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ANTICANCER RESEARCH 35: 2503-2512 (2015)

Review for NSCLC–A Double-edged Sword?

WOLFRAM C. M. DEMPKE

University Hospital of Grosshadern (LMU Munich, Haematology and Oncology), Munich, Germany

Abstract. Advanced or metastatic non-small cell lung only very few trials that have shown a benefit from the (NSCLC) is characterised by a poor prognosis and addition of TKIs to , additional studies using few second- or third-line treatments. First-generation this unselected approach are not recommended. Therefore, epidermal receptor (EGFR) there is a definite need for an improved understanding of the inhibition has paved the way for targeted therapies in lung complex mechanisms that are involved in TKI-mediated cancer. Although these drugs result in excellent responses pathways, and for the development of validated predictive [and significantly improved progression-free survival (PFS)] markers to allow a better treatment decision on the basis of in patients with activating EGFR mutations, only few studies the probability of response. This would certainly help to revealed improved overall survival (OS), and resistance often avoid the unnecessary use of potential toxic drugs in patients develops. , a which targets with known resistance and would facilitate the discovery of vascular endothelium growth factor (VEGF), has been fully new targets and drugs on the basis of resistance mechanisms. developed in NSCLC, and small-molecule tyrosin kinase inhibitors (TKIs) have been approved as first-line therapy for Non-small-cell (NSCLC) accounts for patients with advanced and metastatic NSCLC harbouring approximately 80-85% of all cases of lung cancer, and is the EGFR mutations. In addition, , a novel inhibitor of most common cause of death in men and second only to breast the anaplastic kinase, has been approved for cancer in woman (1). Treatment of NSCLC is guided by second-line treatment of NSCLC. Several new drugs disease stage, histology, and mutation status. Surgery is the targeting not only the EGFR pathways, but also signal treatment of choice for early-stage localized disease, whereas transduction cascades involved in angiogenesis and the multimodality therapy remains the norm for patients with mitogene-activated extracellular signal-regulated kinase locally advanced disease. Patients with advanced metastatic kinase pathways are currently evaluated in phase III clinical disease may derive a benefit from palliative chemotherapy. trials. Experimental monoclonal antibodies are also About 40% of patients with NSCLC present with metastatic currently undergoing phase III clinical trials and have shown or locally advanced disease, which underscores the importance promising activity which might help to improve the of identifying therapeutic schemes that may benefit this large therapeutic landscape of NSCLC. However, many other patient population. Combination chemotherapy, usually drugs prolonged PFS, but failed to demonstrate a significant platinum-based, is currently the first-line therapy of choice (2- improvement of OS. PFS is often used as a predictor for 4). Based on these studies, doublet regimens containing improved OS since it is independent of subsequent treatment, or carboplatin with paclitaxel, , but OS is acknowledged as the key clinical outcome in the docetaxel, vinorelbine or irinotectan are administered. treatment of advanced NSCLC. Furthermore, since there are Although these studies showed no differences in outcomes among combinations between platinum and third-generation chemotherapeutics, there is evidence that cisplatin and should be recommended as a first-line Correspondence to: Wolfram C. M. Dempke, MD, Ph.D., MBA, chemotherapy for non-squamous NSCLC (3). Professor of Haematology and Oncology, AstraZeneca Medical The prognosis for patients with advanced NSCLC is poor. Oncology, DaVinci Building, Melbourn Science Park, Cambridge Recent, large, randomised phase III trials have demonstrated 8SG 6HB, United Kingdom. Tel: +44 7584140943, email: wolfram.dempke@.com that platinum-based chemotherapy combinations yield a median survival time of 8-11 months, a 1-year survival rate Key Words: NSCLC, novel therapies, tyrosine kinase inhibitors, of 30-45% and a 2-year survival rate of 10-20% (4). The monoclonal antibodies, clinical trials, review. treatment of NSCLC is therefore a major unmet need and

0250-7005/2015 $2.00+.40 2503 ANTICANCER RESEARCH 35: 2503-2512 (2015) new therapies focusing on the molecular mechanisms that stage IIIB/IV pulmonary adenocarcinoma demonstrated that mediate the growth of lung cancer cells are urgently needed. is superior to carboplatin/paclitaxel in terms of PFS and objective response rate, as first-line treatment for Targeted Therapies: Approved Drugs pulmonary adenocarcinoma among never-smokers or former light smokers in East-Asias, with the presence of an EGFR In patients with advanced or metastatic NSCLC carrying mutation being a strong predictor of the greater effect of epidermal (EGFR) mutations, the use gefitinib compared with carboplatin/paclitaxel. In the overall of EGFR tyrosine kinase inhibitors (TKIs) improved overall population, PFS was significantly longer in patients treated survival (OS) and safety, when compared with standard with gefitinib than in those treated with paclitaxel/ chemotherapy. There are currently three different TKIs carboplatin (9.5 versus 6.3 months, HR=0.74, 95% CI=0.65- (gefitinib, , ) available for patients with 0.85; p<0.0001) (7). After the results of the IPASS trial, EGFR mutation-positive NSCLC in the first-line setting, gefitinib was approved for advanced and metastatic approved in Europe and USA and the survival rates with use mutation-positive NSCLC in all settings of treatment in of these drugs are very similar. In addition, these drugs are Europe and Asia, but not in the USA since the Federal Drug under clincial evalutation in second-line and adjuvant Administration (FDA) withdrew the approval of the drug in settings [reviewed in (5)]. Although these drugs showed 2012 after post-marketing studies failed to show an OS different incidence of non-haematological toxicity, at this benefit of patients taking gefitinib. time there is no direct data that evaluate the response after a close and correct management. With regard to progression- Erlotinib free survival (PFS), a significant interaction according to ethnicity (Asian versus Caucasian versus mixed) and trial Erlotinib (Tarceva®; Roche, Switzerland) inhibits EGFR design (retrospective versus prospective EGFR analysis), was signalling by binding to the intracellular TK domain. found in a meta-analysis (6) and a trend toward significance Serveral phase I/II trials demonstrated activity of erlotinib in with regard to the type of drug (gefitinib versus erlotinib NSCLC patients [reviewed in (4)]. These data were versus afatinib) was determined. However, no statistically confirmed by the results of the phase III trial BR.21 (8). In significant differences in survival were observed. With regard this trial relevant for the approval of erlotinib as to response, the authors reported a significant interaction second/third-line therapy of advanced NSCLC, 731 patients according to ethnicity, trial design and type of drug. These with stage IIIB/IV NSCLC (unselected for EGFR mutations) data, together with a deeper characterisation of the molecular were randomized in a 2:1 ratio after failure of at least one background sustaining the oncogenic process, may therefore chemotherapy and were treated with erlotinib (150 mg/day) contribute to create a predictive clinicopathological model, or placebo with best supported care (BSC). The study met aimed at improving the magnitude of benefit expected from its primary endpoint with a significant improvement in the use of targeted agents. median OS (6.7 months versus 4.7 months; HR=0.70; p<0.001). Erlotinib also improved the response rate (8.9% Gefitinib versus <1%; p<0.001) and median duration of response (7.9 months versus 3.7 months), as well as the median PFS (2.2 Gefitinib (Iressa®; AstraZeneca, UK) is targeted against the months versus 1.8 months; HR=0.61; p<0.001) (8). tyrosine kinase activity of the EGFR pathway. Gefitinib has an However, a recently published trial (first- and second-line interesting developmental history and has contributed greatly treatment), has established the importance of selecting to our understanding of the biology of NSCLC and the role of patients by EGFR mutation, and have indicated this as the the EGFR signalling pathways. During the phase II dose- gold standard therapy (9). finding studies (IDEAL studies 1 and 2) gefitinib showed Recently, data from two phase III trials EURTAC (10) and activity as monotherapy in patients with advanced NSCLC who OPTIMAL (11) have shown that erlotinib has also activity had received prior chemotherapy with overall response rates of as front-line therapy in NSCLC, thus the drug was approved 19% (IDEAL 1, Asian-European trial) and 10% (IDEAL 2, US by FDA and the European Medicines Agency (EMA) in 2013 trial) (4). Several phase III clinical trials with gefitinib (IPASS, for first-line treatment in patients with NSCLC harbouring NEJ002, First-SIGNAL, West Japan Thoracic Oncology Group EGFR mutations. The approval was based on the results of a Study) have demonstrated its activity in advanced or metastatic randomised, multicenter open-label trial comparing erlotinib NSCLC harboring EGFR mutations (4-7). (N=86) to platinum-based doublet chemotherapy (N=88) in The IPASS trial (IRESSA Pan-Asia Study), a phase III patients with metastatic NSCLC whose tumours had EGFR open-label, randomised, controlled trial conducted in 87 exon 19 deletions or exon 21 (L858R) substitution mutations. centres in East Asia which compared the use of first-line Eligible patients were randomly assigned (1:1) to receive gefitinib with paclitaxel/carboplatin in 1217 patients with erlotinib (150 mg/day orally), or platinum-based doublet

2504 Dempke: New Drugs for NSCLC (Review) chemotherapy. The trial’s primary endpoint was PFS; trials 3 and 6 revealed that afatinib prolonged survival of secondary endpoints included OS and objective response patients with NSCLC with common EGFR mutations rate. The median PFS was 10.4 months in the erlotinib arm compared with standard chemotherapy by a median of 3 and 5.2 months in the platinum-based chemotherapy arm months (27.3 to 24.3 months), significantly reducing the risk (HR=0.34; 95% CI=0.23-0.49, p<0.001). The median OS of death by 19% (HR=0.81, CI=0.66-0.99; p=0.037). The was 22.9 months in the erlotinib arm and 19.5 months in the most pronounced reduction in risk of death, by 41% platinum-based chemotherapy arm (HR=0.93; 95% CI=0.64- (HR=0.59, CI= 0.45-0.77; p<0.001), was noted for patients 1.35, p=0.6482). The overall response rate was 65% in the whose tumours have the most common type of EGFR erlotinib arm and 16% in the platinum-based chemotherapy mutation (namely deletion in exon 19), which is present in arm (10, 11). approximately 48% with an EGFR mutation. For patients Subsequently, the results of the SATURN study also with the exon 21 (L8585R) mutation, there was no impact showed a significant prolongation of PFS and OS with on OS (HR=1.25, CI=0.92-1.71; p=0.160) (16). maintenance erlotinib compared with placebo (for patients Overall, these results confirmed the efficacy of afatinib in with stable disease) (12). Despite considerable controversy, patients with NSCLC selected for EGFR mutations, and in maintenance therapy has become an acceptable treatment 2013 the drug was approved by FDA and EMA as front-line paradigm and erlotinib is also approved for maintenance therapy for patients with advanced and metastatic NSCLC therapy of patients with advanced NSCLC in Europe and the harbouring EGFR mutations. USA (13). Additional results of the LUX-Lung 7 trial, a head-to-head study (phase IIb, N=264) comparing afatinib (40 mg/day) Afatinib with gefitinib (250 mg/day) [first-line treatment, documented EGFR mutations, primary end-point: (OS)], have not been Multitargeted agents represent the next generation of targeted published yet. The trial is active, but not recruiting patients therapies for solid tumors. The benefits of individually (NCT01466660). targeting the EGFR and the vascular epithelium growth factor receptor (VEGFR) signalling pathways have been Crizotinib clinically validated in recent years for a number of solid tumor types including NSCLC. Given the heterogeneity of Anaplastic lymphoma kinase (ALK) is a validated tyrosine this tumour type and potential cross-talk between these key kinase target in several types of cancer, including NSCLC, signalling pathways, multiple inhibitions have the potential anaplastic large-cell lymphoma, and paediatric to offer additional clinical benefits in NSCLC. neuroblastoma. ALK rearrangements are found in Afatinib (Giotrif®; Boehringer Ingelheim, Germany) is an approximately 3-5% of all cases of NSCLC and define a oral irreversible TKI of all members of the EGFR family. distinct molecular NSCLC subtype. The drug has shown promising activity as front-line therapy Crizotinib (Xalkori®; , USA) is an oral small- in patients with EGFR mutation positive (NSCLC) (e.g. molecule TKI targeting ALK, c-MET, and ROS1 (17). In two del19, L858R) compared with standard chemotherapy (4). In single-group studies, crizotinib showed marked antitumour the LUX-Lung 3 trial, patients with mutation-positive activity in patients with ALK-positive NSCLC, with NSCLC were randomly assigned (2:1 ratio) to receive objective response rates of approximately 60% and a median afatinib (40 mg/day) or chemotherapy with cisplatin and PFS of 8.1-9.7 months (18, 19). pemetrexed every three weeks. The results were a median Due to these promising results, a phase III, open-labeled PFS of 11.1 months on afatinib and 6.9 months on trial was conducted comparing crizotinib with chemotherapy (HR=0.58; 95% CI=0.43-0.78; p=0.001) (14). chemotherapy in 347 patients with locally advanced or These efficacy data regarding afatinib in a mixed polulation metastatic ALK-positive NSCLC who had received one were confirmed by the LUX-Lung 6 trial that compared prior platinum-based regimen. Patients were randomly afatinib with standard chemotherapy in an Asian population assigned to receive oral treatment with crizotinib (250 mg (PFS was 11 versus 5.6 months, HR=0.28; 95% CI=0.20- b.i.d) or intravenous chemotherapy with either pemetrexed 0.39; p<0.0001). Diarrhoea (95%) and skin rash (89%) were (500 mg/m²) or docetaxel (75 mg/m²) every three weeks. the most common treatment-related toxicities with afatinib; Patients in the chemotherapy group who had disease the discontinuation rate was 8% for patients receiving progression were permitted to crossover to crizotinib. The afatinib and 12% for those receiving chemotherapy. primary endpoint was PFS. The response rates were 65% Comparing these results with those of pivotal trials with with crizotinib, as compared with 20% with chemotherapy gefitinib and erlotinib, somewhat more toxicities in patients (p<0.001). PFS was 7.7 months in the crizotinib group and treated with afatinib are apparent when compared with 3.0 months in the chemotherapy group (p<0.001). In erlotinib or gefitinib (15). A joint analysis of the LUX-Lung addition, improved quality of life in the crizotinib-treated

2505 ANTICANCER RESEARCH 35: 2503-2512 (2015)

Table I. Selected phase III targeted therapies trials in patients with advanced or metastastic non-small cell lung cancer (NSCLC).

Study Treatment Outcome Source

MONET-1: Paclitaxel/carboplatin plus versus OS unchanged, Scagliotti et al. (24) N=1090 paclitaxel/carboplatin plus placebo toxicity increased ADVGO: Paclitaxel/carboplatin plus Serious adverse events www.pfizer.com Recruiting stopped versus in the figitumumab arm paclitaxel/carboplatin plus placebo BR 26: Second-line, PFS and OS unchanged www.pfizer.com N=720 versus placebo ARCHER-1009: Second-/third-line, PFS unchanged www.pfizer.com N=800 dacomitinib versus erlotinib ARCHER-1050: Dacomitinib versus gefitinib Results expected in 2015 www.clinicaltrials.gov N=440 (patients with EGFR mutation) (Study NCT01774721) ATTRACT-1: Paclitaxel/carboplatin PFS and OS unchanged Lara et al. (25) N=1299 plus ASA404 versus paclitaxel/carboplatin plus placebo ATTRACT-2: Docetaxel plus ASA404 versus OS unchanged www.clinicaltrials.gov N=900 docetaxel plus placebo (Study NCT00738387) VITAL: Docetaxel plus versus OS unchanged Novello et al. (26) N=900 docetaxel plus placebo ZODIAC: Docetaxel plus PFS and OS unchanged Herbst et al. (27) N=1391 versus docetaxel plus placebo BR 29: Paclitaxel/carboplatin plus versus Not reported yet Aggarwal et al. (22) N=750 paclitaxel/carboplatin plus placebo ESCAPE: Paclitaxel/carboplatin plus PFS and OS unchanged Scagliotti et al. (28) N=926 versus paclitaxel/carboplatin plus placebo (study halted) FLEX:* Cisplatin/vinorelbine plus OS increased Pirker et al. (29) N=1125 versus cisplatin/vinorelbine plus placebo (11.3 versus 10.1 months)

*Approval refused by the European Medicines Agency (EMA) due to contrary data from other studies. EGFR: receptor.

patients was also noted. An interim analysis of OS showed Bevacizumab no significant improvement with crizotinib as compared with chemotherapy (p=0.54), however, the apparent lack Bevacizumab (Avastin®; Roche, Switzerland) is a of a survival benefit probably reflects the confounding monoclonal antibody with high affinity for VEGF. The drug effects of crossover, effects that have been observed in is currently approved (FDA, EMA) for the treatment of other randomised trials of molecularly targeted agents in advanced and metastatic non-squamous NSCLC in patients with NSCLC. combination with paclitaxel and carboplatin. Completed Most recently, the results of a phase III trial (PROFIL phase III trials evaluating bevacizumab plus chemotherapy 1014) comparing crizotinib (N=172) with cisplatin have shown prolonged PFS; however, not all trials showed (carboplatin) plus pemetrexed (N=171) as first-line significant improvement of OS (22). Hence, several studies treatment of advanced NSCLC were published (21). In this with bevacizimab plus chemotherapy in advanced or trial, crizotinib was found to significantly prolong PFS metastatic NSCLC are ongoing. (median 10.9 versus 7.0 months; HR=0.454; 95% CI=0.346- In the ECOG 5508 study (NCT01107626), patients 0.596; p<0.0001) in previously untreated patients with (N=1282) will receive bevacizumab alone, pemetrexed alone, ALK-positive advanced non-squamous NSCLC compared or bevacizumab and pemetrexed combined after induction with standard platinum-based chemotherapy and has therapy with carboplatin and paclitaxel plus bevacizumab. The demonstrated that as first-line treatment crizotinib is primary endpoint is OS. The study is still recruiting patients. superior to standard chemotherapy doublet regimens in In another study (NTC00976456), elderly patients prolonging PFS for patients with ALK-positive advanced (N=250) will receive bevacizumab plus pemetrexed or NSCLC. Based on these findings, the drug was fully bevacizumab plus pemetrexed/carboplatin; the primary approved by FDA and EMA at the end of 2013 as second- endpoint is non-inferiority of bevacizumab/pemetrexed line therapy for ALK-positive advanced or metastatic compared with bevacizumab/pemetrexed/carboplatin based NSCLC. on PFS. The study is active, but no longer recruiting.

2506 Dempke: New Drugs for NSCLC (Review)

The NCT00948675 trial (N=360) is evaluating intent-to-treat population, this benefit did not carry over to chemotherapy with pemetrexed/carboplatin followed by OS and the study was stopped subsequently (31). maintenance therapy with pemetrexed compared with In this regard, it is worth noting that a similar clinical bevacizumab plus carboplatin/paclitaxel followed by phase III exploring the monoclonal antibody to c-MET, maintenance therapy with bevacizumab. The primary (Roche, Switzerland) (erlotinib plus endpoint is PFS. The study is active, but no longer recruiting, omartuzumab versus erlotinib plus placebo) as sceond-line results have not yet been reported. treatment for patients with c-MET mutation-positive NSCLC In terms of adjuvant treatment with bevacizumab, the has been halted due to futility (32). ECOG E1505 study (NCT00324805, N=1500) is currently recruiting patients with completely resected stage IB-IIIA NSCLC to evaluate OS in patients treated with an adjuvant chemotherapy regimen of vinorelbine/cisplatin, docetaxel/ Nintedanib (Vargatef®; Boehringer Ingelheim, Germany) is cisplatin, gemcitabine/cisplatin or pemetrexed/ cisplatin with an angiokinase inhibitor targeting VEGFR1-3, fibroblast or without bevacizumab. The primary endpoint is OS. growth factor receptors 1-3 and platelet-derived growth However, interim safety data showed significant toxicity factor receptor and has also activity against SCR and FLT-3. (grade 3/4) with bevacizumab plus chemotherapy versus To date, phase I and II trials with nintedanib have shown an chemotherapy alone (23). improvement for survival of patients with advanced and metastatic NSCLC, and toxicity profiles seemed to be Potential Drugs for Approval acceptable in these clinical trials (33). In the LUME-Lung 1 phase III trial (N=1300) the Several targeted therapies (small molecules and monoclonal combination of docetaxel (75 mg/m², day 1, every three antibodies) are currently in phase III clinical development weeks) plus nintedanib (200 mg b.i.d.) versus docetaxel plus for NSCLC. These agents have shown promising actitivty in placebo as second-line therapy in patients with advanced or phase I/II studies, however, many drugs failed to metastatic NSCLC was evaluated. OS was found to be significantly improve OS when combined with chemotherapy significantly prolonged in the nintedanib arm (12.6 versus (Table I). On the other hand, results form recently completed 10.3 months) and was even more pronounced in patients and ongoing phase III trials with newer targeted therapies with adenocarcinoma histology (34). Based on these clinical will determine if these drugs will be incorporated into data the drug has been submitted for EMA approval clinical practise. (expected in 2015). The LUME-Lung 2 phase III (NCT00806819) (N=1302) has also been conducted to evaluate nintedanib plus pemetrexed versus pemetrexed plus placebo as second- Tivantinib (ArQule, USA), a staurosporine derivative, is a line treatment for advanced or metastatic NSCLC. small-molecule TKI selectively inhibiting c-MET. c-MET Preliminary data indicated no differences between PFS and activity can have profound effects on cell growth, survival, OS between both arms (www.clinicaltrials.gov). motility, invasion and angiogenesis. Dysregulation of MET signalling has been shown to contribute to tumourigenesis in a number of malignancies. c-MET is also overexpressed in 60-80% of patients with NSCLC, whereas c-MET mutations Selumetinib (AstraZeneca, UK) is an inhibitor of MEK1,2 are found in 20% of these patients (4). (mitogene-activated extracellular signalregulated kinase In a recently published phase II study (N=176) with kinase) downstream of KRAS, with preclinical evidence of patients previously treated for NSCLC, the combination of synergistic activity with docetaxel in KRAS mutant tivantinib (360 mg b.i.d) plus erlotinib (150 mg/day) carcinomas. Since currently no targeted therapies are significantly improved PFS and OS compared with placebo available for KRAS-mutant NSCLC, selumetinib has been plus erlotinib in the subset of patients with non-squamous tested in this patient group. The results from a randomised histology, a population enriched for c-MET overexpression phase II study (N=87) evaluating the combination of (30). Based on these results, a phase III, randomised, double- selumetinib with docetaxel againts docetaxel alone in KRAS blind, placebo-controlled study (MARQUEE) of tivantinib mutation-positive NSCLC patients have demonstrated a high plus erlotinib versus placebo plus erlotinib in previously and durable response rate of 37.2% versus 0 % (p<0.0001), treated patients with locally advanced or metastatic, non- translating into a statistically significant improvement in PFS squamous NSCLC was conducted. The primary endpoint of of 5.3 versus 2.1 months (HR=0.58, p<0.014) (35). this trial was OS. However, although the interim analysis Following these results, selumetinib is being evaluated as showed a statistically significant improvement in PFS in the combination therapy (SELECT-1). This study is a

2507 ANTICANCER RESEARCH 35: 2503-2512 (2015) randomised, double-blind, placebo-controlled trial (N=634) of a phase III trial (SQUIRE) (N=1093) of in that will evaluate the safety and efficacy of selumetinib (75 combination with gemcitabine and cisplatin versus gemcitabine mg b.i.d. orally) plus docetaxel (75 mg/m² intravenously, on and cisplatin plus placebo in squamous NSCLC have been day 1 of every 21 days) as a second-line therapy in locally reported (40). The study results showed that patients in the advanced or metastatic KRAS mutation-positive NSCLC. The necitumumab plus chemotherapy arm had an improvement in study is designed to evaluate PFS as the primary endpoint OS (HR=0.84, p=0.012) with a median survival of 11.5 months and OS as a secondary endpoint. This trial is currently compared to 9.9 months for patients treated in the enrolling patients (NTC01933932) and is to date the only chemotherapy-only arm. PFS and the disease control rate, study which evaluates targeted therapy in patients with defined as patients demonstrating either a complete or partial NSCLC harbouring KRAS mutations. response or stable disease, were also significantly improved. Based on this study a regulatory submission of necitumumab is anticipated early next year as first-line therapy for patients with NSCLC (stage IIIB/IV) with squamous histology. Ramucirumab (Cyramza®; Lilly, USA) is an investigational monoclonal antibody that binds to VEGFR-2 and blocks ligand binding and activation. The drug has been tested in several phase II NSCLC clinical trials and has showed overall Ceritinib (Zykladia®; Novartis, Switzerland) is a small molecule response rates up to 55% (36). Due to these encouraging that targets ALK- and -like growth factor (IGF) 1 results, an international, randomised, placebo-controlled, receptor TKIs. NSCLCs harbouring ALK gene rearrangements double-blinded phase III trial (REVEL, N=1242) has are sensitive to the TKI crizotinib, but invariably develop examined the efficacy and safety of remucirumab treatment resistance (41). Ceritinib is a novel, more potent ALK inhibitor administered in combination with docetaxel, as compared with than crizotinib, with significant antitumour activity in preclinical docetaxel administered with placebo, in patients with stage models (41). Moreover, the drug showed promising actitivty in IIIB/IV NSCLC whose disease progressed during or after first- patients with NSCLC habouring ALK mutations (mainly the line platinum-based chemotherapy with or without gatekeeper mutation L1196M). In a recently reported phase I maintenance treatment. The primary endpoint was OS; trial ceritinib demonstrated a partial response rate of 56% secondary endpoints included PFS, overall response rate, (44/79) in patients with crizotinib-resistant advanced or disease control rate, patient-reported outcomes, and metastatic NSCLC (42). The drug is even active in patients with assessment of safety and tolerability of ramucirumab. Eligible brain metastasis from NSCLC. patients were randomized at a 1:1 ratio to receive either Due to these encouraging results the drug is currently docetaxel (75 mg/m²) plus ramucirumab (10 mg/kg) or being evaluated in two phase III trials. In the first study docetaxel (75 mg/m²) plus placebo. Recently published results (NCT 01828099), untreated patients with ALK-positive from this study have shown that patients treated on the NSCLC (N=348) are randomised between ceritinib alone ramucirumab/docetaxel arm (N=628) achieved a median OS versus chemotherapy; the primary endpoint is PFS. In the of 10.5 months compared to 9.1 months for patients on the second study (NCT01828112), patients with previously docetaxel/ placebo arm N=625). The OS HR for those treated treated ALK-positive NSCLC (pretreated with platinum- in the ramuricumab/docetaxel arm was 0.86 (95% CI=0.751- doublet chemotherapy plus crizotinib) (N=236) are 0.979, p=0.023), which corresponds to a 14% reduction in risk randomised between ceritinib alone versus chemotherapy. of death (37). Based on these data ramuricumab was approved Again, the primary endpoint is PFS. Both studies are by the FDA at the end of 2014, EMA approval is pending. currently recruitung patients. It should be noted that ceritinib (although already approved Necitumumab by the FDA) is not the only promising drug in patients with crizotinib-resistant disease CH5424802 (ALK inhibitor, Necitumunab (Lilly, USA) is a fully human IgG1 monoclonal Chugai), AP26113 (ALK inhibitor, Ariad) and the heat-shock antibody targeting EGFR, having the potential benefit of lower protein 90 inhibitor AUY922 (Novartis) had demonstrated risk of hypersensitivity reaction as compared with cetuximab considerable activity in this cluster of patients in phase I/II and also equivalent antibody-dependent cell-mediated studies and due to a more potent CNS penetration (43). cytotoxicity (38). It has shown promising activity in several phase II clinical trials in NSCLC (39). Recently, a phase III Further Considerations clinical trial evaluating the addition of necitumumab to pemetrexed and cisplatin in non-squamous NSCLC was Targeted therapies are currently being evaluated in a variety of prematurely closed due to concerns about the increased risk of treatment settings in NSCLC and novel strategies of disrupting thrombembolic events in the experimental arm (39). The results tyrosine kinase-controlled pathways have been investigated.

2508 Dempke: New Drugs for NSCLC (Review)

Table II: Overall survival (OS) benefits in patients with advanced or metastastic non-small cell lung cancer (NSCLC) following treatment with targeted therapies.

Drug Study design N Median OS benefit

Nindetanib Docetaxel plus nindetanib versus 1341 2.1 Months docetaxel (second-line) (adenocarcinoma only) (34) Tivantinib Erlotinib plus tivantinib versus 176 3.4 Months erlotinib (second-line) (phase II trial) (30) Necitumumab Cisplatin/gemcitabine plus 1093 1.6 Months necitumumab versus (squamous cell carcinoma only) (40) cisplatin/gemcitabine plus placebo (first-ine) Ramucirumab Docetaxel plus ramuricumab versus 1250 1.4 Months (37) docetaxel plus placebo (second- line) Bevacizumab Carboplatin/paclitaxel plus bevacizumab versus 878 2.0 Months (22) carboplatin/paclitaxel plus placebo (first-line) Cetuximab Platinum-based doublet plus cetuximab versus 1125 1.2 Months (29) platinum-based doublet plus placebo (first-line)

However, many of the recently reported trials have failed to To date, no perspective studies have yet compared gefitinib, improve OS which might be due to several key reasons. erlotinib, and afatinib for adverse events (AEs) and efficacy, Firstly, without a validated biomarker, specific subgroups irrespective of EGFR mutation status. However, some of patients who are more likely to respond cannot be retrospective trials have been published suggesting that selected. Furthermore, the redundancy in tyrosine kinase- gefitinib does have the more favourable toxicity profile when triggered pathways leads to primary and secondary resistance compared with erlotinib and afatinib. One such study (46) to an agent that targets a specific signal transduction cascade; compared AEs between gefitinib and erlotinib in patients with as a result, agents that target multiple pathways are currently NSCLC. The authors found that the erlotinib-treated group under investigation. Finally, it is unlikely that any TKI could (N=35) had more AEs, including rash, fatigue, stomatitis, achieve complete inhibition of its target(s), which may result anorexia and constipation. On the other hand, liver dysfunction in reduced but not completety abrogated signalling (22). and nail changes were more frequent in the gefitinib-treated Moreover, the reasons that TKIs have failed to improve group (N=107). AEs of grade 2 or more, including rash, survival when added to chemotherapy remain far from clear. fatigue, and nausea, were again more frequent in the erlotinib- A possible potential mechanism for the lack of synergy treated group (46). This group also showed more of a tendancy between these agents and chemotherapy may be the G1 phase to require dose reduction due to their AEs, suggesting that cell-cycle arrest caused by TKIs, which then may interfere gefitinib may have a better toxicity profile than erlotinib. with the cell cycle-dependent cytotoxicity of chemotherapy A more recently published meta-analysis adds weight to (44). In addition, most of the TKIs are associated with this proposal. Haspinger et al. performed a systematic significant additional toxicity suggesting that combination review and meta-analysis in order to estimate through with chemotherapy might not be the best setting for the use indirect comparison the relative risk benefit associated with of multitargeted TKIs. gefitinib, erlotinib, and afatinib. Data extraction was Since there are only very few trials that have shown a performed by two independent reviewers ad focused on benefit from the addition of TKIs to chemotherapy, benefit (overall response rate, PFS) and selected harm additional studies using this unselected approach are not outcomes (diarrhoea, rash, nail disorders, liver recommended. Therefore, there is a definite need for an dysfunction). They found that all three TKIs had similar improved understanding of the complex mechanisms that are activity and efficacy (overall response rate, PFS) while the involved in the TKI-mediated pathways, and for the toxicity was less favourable for afatinib, with a significant development of validated predictive markers to allow a better higher risk of diarrhoea, rash, and nail disorders (47). treatment decision on the basis of the probability of Based on these safety results, the authors suggested that response. This would certainly help to avoid the unnecessary afatinib may not be the first choice for treatment of patients use of potentially toxic drugs in patients with known with NSCLC harbouring EFGR mutations. In addition, resistance and would facilitate the discovery of new targets these findings suggest a more favourable toxicity profile and drugs on the basis of resistance mechanisms (45). and quality of life with gefitinib.

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The question remains whether the benefit of targeted therapy Disclaimer for NSCLC may be best defined by PFS since in this regard published are still unconclusive. Truly, PFS is regarded as a The Author states there are no conflicts of interest in regard to this good predictor for improved OS (and is independent of article. subsequent treatment), but OS is acknowledged as the key clinical outcome in the treatment of advanced NSCLC. All References large previous randomised phase III trials assessing first-line treatment demonstrated a significantly higher response rate and 1 Ramalingam S and Belani C: Systemic chemotherapy for longer PFS in patients treated with first-generation EGFR- advanced non-small cell lung cancer: recent advances and future TKIs, including gefitinib and erlotinib, than in patients treated directions. Oncologist 13 (Suppl 1): 5-13, 2008. with standard platinum-based combination chemotherapy. 2 Shepherd FA: Second-line chemotherapy for non-small cell lung cancer. Expert Rev Anticancer Ther 3: 435-442, 2003. Although these trials met their primary endpoint with 3 Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, significantly longer PFS, no significant difference was observed Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin in terms of OS. However, no restrictions were imposed on M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, treatment after the end of protocol therapy in any of these trials De Marinis F, Simms L, Sugarman KP and Gandara D: Phase III and the majority of patients in the control arm received EGFR- study comparing cisplatin plus gemcitabine with cisplatin plus TKI therapy at least once. pemetrexed in chemotherapy-naive patients with advanced-stage None of these randomised trials has yet demonstrated a non-small-cell lung cancer. J Clin Oncol 26: 3543-3551, 2008. statistically significant improvement with these TKIs in 4 Dempke WC, Suto T and Reck M: Targeted therapies for non- small cell lung cancer. Lung Cancer 67: 257-274, 2010. terms of OS, which is of course the strongest endpoint for 5 Tartarone A, Lerose R, Lazzari G, Gregore V and Aieta M: clinical research in oncology, in a condition of no effective Which tyrosine kinase inhibitor should be recommended as treatment afterwards. When effective treatment is given as initial treatment for non-small-cell lung cancer patients with post therapy, it will be difficult to distinguish the treatment EGFR mutations? Med Oncol 31: 78-85, 2014. effect of original and subsequent treatments because 6 Pilotto S, Di Maio M, Peretti U, Kinspergher S, Brunelli M, differences in OS are potentially confounded by crossover, Massari F, Sperduti I, Giannarelli D, De Marinis F, Tortora G and a relevant number of patients assigned to chemotherapy and Bria E: Predictors of outcome for patients with lung adeno- arms received TKIS as second- or third-line treatment after carcinoma carrying the epidermal growth factor receptor mutation receiving first-line tyrosine kinase inhibitors: sensitivity disease progression. Intuitively, the high proportion of and meta-regression analysis of randomized trials. Crit Rev crossover may extend the benefit associated with the Oncol Hematol 90: 135-145, 2014. administration of TKIs to patients assigned to the control 7 Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, arm, and its ‘salvage’-effect may compensate for the Sunpawereyoung P, Han B, Margono B, Ichinose Y, Nishiwaki relevant differences in PFS of first-line treatment Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffiled EL, consistently demonstrated in all TKI trials. Watkins CL, Armour AA and Fukuoka M: Gefitinib or Nevertheless, future studies should clearly focus on OS carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361: 947-957, 2009. as a primary endpoint for any type of targeted therapy in 8 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, patients with NSCLC. Since published data for significant Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, OS benefits in NSCLC are moderate (Table II), more Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston meaningful results for patients are clearly needed. ASCO D, Bezjak A, Clark G, Santabarbara P and Seymour L: Erlotinib Guidelines recommend for advanced or metastatic NSCLC in previously treated non-small-cell lung cancer. N Engl J Med that clinical trials should aim to improve OS by 25% to 353: 123-132, 2005. 30%, with a minimal increase in toxicity (48). For 9 Zer A and Leighl NB. Second-line therapy in non-small-cell lung cancer: the DELTA between different genotypes widens. J Clin squamous cell disease, that benefit should be 2.5 to 3.0 Oncol 32: 1874-81, 2014. months (target HR=0.77-0.80); for non-squamous cell 10 Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, disease it should be 3.25-4.0 months (target HR=0.76-0.80). Felip E, Palermo R, Garcia-Gomez R, Pallares C, Sanchez JM, These recommendations, however, are not intended to set Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De standards for regulatory approval or insurance coverage but Marinis F, Corre E, Bover I, Illiano A, Dansin E, De Castro J, rather to encourage patients and investigators to demand Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, more from clinical trials. Moreno MA, Terrasa J, Munoz-Langa J, Valdivia J, Isla D, In conclusion, personalised medicine for NSCLC patients Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, EGFR is now a reality, and patients with mutations should be Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, treated with the best available TKI. From all published data, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskvi A, Queralt gefitinib currently represents an ideal first-line treatment C, De Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M option for this molecularly selected subgroup of patients. and Paz-Ares L: Erlotinib versus standard chemotherapy for

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European patients with advanced EGFR mutation-positive non- 20 Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, De small-cell lung cancer (EURTAC): a multicentre, open-label, Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, randomised phase III trial. Lancet Oncol 13: 239-246, 2012. O’Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, 11 Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD and Jänne PA: Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen Crizotinib versus chemotherapy in advanced ALK-positive lung L, Ye M, Huang J, Zhi X, Zhnag Y, Xiu Q, Ma J, Zhang L and You cancer. N Engl J Med 368: 2385-2394, 2013. C: Erlotinib versus chemotherapy as first-line treatment for patients 21 Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Felip E, with advanced EGFR mutation-positive non-small-cell lung cancer Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, (OPTIMAL, CTONG-0802): a multicentre, open-label, Tursi J and Blackhall F: First-line crizotinib versus chemotherapy randomised, phase III study. Lancet Oncol 12: 735-742, 2011. in ALK-positive lung cancer. N Engl J Med 371: 2167-2177, 2014. 12 Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas A, Szczesna A, 22 Aggarwal C, Somaiah N and Simon GR: Antiangiogenetic Juhasz E, Gonzalez EE, Molinier O, Klingelschmitt G and agents in the management of non-small cell lung cancer: Where Giaccone G. SATURN: a double-blind, randomized, phase III study do we stand now, where are we headed? 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J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, 24 Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Shahidi M and Schuler M: Phase III study of afatinib or cisplatin Blackhall F, Pirker R, Galiulin R, Ciluleanu TE, Sydorenko O, plus pemetrexed in patients with metastatic lung adenocarcinoma Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, with EGFR mutations. J Clin Oncol 31: 3327-3334, 2013. Hei YJ, Galimi F and Spigel DR: International, randomized, 15 Yang JC, Hirsh V, Schuler M, Yamamoto N, O’Byrne KJ, Mok placebo-controlled, double-blind phase III study of motesanib TS, Zazulina V, Shahidi M, Lungerhausen J, Massey D, Palmer plus carboplatin/paclitaxel in patients with advanced M and Sequist LV: Symptom control and quality of life in LUX- nonsquamous non-small-cell lung cancer: MONET1. J Clin Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in Oncol 30: 2829-2836, 2011. patients with advanced lung adenocarcinoma with EGFR 25 Lara PN, Douillard JY, Nakagawa K, von Pawel J, McKeage MJ, mutations. J Clin Oncol 31: 3343-3350, 2013. Albert I, Losonczy G, Reck M, Heo DS, Fan X, Fandi A and 16 Yang JCH, Sequist LV, Schuler M, Mok T, Yamamoto N, Scagliotti G: Randomized phase III placebo-controlled trial of O’Byrne KJ, Hirsh V, Geater SL, Zhou C, Massey D, Zazulina V carboplatin and paclitaxel with or without the vascular disrupting and Wu YL: Overall survival (OS) in patients (pts) with agent vadimezan (ASA404) in advanced non-small-cell lung advanced non-small-cell lung cancer (NSCLC) harbouring cancer. 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