were 50 and 37% for patients treated with and without cetuximab, respectively [13 ]. Among patients with low EGFR expression, survival was not different between both treatment arms. The treatment interaction test was significant. The survival benefit obtained with chemotherapy and cetuximab in patients with high EGFR expression was seen across all major subgroups, in particular in both adenocarcinomas and squamous cell carcinomas. Toxicity according to treatment arm was similar in the high and low EGFR expression groups [13 ]. Based on these data, EGFR expression levels may lend themselves as predictive biomarkers for the selection of those patients who will derive a clinically relevant benefit from the addition of cetuximab to first-line chemotherapy with platinumbased doublets. EGFR copy numbers determined by FISH analysis may also be a predictive biomarker [14]. The SWOG biomarker validation study aims at validating the EGFR imunohistochemistry score and EGFR copy numbers assessed by FISH as predictive biomarkers. Within this trial, patients with advanced NSCLC are randomized to carboplatin/ paclitaxel (with or without bevacizumab) and cetuximab or carboplatin/paclitaxel (with or without bevacizumab). &&
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Cetuximab in stage III non-small-cell lung cancer Cetuximab has also been evaluated in combination with chemoradiotherapy in patients with locally advanced NSCLC [15,16]. In the RTOG 0617 trial, the addition of cetuximab to chemoradiotherapy did not increase survival in patients with unresectable stage III NSCLC [16]. In a subgroup analysis based on an EGFR IHC score like in the FLEX trial, however, patients with high IHC scores of their tumors appear to benefit from the addition of cetuximab. Therefore, further studies of chemoradiotherapy and cetuximab are warranted in patients with high EGFR expression in their tumors.
Necitumumab Necitumumab is a recombinant fully human antiEGFR monoclonal antibody. Two phase III trials (INSPIRE, SQUIRE) currently evaluate whether the addition of necitumumab to first-line chemotherapy Volume 26 Number 2 March 2014
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improves survival of patients with advanced NSCLC. The INSPIRE trial (ClinicalTrials.gov identifier: NCT00982111) evaluates cisplatin and pemetrexed with and without necitumumab in patients with nonsquamous cell NSCLC. The trial has prematurely been terminated because of increased rates of thromboembolic events in patients treated with chemotherapy and necitumumab. The SQUIRE trial (ClinicalTrials.gov identifier: NCT00981058) evaluates cisplatin and gemcitabine with and without necitumumab in patients with squamous cell NSCLC. According to a press release, the trial met its primary endpoint.
Other antiepidermal growth factor receptor monoclonal antibodies Matuzumab, a humanized anti-EGFR monoclonal IgG1 antibody, and panitumumab, a fully human anti-EGFR IgG2 monoclonal antibody, have been studied in phase II trials [17,18] but not in phase III trials.
EPIDERMAL GROWTH FACTOR RECEPTOR-DIRECTED TYROSINE KINASE INHIBITORS EGFR-directed tyrosine kinase inhibitors (TKIs) inhibit receptor signaling through competitively blocking the binding of adenosine triphosphate to the cytoplasmic domain of EGFR. In the EU, erlotinib has been approved for patients with advanced NSCLC who had previously been treated with chemotherapy and as a maintenance therapy in patients with stable disease under first-line chemotherapy. Gefitinib also increased survival when given as maintenance therapy following first-line chemotherapy in unselected patients with advanced NSCLC [19]. Patients who dramatically responded to EGFRdirected TKIs were found to harbor EGFR-activating mutations, for example exon 19 deletions or exon 21-point mutations, in their tumors [20–22]. This was then prospectively confirmed in several phase III trials in patients with advanced EGFR-mutation positive NSCLC [23–25,26 ]. In these trials, treatment with erlotinib or gefitinib until disease progression resulted in superior progression-free survival and better quality of life compared with platinum-based first-line chemotherapy. Based on these results, erlotinib and gefitinib have been approved in the EU for the treatment of patients with EGFR-activating mutations in the first-line setting (erlotinib) or independent of the treatment line (gefitinib). Several second generation TKIs are in clinical development. &
Afatinib Afatinib is an orally available and irreversibly binding ErbB family blocker. Two phase III trials (LUXLung 3 and 6) compared afatinib with chemotherapy in patients with advanced adenocarcinomas harboring EGFR mutations [27 ,28]. In the LUX-Lung 3 phase III trial, 1269 patients were screened for EGFR-activating mutations by a central laboratory [27 ]. Mutations were confirmed in 452 patients with exon 19 deletions in 49%, L858R mutations in 40% and other mutations in about 10% of the patients. Three-hundred and fortyfive patients with mutations have been randomized to either afatinib 40 mg daily or chemotherapy with cisplatin and pemetrexed. Stratification factors were mutation type and race. Afatinib was planned until disease progression and chemotherapy for up to six cycles. The afatinib dose had to be reduced to less than 40 mg daily in 52% of the patients and more than one dose reduction was required in 19% of the patients. Fifty-five percent of the patients received six cycles of chemotherapy and 75% received four or more cycles. Seventy-two percent of the patients were of East Asian ethnicity, 26% were white, 65% were females and 68% were never-smokers. Based on independent radiological review, afatinib resulted in prolongation of progression-free survival compared to chemotherapy with a hazard ratio of 0.58 (95% CI 0.43–0.78; P ¼ 0.001). Median progressionfree survival times were 11.1 and 6.9 months, respectively. The benefit was seen across all major subgroups. In patients (n ¼ 308) with exon 19 deletions or L858R mutations, progression-free survival time was prolonged with a hazard ratio of 0.47 (95% CI 0.34–0.65) and median survival times were 13.6 months in the afatinib group and 6.9 months in the chemotherapy group. Patientreported outcomes also favored afatinib which resulted in better control of cough, dyspnea and pain [29]. Afatinib improved dyspnea and delayed the time to deterioration of cough (hazard ratio of 0.6; 95% CI 0.41–0.87; P ¼ 0.007) and dyspnea (hazard ratio of 0.68; 95% CI 0.50–0.98; P ¼ 0.015). Diarrhea, dysphagia and sore mouth were more frequently seen with afatinib. OS was not different between both treatment arms. Treatment-related adverse events grade 3 or higher were seen in 49% of patients receiving afatinib and 48% of patients receiving chemotherapy. The most common afatinib-related adverse events were diarrhea (all grades in 95%, grade 3 in 14%), rash/acne (all grades in 89%, grade 3 in 16%) and stomatitis/mucositis (all grades in 72%, grade 3 in 9%). Adverse events were clinically acceptable under consideration of dose reductions and treatment delays. Based on the LUX-Lung 3 results, afatinib has been approved in
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the EU for first-line therapy of patients with advanced EGFR mutation-positive NSCLC. A benefit was also seen in the LUX-Lung 6 trial that was performed in China and Korea [28]. Afatinib compared with cisplatin and gemcitabine prolonged progression-free survival in patients with advanced EGFR-mutation-positive adenocarcinomas. The LUX-Lung 1 trial compared afatinib with placebo in patients (n ¼ 585) who had been treated with one or two chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib [30]. OS as the primary endpoint was not different between the two arms but progression-free survival was prolonged with afatinib.
Dacomitinib Dacomitinib, an irreversible oral pan-HER inhibitor, is currently evaluated in several phase III trials in patients with advanced NSCLC. The ARCHER 1009 trial compares dacomitinib with erlotinib in patients following progression after or intolerance to at least one prior chemotherapy regimen (ClinicalTrials.gov identifier NCT01360554). The primary endpoint of the trial is progression-free survival per independent radiological review. The BR.26 phase III trial compares dacomitinib with placebo in patients who have progressed after at least one line of chemotherapy and erlotinib or gefitinib. The primary endpoint is OS. The ARCHER 1050 phase III trial compares dacomitinib with gefitinib in the first-line treatment of patients with EGFR-mutation-positive NSCLC (ClinicalTrials.gov identifier NCT01774721).
ongoing MetLung phase III trial aims at confirming the benefit of erlotinib and onartuzumab compared with erlotinib in the second-line or third-line treatment of patients with advanced NSCLC who have high MET expression in their tumors.
RAS INHIBITORS The RAS/RAF/MEK/ERK pathway is often deregulated in cancers including NSCLC. RAS mutations are seen in approximately 20% of NSCLC and 30% of adenocarcinomas. These mutations preferentially occur in exon 12 and only occasionally in exon 13. Whether NSCLC patients with KRAS mutations in their tumors have worse prognosis compared to those with wild-type tumors, remains controversial. Patients with KRAS-mutated NSCLC, however, do not respond to EGFR-directed TKIs. Inhibition of KRAS is attempted in the hope of improving outcome in patients with KRAS-mutant NSCLC. So far, however, direct blocking of KRAS has failed. Therefore, inhibition of downstream targets of the MAPK cascade such as RAF, MEK or ERK may be a more promising strategy [32]. Besides BRAF inhibitors such as vemurafenib and dabrafenib, several MEK inhibitors, for example trametinib and selumetinib, are in clinical development.
Selumetinib Selumetinib (AZD6244), an oral inhibitor of MEK, has shown synergistic activity with docetaxel in preclinical models. Based on these findings, docetaxel and selumetinib have been studied in a randomized placebo-controlled phase II trial in 87 patients with advanced KRAS-mutant NSCLC who had previously been treated with first-line chemotherapy [33 ]. The combined treatment resulted in a statistically nonsignificant prolongation of OS. The hazard ratio for death was 0.80 (95% CI 0.56–1.14) and median survival times were 9.4 and 5.2 months, respectively. Progression-free survival (HR 0.58, P ¼ 0.01; median 5.3 versus 2.1 months), response rates (37 versus 0%, P < 0.0001) and patientreported outcomes were significantly improved in the selumetinib arm. Adverse events of grade 3 or higher were increased with selumetinib in terms of neutropenia (67 versus 55%), neutropenic fever (18% versus none) and asthenia (9% versus none). Diarrhea, vomiting, stomatitis and dry skin were also more frequently seen in the selumetinib arm. Patients receiving docetaxel and selumetinib also required more hospitalizations. Thus the trial demonstrated improved outcome with docetaxel and selumetinib compared with docetaxel alone, but at the expense of greater toxicity. The interpretation of &
Onartuzumab Increased MET signaling is associated with resistance to EGFR-directed TKIs. Thus, MET inhibition may improve outcome in patients treated with these TKIs. Onartuzumab is a humanized, monovalent monoclonal antibody directed against the MET receptor. In a randomized phase II trial in patients with recurrent NSCLC, erlotinib and onartuzumab compared with erlotinib did not improve progression-free survival in the intent-to-treat population [31]. Based on immunohistochemical MET expression, however, a difference in outcome was observed. The combined treatment resulted in improved progression-free survival in patients with high MET expression (hazard ratio 0.53) and in shorter progression-free survival in patients with low MET expression (hazard ratio 1.82). The 148
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these results is complicated by several shortcomings of the trial. Firstly, the outcome with docetaxel alone was poor compared with the ones seen in previous studies with docetaxel in an unselected patient population. Whether the poor outcome with docetaxel in the present study is due to chemotherapy resistance of KRAS-mutant NSCLC, is unclear. Secondly, slight imbalances in patient characteristics favoring the selumetinib arm (e.g. adenocarcinomas 68 versus 53%, IIIB 11 versus 2%, responders to first-line chemotherapy 38 versus 18%) were obvious. Despites these caveats, a phase III trial has been initiated in order to determine whether selumetinib added to second-line therapy with docetaxel improves survival in patients with advanced KRAS-mutant NSCLC.
ANAPLASTIC LYMPHOMA KINASE INHIBITORS Anaplastic lymphoma kinase (ALK) fusion genes can be detected in a subset of NSCLC, mostly adenocarcinomas. EML4-ALK fusion genes can be detected in approximately 4% of patients with advanced NSCLC. The presence of these fusion genes is currently proven by FISH analysis using break-apart probes for EML4 and ALK genes. EML4-ALK fusion proteins drive cancer growth. Therefore, ALK inhibitors should improve outcome in patients who have this genetic aberration in their tumors.
Crizotinib Crizotinib has shown good efficacy in patients with advanced NSCLC who show an ALK re-arrangement in their tumors [34,35,36 ]. EML4-ALK fusion protein is detected by FISH analysis. IHC is often used for screening followed by FISH as confirmatory analysis. In the PROFILE 1007 phase III trial, crizotinib has been compared with chemotherapy in patients with ALK-positive NSCLC who had received one prior platin-based chemotherapy regimen [36 ]. A total of 4967 patients were screened and 347 patients were randomized to either crizotinib 250 mg twice daily or to chemotherapy with pemetrexed or docetaxel. Crossover to crizotinib was allowed for patients of the chemotherapy arm at the time of disease progression. Randomized patients had the following baseline characteristics: age median 50 years, 66% females, 63% never-smokers, 91% ECOG 0–1, 95% adenocarcinoma. Crizotinib increased progression-free survival compared with chemotherapy. The hazard ratio for progression or death was 0.49 (95% CI 0.37–0.64; P < 0.001). Median progression-free survival times &&
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were 7.7 and 3 months, respectively. Response rates were also higher with crizotinib (65 versus 20%). OS based on an interim analysis was not different between both treatment arms. Crizotinib resulted in better improvement in tumor-related symptoms and global quality of life. The main crizotinibrelated adverse events were visual disorders, gastrointestinal side-effects and elevated liver aminotransferase levels. Based on these data, crizotinib has been approved as second-line therapy for patients with advanced ALK-positive NSCLC in the EU. The PROFILE 1014 trial compares crizotinib with chemotherapy in the first-line treatment of patients with ALK-positive NSCLC. The primary endpoint of the trial will be progression-free survival.
Second-generation anaplastic lymphoma kinase inhibitors Several second-generation ALK inhibitors are in clinical development. Alectinib (CH5424802) has shown better activity compared with crizotinib in preclinical models. In a phase I–II trial in patients with ALK-positive tumors and refractory to crizotinib treatment [37 ], the dose-limiting toxicities were grade 3 headache and grade 3 neutropenia. The most common adverse event was fatigue which was seen in 30% of the patients. A dose of 300 mg twice daily has been established as the recommended dose for phase II trials. In a phase II trial, responses were seen in 93% of previously untreated patients with advanced ALK-positive NSCLC [37 ]. A phase III trial comparing alectinib with crizotinib in the first-line treatment of patients with advanced ALK-positive NSCLC is planned. &
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ANGIOGENESIS INHIBITORS Several angiogenesis inhibitors have been studied for their potential to improve outcome in patients with NSCLC. These agents include monoclonal antibodies against vascular endothelial growth factor (VEGF) or VEGF receptors (VEGFR), VEGFR-directed TKIs, or several others.
Bevacizumab Bevacizumab is currently further evaluated in two important phase III trials. The AvaALL trial assesses whether continuation of bevacizumab beyond progression over all treatment lines increases survival in patients with advanced nonsquamous NSCLC. The ECOG trial determines whether bevacizumab added to adjuvant chemotherapy increases survival
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compared with chemotherapy alone. Chemotherapy consists of four cycles of a platin-based doublet. Bevacizumab treatment is planned to be continued after the end of chemotherapy for 1 year.
Nintedanib Nintedanib is an oral inhibitor of receptors for VEGF, PDGF receptors and FGF. It has been studied at a dose of 200 mg twice daily in two placebocontrolled phase III trials (LUME-Lung 1 and LUME-Lung 2) in combination with docetaxel or pemetrexed in patients with advanced NSCLC (LUME-Lung 1) or advanced lung adenocarcinomas (LUME-Lung 2) previously treated with chemotherapy [38,39]. The LUME-Lung 1 trial, which enrolled 1314 patients with advanced NSCLC, demonstrated increased progression-free survival for docetaxel and nintedanib compared with docetaxel and placebo [38]. The hazard ratio was 0.79 (95% CI 0.68–0.92; P ¼ 0.002) and median progression-free survival times were 3.4 and 2.7 months, respectively. OS as a secondary endpoint was not prolonged in the total population. In a preplanned subgroup analysis, however, OS was prolonged in patients with adenocarcinomas with a hazard ratio of 0.83 (P ¼ 0.036; median 12.6 versus 10.3 months). Disease control rates were higher with docetaxel and nintedanib in all patients (odds ratio, OR 1.68; P < 0.0001), all adenocarcinoma patients (OR 1.93; P < 0.0001), and adenocarcinoma patients with start of first-line chemotherapy within less than 9 months (OR 2.9; P < 0.0001). The most common adverse events were diarrhea (any grade 42 versus 22%, grade 3 6.6 versus 2.6%) and elevation of liver enzymes (any grade 28 versus 8%, grade 3 8 versus 1%). Hypertension, bleedings, thrombotic events and withdrawals due to adverse events were similar in both treatment arms. The LUME-Lung 2 trial compared pemetrexed and nintedanib with pemetrexed and placebo in patients with advanced nonsquamous NSCLC [39]. The trial had randomized 713 of the 1300 planned patients when it was halted after an interim analysis had suggested lack of improvement in outcome by the addition of nintedanib. The final analysis of the intent-to-treat population, however, indicated significantly prolonged progression-free survival for pemetrexed and nintedanib with a hazard ratio of 0.83 (95% CI 0.7–0.99; P ¼ 0.04) and median progression-free survival times of 4.4 and 3.6 months, respectively. However, OS (hazard ratio 1.03) and response rates (9% in both arms) were not different between the two treatment arms. 150
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Aflibercept Aflibercept (VEGF trap) is an engineered soluble receptor made from extracellular domains of VEGFR1 and VEGFR2. Aflibercept binds to all isoforms of VEGF, although its binding to VEGF-A and VEGF-B is with higher affinity compared with bevacizumab. The main adverse events of aflibercept are hypertension and proteinuria. Aflibercept added to second-line chemotherapy with docetaxel failed to improve OS (hazard ratio 1.01) in patients (n ¼ 913) with advanced nonsquamous NSCLC in a phase III trial [40].
Vascular disrupting agent Vascular disruption of existing tumor blood vessels by vadimezan (ASA404) has also been studied in patients with advanced NSCLC [41,42]. In a phase III trial, however, the addition of vadimezan to firstline chemotherapy with paclitaxel and carboplatin failed to improve survival in patients (n ¼ 1299) with advanced NSCLC [41].
DUAL AND MULTIKINASE INHIBITORS Recently, sorafenib and motesanib failed to improve survival when added to first-line chemotherapy in patients with advanced NSCLC [43–45]. Sunitinib did not improve outcome of second-line therapy with pemetrexed [46]. Acknowledgements None. Conflicts of interest R.P. received speaker’s fee and honoraria for advisory boards from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Serono, Pfizer, Roche and Synta.
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Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350:2129–2139. 22. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304:1497–1500. 23. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for nonsmall-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362:2380– 2388. 24. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010; 11:121–128. 25. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12:735–742. 26. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemother& apy 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; 13:239–246. Erlotinib is active also in white patients with EGFR-mutant NSCLC.
27. Sequist LV, Yang JC-H, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31:3327–3334. Afatinib improves outcome compared with cisplatin-based chemotherapy in advanced EGFR-mutant NSCLC. 28. Wu YL, Zhou C, Hu C-P, et al. LUX-Lung 6: a randomized, open-label, phase III study of afatinib (A) versus gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR Mþ) advanced adenocarcinoma of the lung. J Clin Oncol 2013; 31 (suppl; abstract 8016). 29. Yang JC-H, Hirsh V, Schuler M, et al. Symptom control and qualtiy of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31:3342–3350. 30. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012; 13:528–538. 31. Spigel DR, Ervin TJ, Ramlau RA, et al. Randomized phase II trial of onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2013; 31:4105–4114. 32. McArthur GA. The coming of age of MEK. Lancet Oncol 2012; 13:744–745. 33. Ja¨nne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS& mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013; 14:38–47. Selumetinib targets KRAS-mutant NSCLC. 34. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363:1693–1703. 35. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009; 27:4247–4253. 36. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in && advanced ALK-positive lung cancer. N Engl J Med 2013; 368:2385–2394. First randomized phase III trial for crizotinib. 37. Seto T, Kiura K, Nishio M, Nakagawa K, et al. CH5424802 (RO5424802) & for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol 2013; 14:590–598. Second generation ALK-inhibitor has high efficacy in ALK-positive patients. 38. Reck M, Kaiser R, Mellemgaard A, et al. Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial. J Clin Oncol 2013; 31 (suppl; abstract LBA8011). 39. Hanna NH, Kaiser R, Sullivan RN, et al. Lume-Lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) after failure of first-line chemotherapy. J Clin Oncol 2013; 31 (suppl; abstract 8034). 40. Ramlau R, Gorbunova V, Ciuleanu TE, et al. Aflibercept and docetaxel versus docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol 2012; 30:3640–3647. 41. Lara PN Jr, Douillard JY, Nakagawa K, et al. Randomized phase III placebocontrolled trial of carboplatin and paclitaxel with or without the vasculardisruptingagent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol 2011; 29:2965–2971. 42. Sessa C, Lorusso P, Tolcher A, et al. Phase I safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors. Clin Cancer Res 2013; 19:4832–4842. 43. Scagliotti G, Novello S, von Pawel J, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 2010; 28:1835–1842. 44. Paz-Ares LG, Biesma B, Heigener D, et al. Phase III, randomized, doubleblind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol 2012; 30:3084–3092. 45. Scagliotti GV, Vynnychenko I, Park K, et al. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/ paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol 2012; 30:2829–2836. 46. Scagliotti GV, Krzakowski M, Szczesna A, et al. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-smallcell lung cancer: a phase III trial. J Clin Oncol 2012; 30:2070–2078. &&
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Novel drugs against non-small-cell lung cancer Robert Pirker
Purpose of review Important therapeutic advances for patients with advanced non-small-cell lung cancer (NSCLC) with focus on individualized therapy have recently occurred and are summarized in this review. Recent findings Cetuximab added to first-line chemotherapy has been shown to improve survival in patients with high epidermal growth factor receptor (EGFR) expression in their tumors. Afatinib has shown improved progression-free survival and better quality of life compared to chemotherapy in patients with EGFRmutation-positive adenocarcinomas. Several other EGFR-directed agents are in clinical development. Crizotinib improved progression-free survival compared to second-line chemotherapy with docetaxel or pemetrexed in patients with advanced anaplastic lymphoma kinase-positive NSCLC. Selumetinib added to docetaxel has improved outcome compared with docetaxel in a randomized phase II trial in patients with advanced KRAS-mutant NSCLC and this combination is currently studied in a phase III trial. Nintedanib added to docetaxel improved progression-free survival in the second-line therapy of patients with advanced NSCLC but many other angiogenesis inhibitors failed to improve clinical outcome in phase III trials. Several other targeted therapies are currently evaluated in phase III trials in patients with advanced NSCLC. Summary Recent trials have led to the approval of afatinib and crizotinib for subsets of patients with advanced NSCLC. Keywords afatinib, cetuximab, crizotinib, selumetinib, targeted therapy
INTRODUCTION Chemotherapy of non-small-cell lung cancer (NSCLC) with a platinum-based doublet containing a third generation anticancer drug has been well established. Advances in the systemic treatment can be achieved through better understanding of the molecular pathogenesis of lung cancer and the molecular mechanisms of action of anticancer drugs. In particular, identification of driver mutations may offer novel therapeutic opportunities [1,2]. Targeted therapies based on molecular changes of tumor cells may offer higher efficacy and greater specificity. Many targeted agents have been studied in lung cancer. Bevacizumab has been approved in combination with first-line chemotherapy for patients with nonsquamous NSCLC. In the European Union (EU), erlotinib has been approved for patients with advanced NSCLC who had previously been treated with chemotherapy and as a maintenance therapy in patients with stable disease under first-line chemotherapy. This article summarizes novel agents that have been or are currently studied in phase III trials.
EPIDERMAL GROWTH FACTOR RECEPTORDIRECTED MONOCLONAL ANTIBODIES Targeting the epidermal growth factor receptor (EGFR) is an important therapeutic strategy in patients with NSCLC [3]. Several EGFR-directed monoclonal antibodies have been evaluated within clinical trials [3–5]. These antibodies block receptor signaling through competitively binding to EGFR on the surface of tumor cells but may act also via antibody-dependent cellular cytotoxicity or other immunological mechanisms [3,6].
Cetuximab Cetuximab has been studied in combination with first-line chemotherapy in two phase III trials [7,8]. Department of Medicine I, Medical University of Vienna, Vienna, Austria Correspondence to Robert Pirker, MD, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel: +43 1 40400 4422; fax: +43 1 40400 4461; e-mail: [email protected] Curr Opin Oncol 2014, 26:145–151 DOI:10.1097/CCO.0000000000000056
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KEY POINTS High EGFR expression based on an IHC score appears to be a predictive biomarker for cetuximab when added to first-line chemotherapy. Afatinib increases progression-free survival and quality of life compared with cisplatin and pemetrexed in patients with advanced EGFR-mutant NSCLC. Crizotinib is superior to second-line chemotherapy in patients with advanced ALK-positive NSCLC. Selumetinib is a promising agent for the treatment of KRAS-mutant NSCLC.
The FLEX trial evaluated cisplatin and vinorelbine with and without cetuximab in 1125 patients with advanced NSCLC and enriched for EGFR expression [7]. The trial demonstrated an improvement in overall survival (OS) for chemotherapy and cetuximab with a hazard ratio of 0.87 (P ¼ 0.044). Median survival times were 11.3 and 10.1 months, respectively. The BMS099 trial phase III trial failed to demonstrate an improvement in progression-free survival for cetuximab added to carboplatin and a taxane (paclitaxel or docetaxel) in patients (n ¼ 676) with advanced NSCLC but unselected for EGFR expression [8]. A meta-analysis based on 2018 patients with advanced NSCLC from four randomized trials confirmed the benefit of chemotherapy and cetuximab compared with chemotherapy alone in terms of OS, progression-free survival and response rates [9]. The hazard ratio for death was 0.878 (95% confidence interval, CI 0.795–0.969; P ¼ 0.01) in favor of chemotherapy and cetuximab.
Characterization of predictive biomarkers First-cycle rash was shown to be associated with better prognosis [10]. KRAS wildtype, EGFR copy numbers and EGFR-activating mutations did not predict benefit from cetuximab [11,12]. EGFR expression based on an immunohistochemistry (IHC) score was then shown to predict benefit from cetuximab in patients of the FLEX trial [13 ]. Immunohistochemical EGFR expression was assessed by means of the pharmDx kit (Dako, Glostrup, Denmark). Membrane staining intensity was divided into no staining, weak, intermediate and strong staining. The percentages of cells at the various staining intensities were determined and an IHC score was calculated as described [13 ]. For further analysis, patients were grouped into those with high (IHC score 200) and low (score < 200) &&
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EGFR expression. High EGFR expression was detected in 31% of patients. Among these patients, the hazard ratio for death was 0.73 (95% CI 0.58–0.93; P ¼ 0.011) in favor of chemotherapy and cetuximab compared with chemotherapy alone. Median survival times were 12.0 (95% CI 10.2–15.2) and 9.6 months (95% CI 7.6–10.6), and 1-year survival rates were 50 and 37% for patients treated with and without cetuximab, respectively [13 ]. Among patients with low EGFR expression, survival was not different between both treatment arms. The treatment interaction test was significant. The survival benefit obtained with chemotherapy and cetuximab in patients with high EGFR expression was seen across all major subgroups, in particular in both adenocarcinomas and squamous cell carcinomas. Toxicity according to treatment arm was similar in the high and low EGFR expression groups [13 ]. Based on these data, EGFR expression levels may lend themselves as predictive biomarkers for the selection of those patients who will derive a clinically relevant benefit from the addition of cetuximab to first-line chemotherapy with platinumbased doublets. EGFR copy numbers determined by FISH analysis may also be a predictive biomarker [14]. The SWOG biomarker validation study aims at validating the EGFR imunohistochemistry score and EGFR copy numbers assessed by FISH as predictive biomarkers. Within this trial, patients with advanced NSCLC are randomized to carboplatin/ paclitaxel (with or without bevacizumab) and cetuximab or carboplatin/paclitaxel (with or without bevacizumab). &&
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Cetuximab in stage III non-small-cell lung cancer Cetuximab has also been evaluated in combination with chemoradiotherapy in patients with locally advanced NSCLC [15,16]. In the RTOG 0617 trial, the addition of cetuximab to chemoradiotherapy did not increase survival in patients with unresectable stage III NSCLC [16]. In a subgroup analysis based on an EGFR IHC score like in the FLEX trial, however, patients with high IHC scores of their tumors appear to benefit from the addition of cetuximab. Therefore, further studies of chemoradiotherapy and cetuximab are warranted in patients with high EGFR expression in their tumors.
Necitumumab Necitumumab is a recombinant fully human antiEGFR monoclonal antibody. Two phase III trials (INSPIRE, SQUIRE) currently evaluate whether the addition of necitumumab to first-line chemotherapy Volume 26 Number 2 March 2014
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improves survival of patients with advanced NSCLC. The INSPIRE trial (ClinicalTrials.gov identifier: NCT00982111) evaluates cisplatin and pemetrexed with and without necitumumab in patients with nonsquamous cell NSCLC. The trial has prematurely been terminated because of increased rates of thromboembolic events in patients treated with chemotherapy and necitumumab. The SQUIRE trial (ClinicalTrials.gov identifier: NCT00981058) evaluates cisplatin and gemcitabine with and without necitumumab in patients with squamous cell NSCLC. According to a press release, the trial met its primary endpoint.
Other antiepidermal growth factor receptor monoclonal antibodies Matuzumab, a humanized anti-EGFR monoclonal IgG1 antibody, and panitumumab, a fully human anti-EGFR IgG2 monoclonal antibody, have been studied in phase II trials [17,18] but not in phase III trials.
EPIDERMAL GROWTH FACTOR RECEPTOR-DIRECTED TYROSINE KINASE INHIBITORS EGFR-directed tyrosine kinase inhibitors (TKIs) inhibit receptor signaling through competitively blocking the binding of adenosine triphosphate to the cytoplasmic domain of EGFR. In the EU, erlotinib has been approved for patients with advanced NSCLC who had previously been treated with chemotherapy and as a maintenance therapy in patients with stable disease under first-line chemotherapy. Gefitinib also increased survival when given as maintenance therapy following first-line chemotherapy in unselected patients with advanced NSCLC [19]. Patients who dramatically responded to EGFRdirected TKIs were found to harbor EGFR-activating mutations, for example exon 19 deletions or exon 21-point mutations, in their tumors [20–22]. This was then prospectively confirmed in several phase III trials in patients with advanced EGFR-mutation positive NSCLC [23–25,26 ]. In these trials, treatment with erlotinib or gefitinib until disease progression resulted in superior progression-free survival and better quality of life compared with platinum-based first-line chemotherapy. Based on these results, erlotinib and gefitinib have been approved in the EU for the treatment of patients with EGFR-activating mutations in the first-line setting (erlotinib) or independent of the treatment line (gefitinib). Several second generation TKIs are in clinical development. &
Afatinib Afatinib is an orally available and irreversibly binding ErbB family blocker. Two phase III trials (LUXLung 3 and 6) compared afatinib with chemotherapy in patients with advanced adenocarcinomas harboring EGFR mutations [27 ,28]. In the LUX-Lung 3 phase III trial, 1269 patients were screened for EGFR-activating mutations by a central laboratory [27 ]. Mutations were confirmed in 452 patients with exon 19 deletions in 49%, L858R mutations in 40% and other mutations in about 10% of the patients. Three-hundred and fortyfive patients with mutations have been randomized to either afatinib 40 mg daily or chemotherapy with cisplatin and pemetrexed. Stratification factors were mutation type and race. Afatinib was planned until disease progression and chemotherapy for up to six cycles. The afatinib dose had to be reduced to less than 40 mg daily in 52% of the patients and more than one dose reduction was required in 19% of the patients. Fifty-five percent of the patients received six cycles of chemotherapy and 75% received four or more cycles. Seventy-two percent of the patients were of East Asian ethnicity, 26% were white, 65% were females and 68% were never-smokers. Based on independent radiological review, afatinib resulted in prolongation of progression-free survival compared to chemotherapy with a hazard ratio of 0.58 (95% CI 0.43–0.78; P ¼ 0.001). Median progressionfree survival times were 11.1 and 6.9 months, respectively. The benefit was seen across all major subgroups. In patients (n ¼ 308) with exon 19 deletions or L858R mutations, progression-free survival time was prolonged with a hazard ratio of 0.47 (95% CI 0.34–0.65) and median survival times were 13.6 months in the afatinib group and 6.9 months in the chemotherapy group. Patientreported outcomes also favored afatinib which resulted in better control of cough, dyspnea and pain [29]. Afatinib improved dyspnea and delayed the time to deterioration of cough (hazard ratio of 0.6; 95% CI 0.41–0.87; P ¼ 0.007) and dyspnea (hazard ratio of 0.68; 95% CI 0.50–0.98; P ¼ 0.015). Diarrhea, dysphagia and sore mouth were more frequently seen with afatinib. OS was not different between both treatment arms. Treatment-related adverse events grade 3 or higher were seen in 49% of patients receiving afatinib and 48% of patients receiving chemotherapy. The most common afatinib-related adverse events were diarrhea (all grades in 95%, grade 3 in 14%), rash/acne (all grades in 89%, grade 3 in 16%) and stomatitis/mucositis (all grades in 72%, grade 3 in 9%). Adverse events were clinically acceptable under consideration of dose reductions and treatment delays. Based on the LUX-Lung 3 results, afatinib has been approved in
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the EU for first-line therapy of patients with advanced EGFR mutation-positive NSCLC. A benefit was also seen in the LUX-Lung 6 trial that was performed in China and Korea [28]. Afatinib compared with cisplatin and gemcitabine prolonged progression-free survival in patients with advanced EGFR-mutation-positive adenocarcinomas. The LUX-Lung 1 trial compared afatinib with placebo in patients (n ¼ 585) who had been treated with one or two chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib [30]. OS as the primary endpoint was not different between the two arms but progression-free survival was prolonged with afatinib.
Dacomitinib Dacomitinib, an irreversible oral pan-HER inhibitor, is currently evaluated in several phase III trials in patients with advanced NSCLC. The ARCHER 1009 trial compares dacomitinib with erlotinib in patients following progression after or intolerance to at least one prior chemotherapy regimen (ClinicalTrials.gov identifier NCT01360554). The primary endpoint of the trial is progression-free survival per independent radiological review. The BR.26 phase III trial compares dacomitinib with placebo in patients who have progressed after at least one line of chemotherapy and erlotinib or gefitinib. The primary endpoint is OS. The ARCHER 1050 phase III trial compares dacomitinib with gefitinib in the first-line treatment of patients with EGFR-mutation-positive NSCLC (ClinicalTrials.gov identifier NCT01774721).
ongoing MetLung phase III trial aims at confirming the benefit of erlotinib and onartuzumab compared with erlotinib in the second-line or third-line treatment of patients with advanced NSCLC who have high MET expression in their tumors.
RAS INHIBITORS The RAS/RAF/MEK/ERK pathway is often deregulated in cancers including NSCLC. RAS mutations are seen in approximately 20% of NSCLC and 30% of adenocarcinomas. These mutations preferentially occur in exon 12 and only occasionally in exon 13. Whether NSCLC patients with KRAS mutations in their tumors have worse prognosis compared to those with wild-type tumors, remains controversial. Patients with KRAS-mutated NSCLC, however, do not respond to EGFR-directed TKIs. Inhibition of KRAS is attempted in the hope of improving outcome in patients with KRAS-mutant NSCLC. So far, however, direct blocking of KRAS has failed. Therefore, inhibition of downstream targets of the MAPK cascade such as RAF, MEK or ERK may be a more promising strategy [32]. Besides BRAF inhibitors such as vemurafenib and dabrafenib, several MEK inhibitors, for example trametinib and selumetinib, are in clinical development.
Selumetinib Selumetinib (AZD6244), an oral inhibitor of MEK, has shown synergistic activity with docetaxel in preclinical models. Based on these findings, docetaxel and selumetinib have been studied in a randomized placebo-controlled phase II trial in 87 patients with advanced KRAS-mutant NSCLC who had previously been treated with first-line chemotherapy [33 ]. The combined treatment resulted in a statistically nonsignificant prolongation of OS. The hazard ratio for death was 0.80 (95% CI 0.56–1.14) and median survival times were 9.4 and 5.2 months, respectively. Progression-free survival (HR 0.58, P ¼ 0.01; median 5.3 versus 2.1 months), response rates (37 versus 0%, P < 0.0001) and patientreported outcomes were significantly improved in the selumetinib arm. Adverse events of grade 3 or higher were increased with selumetinib in terms of neutropenia (67 versus 55%), neutropenic fever (18% versus none) and asthenia (9% versus none). Diarrhea, vomiting, stomatitis and dry skin were also more frequently seen in the selumetinib arm. Patients receiving docetaxel and selumetinib also required more hospitalizations. Thus the trial demonstrated improved outcome with docetaxel and selumetinib compared with docetaxel alone, but at the expense of greater toxicity. The interpretation of &
Onartuzumab Increased MET signaling is associated with resistance to EGFR-directed TKIs. Thus, MET inhibition may improve outcome in patients treated with these TKIs. Onartuzumab is a humanized, monovalent monoclonal antibody directed against the MET receptor. In a randomized phase II trial in patients with recurrent NSCLC, erlotinib and onartuzumab compared with erlotinib did not improve progression-free survival in the intent-to-treat population [31]. Based on immunohistochemical MET expression, however, a difference in outcome was observed. The combined treatment resulted in improved progression-free survival in patients with high MET expression (hazard ratio 0.53) and in shorter progression-free survival in patients with low MET expression (hazard ratio 1.82). The 148
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these results is complicated by several shortcomings of the trial. Firstly, the outcome with docetaxel alone was poor compared with the ones seen in previous studies with docetaxel in an unselected patient population. Whether the poor outcome with docetaxel in the present study is due to chemotherapy resistance of KRAS-mutant NSCLC, is unclear. Secondly, slight imbalances in patient characteristics favoring the selumetinib arm (e.g. adenocarcinomas 68 versus 53%, IIIB 11 versus 2%, responders to first-line chemotherapy 38 versus 18%) were obvious. Despites these caveats, a phase III trial has been initiated in order to determine whether selumetinib added to second-line therapy with docetaxel improves survival in patients with advanced KRAS-mutant NSCLC.
ANAPLASTIC LYMPHOMA KINASE INHIBITORS Anaplastic lymphoma kinase (ALK) fusion genes can be detected in a subset of NSCLC, mostly adenocarcinomas. EML4-ALK fusion genes can be detected in approximately 4% of patients with advanced NSCLC. The presence of these fusion genes is currently proven by FISH analysis using break-apart probes for EML4 and ALK genes. EML4-ALK fusion proteins drive cancer growth. Therefore, ALK inhibitors should improve outcome in patients who have this genetic aberration in their tumors.
Crizotinib Crizotinib has shown good efficacy in patients with advanced NSCLC who show an ALK re-arrangement in their tumors [34,35,36 ]. EML4-ALK fusion protein is detected by FISH analysis. IHC is often used for screening followed by FISH as confirmatory analysis. In the PROFILE 1007 phase III trial, crizotinib has been compared with chemotherapy in patients with ALK-positive NSCLC who had received one prior platin-based chemotherapy regimen [36 ]. A total of 4967 patients were screened and 347 patients were randomized to either crizotinib 250 mg twice daily or to chemotherapy with pemetrexed or docetaxel. Crossover to crizotinib was allowed for patients of the chemotherapy arm at the time of disease progression. Randomized patients had the following baseline characteristics: age median 50 years, 66% females, 63% never-smokers, 91% ECOG 0–1, 95% adenocarcinoma. Crizotinib increased progression-free survival compared with chemotherapy. The hazard ratio for progression or death was 0.49 (95% CI 0.37–0.64; P < 0.001). Median progression-free survival times &&
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were 7.7 and 3 months, respectively. Response rates were also higher with crizotinib (65 versus 20%). OS based on an interim analysis was not different between both treatment arms. Crizotinib resulted in better improvement in tumor-related symptoms and global quality of life. The main crizotinibrelated adverse events were visual disorders, gastrointestinal side-effects and elevated liver aminotransferase levels. Based on these data, crizotinib has been approved as second-line therapy for patients with advanced ALK-positive NSCLC in the EU. The PROFILE 1014 trial compares crizotinib with chemotherapy in the first-line treatment of patients with ALK-positive NSCLC. The primary endpoint of the trial will be progression-free survival.
Second-generation anaplastic lymphoma kinase inhibitors Several second-generation ALK inhibitors are in clinical development. Alectinib (CH5424802) has shown better activity compared with crizotinib in preclinical models. In a phase I–II trial in patients with ALK-positive tumors and refractory to crizotinib treatment [37 ], the dose-limiting toxicities were grade 3 headache and grade 3 neutropenia. The most common adverse event was fatigue which was seen in 30% of the patients. A dose of 300 mg twice daily has been established as the recommended dose for phase II trials. In a phase II trial, responses were seen in 93% of previously untreated patients with advanced ALK-positive NSCLC [37 ]. A phase III trial comparing alectinib with crizotinib in the first-line treatment of patients with advanced ALK-positive NSCLC is planned. &
&
ANGIOGENESIS INHIBITORS Several angiogenesis inhibitors have been studied for their potential to improve outcome in patients with NSCLC. These agents include monoclonal antibodies against vascular endothelial growth factor (VEGF) or VEGF receptors (VEGFR), VEGFR-directed TKIs, or several others.
Bevacizumab Bevacizumab is currently further evaluated in two important phase III trials. The AvaALL trial assesses whether continuation of bevacizumab beyond progression over all treatment lines increases survival in patients with advanced nonsquamous NSCLC. The ECOG trial determines whether bevacizumab added to adjuvant chemotherapy increases survival
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compared with chemotherapy alone. Chemotherapy consists of four cycles of a platin-based doublet. Bevacizumab treatment is planned to be continued after the end of chemotherapy for 1 year.
Nintedanib Nintedanib is an oral inhibitor of receptors for VEGF, PDGF receptors and FGF. It has been studied at a dose of 200 mg twice daily in two placebocontrolled phase III trials (LUME-Lung 1 and LUME-Lung 2) in combination with docetaxel or pemetrexed in patients with advanced NSCLC (LUME-Lung 1) or advanced lung adenocarcinomas (LUME-Lung 2) previously treated with chemotherapy [38,39]. The LUME-Lung 1 trial, which enrolled 1314 patients with advanced NSCLC, demonstrated increased progression-free survival for docetaxel and nintedanib compared with docetaxel and placebo [38]. The hazard ratio was 0.79 (95% CI 0.68–0.92; P ¼ 0.002) and median progression-free survival times were 3.4 and 2.7 months, respectively. OS as a secondary endpoint was not prolonged in the total population. In a preplanned subgroup analysis, however, OS was prolonged in patients with adenocarcinomas with a hazard ratio of 0.83 (P ¼ 0.036; median 12.6 versus 10.3 months). Disease control rates were higher with docetaxel and nintedanib in all patients (odds ratio, OR 1.68; P < 0.0001), all adenocarcinoma patients (OR 1.93; P < 0.0001), and adenocarcinoma patients with start of first-line chemotherapy within less than 9 months (OR 2.9; P < 0.0001). The most common adverse events were diarrhea (any grade 42 versus 22%, grade 3 6.6 versus 2.6%) and elevation of liver enzymes (any grade 28 versus 8%, grade 3 8 versus 1%). Hypertension, bleedings, thrombotic events and withdrawals due to adverse events were similar in both treatment arms. The LUME-Lung 2 trial compared pemetrexed and nintedanib with pemetrexed and placebo in patients with advanced nonsquamous NSCLC [39]. The trial had randomized 713 of the 1300 planned patients when it was halted after an interim analysis had suggested lack of improvement in outcome by the addition of nintedanib. The final analysis of the intent-to-treat population, however, indicated significantly prolonged progression-free survival for pemetrexed and nintedanib with a hazard ratio of 0.83 (95% CI 0.7–0.99; P ¼ 0.04) and median progression-free survival times of 4.4 and 3.6 months, respectively. However, OS (hazard ratio 1.03) and response rates (9% in both arms) were not different between the two treatment arms. 150
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Aflibercept Aflibercept (VEGF trap) is an engineered soluble receptor made from extracellular domains of VEGFR1 and VEGFR2. Aflibercept binds to all isoforms of VEGF, although its binding to VEGF-A and VEGF-B is with higher affinity compared with bevacizumab. The main adverse events of aflibercept are hypertension and proteinuria. Aflibercept added to second-line chemotherapy with docetaxel failed to improve OS (hazard ratio 1.01) in patients (n ¼ 913) with advanced nonsquamous NSCLC in a phase III trial [40].
Vascular disrupting agent Vascular disruption of existing tumor blood vessels by vadimezan (ASA404) has also been studied in patients with advanced NSCLC [41,42]. In a phase III trial, however, the addition of vadimezan to firstline chemotherapy with paclitaxel and carboplatin failed to improve survival in patients (n ¼ 1299) with advanced NSCLC [41].
DUAL AND MULTIKINASE INHIBITORS Recently, sorafenib and motesanib failed to improve survival when added to first-line chemotherapy in patients with advanced NSCLC [43–45]. Sunitinib did not improve outcome of second-line therapy with pemetrexed [46]. Acknowledgements None. Conflicts of interest R.P. received speaker’s fee and honoraria for advisory boards from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Serono, Pfizer, Roche and Synta.
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