Cancer Treatment Reviews

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1 Cancer Treatment Reviews 35 (2009) Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: ANTI-TUMOUR TREATMENT Pemetrexed in first-line treatment of non-small cell lung cancer Emilio Esteban a, *, Marta Casillas b,c, Alejo Cassinello b,c a Oncology Service, Hospital de Asturias, C/Celestino Villamil S/N, Oviedo, Spain b Clinical Research Department, Lilly SA, Avenida de la Industria, 30, Alcobendas, Madrid, Spain article info summary Article history: Received 9 December 2008 Accepted 3 February 2009 Keywords: Pemetrexed NSCLC Non-small cell lung cancer First-line setting Front-line therapy Chemonaïve Histologic types Pemetrexed is an antitumor agent traditionally used as monotherapy for the second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) as well as in combination with cisplatin for the treatment of chemonaïve patients with unresectable malignant pleural mesothelioma. Recently, pemetrexed has been approved in combination with cisplatin for the first-line treatment of patients with locally advanced or metastatic NSCLC other than predominantly squamous cell histology. Studies that support the development of this indication are detailed in this review. We performed a Pub- Med/Medline database search to identify relevant literature from 1998 until August Bibliographies from identified references were searched, as well as were abstracts from the most relevant congresses in lung cancer area (American Society of Clinical Oncology Congress, World Conferences of Lung Cancer). We detailed pemetrexed studies in the first-line setting of NSCLC treatment, in monotherapy, in combination with platinum and also, with other agents. Data regarding efficacy differences related to different histologic types were also analyzed. Ó 2009 Published by Elsevier Ltd. Introduction: non-small cell lung cancer and treatment Lung cancer is one of the most common malignancies, with a worldwide incidence of over 1.3 million cases. 1 In Europe, in 2006, studies estimated lung cancer to be the third leading cancer in incidence (386,300,12.1%) and the most common cause of death (334,800,19.7%). 2 In the United States, in 2007, an estimated 213,380 new cases of lung cancer were diagnosed, accounting for approximately 15% of all cancer diagnoses and 29% of cancer deaths. 3 Non-small cell lung cancer (NSCLC) represents approximately 80 87% of all lung cancer cases in the United States 3 and 65 75% of these cases are detected as locally advanced (Stage III) or metastatic disease (Stage IV), 4 6 so palliative treatments are often the only therapeutic option. Most recent guidelines 7 9 recommend platinum-based doublets in the first-line setting for the treatment of patients with good performance status (PS), although the use of certain non-platinum doublets is a reasonable alternative if available Phase I/II data show activity and tolerable toxicity. The combination of gemcitabine and cisplatin, a standard treatment for advanced Stage IIIB and Stage IV NSCLC, has been approved in many countries as the standard first-line chemotherapy treatment for NSCLC. 10 Several Phase II and III clinical studies * Corresponding author. Tel./fax: addresses: eestebang@seom.org (E. Esteban), casillas_marta@lilly.com (M. Casillas), cassinello_alejo@lilly.com (A. Cassinello). c Tel.: ; fax: have confirmed that combination therapy with gemcitabine and cisplatin is an effective regimen for NSCLC Pemetrexed: structure and mechanism Pemetrexed disodium (Eli Lilly and Company, Indianapolis, Indiana, USA) is a multitargeted antifolate (Fig. 1). Its mechanism of action consists of the inhibition of three key enzymes in the folate metabolic pathway, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT), and to a lesser extent, aminoimidazole carboxamide ribonucleotide transformylase (AICARFT) and CI-tetrahydrofolate synthase (Fig. 2). This mechanism leads to depletion of fully reduced folate, ultimately resulting in disruption of nucleotide synthesis for both pyrimidines and purines. Pemetrexed, once in the cell, is an excellent substrate for polylpolyglutamate synthetase, leading to extensive intracellular polyglutamate derivates that are more potent inhibitors of the described enzymes. Polyglutamated pemetrexed is retained intracellularly longer than the parent compound, resulting in more prolonged cytotoxic effects. 20,21 Preclinical human and murine tumor models have shown a relatively broad range of antitumor activity for this agent, 22 leading to its clinical development for a variety of human malignancies, including NSCLC. Pharmacokinetics and pharmacodynamics The pharmacokinetic properties of pemetrexed have been reported in patients receiving intravenous pemetrexed 500 mg/m /$ - see front matter Ó 2009 Published by Elsevier Ltd. doi: /j.ctrv

2 E. Esteban et al. / Cancer Treatment Reviews 35 (2009) H 2 N H N O N N H plus carboplatin or plus cisplatin. The time to maximum plasma concentration of pemetrexed was h (median = 0.18 h) when administered in combination with carboplatin. Mean maximum plasma concentrations (Cmax) of pemetrexed in combination with carboplatin or cisplatin were 116 lg/ml and 72.2 lg/ml (coefficient of variance [CV] 11% and 49%). Corresponding mean area under the plasma concentration-time curve (AUC) values were 174 and 122 lg h/ml (CV 18% and 47%). Cmax and AUC values of pemetrexed as monotherapy indicate that the pharmacokinetics of pemetrexed were linear across a wide dose range ( mg/m 2 ). The volume of distribution at steady state of pemetrexed was 14.1L (CV 17%) when combined with carboplatin and 19.1 L (CV 62%) when combined with cisplatin. Approximately 80% of pemetrexed is bound to plasma protein as determined from an in vitro human plasma binding assay. 23 Pemetrexed is mainly excreted in the urine and 70 90% of the dose is eliminated as unchanged drug within 24 h of administration. In patients with normal renal function, the elimination halflife is 3.5 h. The half-life and exposure to drug increase as renal function decreases. According to the Summary of Product Characteristics (SPC), when used as single-agent as well as combination with cisplatin no dose adjustment is necessary for patients with creatinine clearance above 45 ml/min and pemetrexed use should be avoided in patients with creatinine clearance below this level. 24 Use of folate supplements Fig. 1. Pemetrexed structure. In the early clinical experience with pemetrexed, prior to standard vitamin supplementation, toxicities like neutropenia, skin rash, diarrhea, mucositis or nausea/vomiting were often severe and unpredictable. Because pemetrexed inhibits the folate dependent enzymes, hypotheses based on preclinical data state that O N H C O O H C O O H toxicity might be more severe in folate deficient patients. 25 In the clinical setting, and according to an analysis of the pooled toxicity data from several pemetrexed trials, there are data to support that folic acid (FA) and vitamin B 12 supplementation is important in modulating the toxicity of pemetrexed and improving its therapeutic index. 26 Nowadays, pemetrexed is well tolerated with standard vitamin supplementation, which consists of oral folic acid at lg administered at least five continuous days prior to pemetrexed and continuing daily throughout therapy and vitamin B 12 at 1000 lg administered intramuscularly prior to first dose of pemetrexed and repeated every 9 weeks while patient is on treatment. 27 A current study is examining the possibility of simplifying the folic acid and steroid schedule required with pemetrexed use without increasing toxicity. 28 Approved indications Pemetrexed was approved in 2004 as second-line therapy in patients with previously chemotherapy-treated advanced NSCLC, based on a randomized, open-label, Phase III trial. 29 In the study, 571 patients with a performance status of two or less were randomized and received pemetrexed (283 patients) or docetaxel (288 patients). Patients received pemetrexed 500 mg/m 2 or docetaxel 75 mg/m 2 every 21 days. Pemetrexed-treated patients received vitamin B 12 and folate and both arms received dexamethasone prophylaxis. In the overall study population, there were no significant differences in overall response rates (ORR) for both drugs (9.1% versus 8.8%), either in the median progressionfree survival (PFS) (2.9 months for both arms) or the median overall survival time (8.3 months for pemetrexed and 7.9 months for docetaxel, [HR 0.99; 95% CI, ]). However, the toxicities were greater in the docetaxel arm: 40.2% of docetaxel patients had grade 3 4 neutropenia versus 5.3% of pemetrexed patients (p < 0.001); the frequency of febrile neutropenia was significantly greater in the docetaxel arm (12.7% versus 1.9%, p < 0.001) and neutropenia-related infection was also higher (3.3% versus 0.0%, p = 0.004). Hospitalization for neutropenic fever was significantly higher in the docetaxel arm (13.4% versus 1.5%, p < 0.001). Pemetrexed was also approved for malignant pleural mesothelioma (MPM), based on a Phase III randomized, single-blind, controlled, multicenter trial that compared cisplatin alone versus cisplatin plus pemetrexed. 30 The study ed 448 chemonaïve patients who were randomized to receive pemetrexed 500 mg/ Fig. 2. Mechanism of action.

3 366 E. Esteban et al. / Cancer Treatment Reviews 35 (2009) m 2 followed by cisplatin 75 mg/m 2 (226 patients) or cisplatin alone at the same dose. ORR was 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (p < ) and median overall survival (OS) was 12.1 months in the doublet arm versus 9.3 months in the control arm (p = 0.02). Based on this study, pemetrexed/cisplatin became the standard for care for patients with unresectable MPM. Recently, pemetrexed has also been approved in combination with cisplatin for the first-line treatment of patients with locally advanced or metastatic NSCLC other than predominantly squamous cell histology. 27 Studies that support the development of this indication are detailed in this review. Pemetrexed as first-line NSCLC treatment Pemetrexed has been evaluated as single-agent treatment or combined with other agents as first-line treatment for NSCLC in numerous Phase II clinical trials. Phase II: pemetrexed as single-agent The single-agent activity of pemetrexed in the first-line treatment of advanced NSCLC has been analyzed in two open-label, Phase II trials. 31,32 The designs of these two trials were similar and the primary objective of each was to determine the response rate to single-agent pemetrexed in chemonaïve patients. Patients in these trials had advanced Stage IIIB or Stage IV disease with at least one measurable lesion. Details of the studies are presented in Table 1. The ORR was 16% in the Clarke study 31 and 23% in the Rusthoven study. 32 Median time to progression (TTP) was 4.4 and 3.8 months, respectively. Median OS was 7.2 months and 9.2 months, respectively, with rates of 32% and 25%. These two trials were completed before the systematic vitamin supplementation was instituted, which may explain the safety profile observed in these trials. More recently, and with the vitamin supplementation instituted, Gridelli et al. 33 developed another Phase II study in which patients with Stage IIIB or Stage IV disease and ECOG of 0 2 were randomized to receive single-agent pemetrexed (500 mg/m 2 )orto the sequential pemetrexed/gemcitabine (single-agent pemetrexed at the same dose on cycles 1 and 2 and for single-agent gemcitabine cycles 3 and mg/m 2 on days 1 and 8). Eighty-seven patients were included (44 pemetrexed and 43 in the pemetrexed/ gemcitabine arm). Tumor response rates for the pemetrexed and pemetrexed/gemcitabine arms were 4.5% and 11.6%, respectively. The median time to progression as well as progression was 4.5 and 4.1 months for the pemetrexed and pemetrexed/gemcitabine arms, respectively, and the median progression-free survival (PFS) time was 3.3 months for both arms. The median overall survival (OS) time was 4.7 months for the pemetrexed arm and 5.4 months for the pemetrexed/gemcitabine arm, with respective 1- year survival rates of 28.5% and 28.1%. Both hematological and non-hematological toxicities were mild. Authors concluded that single-agent pemetrexed and sequential pemetrexed/gemcitabine showed moderate activity and were well tolerated as first-line treatments for advanced NSCLC in elderly patients or patients unsuitable for platinum-based combination chemotherapy. Combined with platinum: Phase II trials Some Phase II studies in previously untreated patients with NSCLC were conducted to evaluate pemetrexed combined with platinum. The first two studies evaluated the combination of pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 without vitamin supplementation, but with dexamethasone prophylaxis. 34,35 The designs of these two studies were similar, with response as the primary end-point. Previously untreated patients with Stage IIIB or Stage IV NSCLC and at least one bidimensional measurable lesion were eligible for the studies. In the Shepherd study, 35 there was a 45% ORR, a median OS of 8.9 months and a rate of 49%. In the Manegold study, 34 the ORR was 39% with a median TTP and OS of 6.3 and 10.9 months, respectively. Details can be found in Table 2. It is worth noting that the most important toxicities found were hematological, with rates higher than those de- Table 1 Pemetrexed as a single-agent in the first-line setting for NSCLC (Phase II). Author/ references Pemetrexed (dose) Clarke et al mg/m 2 day 1; every 21 days (max 12 cycles) Vit. supp. Rusthoven 500 mg/m 2 every 21 days No 33 7 PR Median et al. 32 TTP # Pts Response Progression Survival Grade 3/4 Toxicities NCI CTC >5% (% of patients) No 59 9 PR Median TTP Median OS Neutropenia (42%); anemia (10%); nausea (14%); vomiting (8%); elevated ALT/AST (20%); cutaneous (31%) 27 SD 4.4 months 7.2 months 15.8% 32% Median OS 3.8 months 9.2 months 23.3% 25.3% Gridelli et al mg/m 2 day 1; every Yes 44 2 PR Median Median OS Anemia (6.8%) 21 days TTP Randomized 15 SD 4.5 months 4.7 months 4.5% 28.5% VS 500 mg/m 2 + gemcitabine Yes 43 5 PR Median Median OS Trombocytopenia (7%) 1200 mg/m 2 TTP 10 SD 4.1 months 5.4 months 11.6% 28.1% Neutropenia (39%); anemia (9%); febrile neutropenia (12%); anorexia (12%); nausea (12%); vomiting (9%); diarrhea (9%); arthralgia (9%); stomatitis (6%); tearing (6%); edema (9%); infection (12%); elevated hepatic enzymes (10%); skin rash (39%); lethargy (27%) Abbreviations: ALT, alanine amino transferase; AST, aspartate amino transferase; NCI CTC, National Cancer Institute Common Toxicity Criteria; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, Overall Survival; PR, partial response; Pts, patients; SD, stable disease; TTP, time to progression.

4 E. Esteban et al. / Cancer Treatment Reviews 35 (2009) Table 2 Pemetrexed in combination with platinums in the first-line setting for NSCLC (Phase II). Author/ references Pemetrexed (dose) Manegold 500 mg/m 2 day 1; et al. 34 every 21 days Shepherd et al mg/m 2 ; day 1; every 21 days Zinner 500 mg/m 2 day 1; et al. 36 every 21 days Koshy 500 mg/m 2 day 1; et al. 37 every 21 days Scagliotti 500 mg/m 2 day 1; et al. 38 every 21 days Concomitant drug/dose Cisplatin 75 mg/m 2 after pemetrexed day 1; every 21 days Cisplatin 75 mg/m 2 day 1; every 21 days Carboplatin AUC = 6 day 1; every 21 days Carboplatin AUC = 6 day 1; every 21 days Carboplatin AUC = 6 day 1; every 21 days Vit. supp. No 36 # Pts Responses Progression Survival Grade 3/4 Toxicities NCI CTC >5%, (% of patients) 36 assess No assess Yes 50 Yes 50 Yes PR Median TTP Median OS 10.9 months 17 SD 6.3 months 50% 39% 13 PR Median DR 6.1 months 45% Median OS 8.9 months 49% 12 PR Median TTP Median OS 13.5 months 25 SD 5.4 months 56% 24% 28% Median TTP 4.9 months Median OS (estimate) 13.5 months 55.3% 12 PR Median TTP Median OS 10.5 months Randomized 17 SD 5.7 months 31.6% VS 500 mg/m 2 ; day 1; every 21 days Oxaliplatin 120 mg/m 2 ; day 1; every 21 days Yes % 1 CR Median TTP Median OS 10.5 months 10 PR 5.5 months 20 SD 49.9% 26.8% Granulocytopenia (59%); anemia (14%); trombocytopenia (17%); nausea/ Vomiting (6%); diarrhea (6%); neuromotor (6%) Leukopenia (23%); granulocytopenia (37%); anemia (20%); fatigue (26%); diarrhea (10%); neuropathy (motor) (6%) Neutropenia (26%) Neutropenia (34%); anemia (10%) Neutropenia (25.6%); febrile neutropenia (5.1%); thrombocytopenia (17.9%); anemia (7.7%); fatigue (7.7%) Neutropenia (7.3%); vomiting (7.3%) Abbreviations: AUC, area under the curve; CR, complete response; DR, duration of response; NCI CTC, National Cancer Institute Common Toxicity Criteria; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PR, partial response; pts, patients; SD, stable disease; TTP, time to progression. scribed in the summary of characteristics of the product because those studies were developed without using folate supplements. Pemetrexed has also been studied in combination with other platinum analogues. In 2005, Zinner 36 published an open study in patients with Stage IIIB or Stage IV NSCLC and a PS of 0 1. Patients were treated with pemetrexed 500 mg/m 2 and carboplatin to an area under the curve (AUC) of six intravenously on day 1 every 3 weeks with vitamin and dexamethasone prophylaxis. The primary end-point of the study was to determine the efficacy and tolerability of a pemetrexed/carboplatin combination at the first-line setting. Of 50 patients included in the study, 24% presented partial response, median TTP and OS were 5.4 months and 13.5 months, respectively, with a of 56%. Main grade 3 4 toxicity was hematological (neutropenia 26%). Koshy et al. 37 reported results from a Phase II trial of carboplatin (AUC of six intravenously given on day 1 every 21 days) and pemetrexed (500 mg/m 2 intravenously day 1 every 21 days). The investigators administered routine steroid prophylaxis and vitamin supplementation. Fifty patients were entered, all with a PS of 0 1. The ORR was 28%, with respective median OS and 1-year survival rates of 13.5 months and 55.3%. Grade 3/4 toxicities included neutropenia (34%), anemia (10%), thrombocytopenia (4%), nausea/vomiting (2%), and diarrhea (2%). Scagliotti et al. 38 reported a randomized, Phase II trial evaluating carboplatin (AUC 6 IV every 21 days) plus pemetrexed (500 mg/m 2 IV every 21 days) as well as oxaliplatin (120 mg/m 2 IV every 21 days) plus pemetrexed (500 mg/m 2 IV every 21 days). All patients received steroid prophylaxis and were supplemented with folic acid and vitamin B 12 during the trial. Overall, the efficacy and safety profile of pemetrexed combined with carboplatin or oxaliplatin showed similar results and compared favorably with new drugs in the same setting. Response rates reported were of approximately 30% for both arms. Median OS was 10.5 months for both arms. Grade 3/4 toxicity on the carboplatin/pemetrexed arm consisted of neutropenia (26%), thrombocytopenia (18%), fatigue (8%), and stomatitis (3%), while the oxaliplatin/pemetrexed arm had an extremely favorable toxicity profile with grade 3/4 toxicities consisting of neutropenia (7%), thrombocytopenia (2%), vomiting (7%), diarrhea (2%), and neuropathy (2%). Combined with platinum: Phase III trials In 2007, Gronberg et al. 39 presented the results of a randomized study in which patients were assigned to receive either pemetrexed 500 mg/m 2 plus carboplatin AUC of 5 day 1 or gemcitabine 1000 mg/m 2 day 1 and 8 plus carboplatin AUC of 5 day 1. The primary objective was to evaluate quality of life (QoL) as defined by global health status and some common toxicities. Overall survival was a secondary end-point of the study. Four hundred thirty-seven patients were included in the study. Baseline data showed a high proportion of patients with poor performance status (22% of patients with ECOG PS = 2) and elderly patients (18% of patients

5 368 E. Esteban et al. / Cancer Treatment Reviews 35 (2009) P75 years old). The starting dose of study treatment administered to elderly patients was reduced to 75% of total dose and the maximum number of cycles permitted was 4. With regard to the primary objective, no statistically significant differences were observed in the QoL scales. Significantly fewer patients in the pemetrexed/carboplatin arm than in the gemcitabine/carboplatin arm experienced grade 3 4 thombocytopenia (24% versus 54%, p < 0.001), leucopenia (22% versus 44%, p < 0.001) and granulocytopenia (38% versus 48%, p = 0.03). The median OS reported was 7.3 months in the pemetrexed/carboplatin arm versus 7.0 months in the gemcitabine/cisplatin group. This short median OS observed on both arms is potentially attributable to the severely ill and elderly population included in this trial. A recently published report of a randomized, open-label Phase III trial is the basis for pemetrexed/cisplatin combination approval in the first-line treatment setting for NSCLC. 40,41 The study compared the combination pemetrexed/cisplatin (arm A) with gemcitabine/cisplatin (arm B) in patients with histological or cytological diagnosis of NSCLC. These patients, not previously treated with systemic chemotherapy, had Stage IIIB or Stage IV NSCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 1. The primary objective of this non-inferiority study was to compare OS of the two regimens. Secondary objectives were ORR, duration of response, PFS, TTP, time to treatment failure (TTF), and toxicity. Patients were stratified according to disease stage, the ECOG PS, history of brain metastases, sex, pathological diagnosis and investigational site. Patients were randomized to receive pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 on day 1 or gemcitabine 1250 mg/m 2 on day 1 and 8 and cisplatin 75 mg/m 2 on day 1 every 21 days for up to six cycles. Patients in both arms received vitamin B 12, folic acid and dexamethasone prophylaxis while receiving treatment. One thousand seven hundred twentyfive patients were randomly assigned to either arm A (862 patients) or arm B (863 patients). Patients characteristics were well balanced between both treatment groups. Efficacy results in the overall study population showed no significant difference in OS for pemetrexed/cisplatin or gemcitabine/ cisplatin (10.3 versus 10.3, HR 0.94; 95% CI, ). Similarly, no significant differences were found between arms in all other efficacy parameters used as secondary objectives (see Table 3). Although both regimens were well tolerated, both hematologic and non-hematologic adverse event profiles were significantly Table 3 Efficacy results of Phase III pemetrexed/cisplatin versus gemcitabine/cisplatin in the first-line setting for NSCLC. 40,41 Pemetrexed/ Gemcitabine/ cisplatin cisplatin N = 762 N = 755 HR or P-value OS (months) (95% CI) 10.3 ( ) 10.3 ( ) 0.94; 95% CI, PFS (months) (95% CI) 4.8 ( ) 5.1 ( ) 1.04; 95% CI, ORR (%) 233 (30.6%) 213 (28.2%) (95% CI) (27.3, 33.9%) (25.0, 31.4%) CR (%) 2 (0.3%) 3 (0.4%) PR (%) 231 (30.3%) 210 (27.8%) SD (%) 314 (41.2%) 346 (45.8%) PD (%) 174 (22.8%) 155 (20.5%) DR (months) (95% CI) ( ) ( ) Survival rate at 43.5% 41.9% - 1 year Survival rate at 2 years 18.9% 14.0% - Abbreviations: CI, confidence interval; CR, complete response; DR, duration of response; HR, hazard ratio; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PD, progression disease; PR, partial response; SD, stable disease. Table 4 Safety results of Phase III pemetrexed/cisplatin versus Gemcitabine/cisplatin in the first-line setting for NSCLC. 40,41 Grade 3/4 toxicities NCI CTC n (%) a Pem/cis Gem/cis P-value N = 839 N = 830 Neutropenia 127 (15.1%) 222 (26.7%) <0.001 Anemia 47 (5.6%) 82 (9.9%) Thrombocytopenia 34 (4.1%) 105 (12.7%) <0.001 Leucopenia 40 (4.8%) 63 (7.6%) Neutropenia febrile 11 (1.3%) 31 (3.7%) Alopecia (any grade) 100 (11.9%) 178 (21.4%) <0.001 Nausea 60 (7.2%) 32 (3.9%) Vomiting 51 (6.1%) 51 (6.1%) Fatigue 56 (6.7%) 41 (4.9%) Dehydration (any grade) 30 (3.6%) 17 (2.0%) Transfusions 138 (16.4%) 240 (28.9%) <0.001 Platelets 15 (1.8%) 37 (4.5%) Erythrocytes 135 (16.1%) 227 (27.3%) <0.001 Erythropoiesis stimulanting agents b 90 (10.4%) 156 (18.1%) <0.001 G-CSF/GM-CSF b 27 (3.1%) 53 (6.1%) Abbreviations: NCI CTC, National Cancer Institute Common Toxicity Criteria; NSCLC, non-small cell lung cancer; G-CSF/GM-CSF, granulocyte colony stimulating factors. a Include toxicities communicated in at least 3% of patients in at least one arm. b Based in an intention-to-treat population. favorable to the pemetrexed/cisplatin doublet, with the exception of nausea. Despite this finding, no differences in the rate of vomiting were found between arms. It is also of note that patients on pemetrexed/cisplatin required significantly fewer red blood cell and platelet transfusions, as well as less erythropoietin stimulant agents and granulocyte colony stimulating factors (G-CSFs) or granulocyte macrophage colony stimulating factor (GM-CSF), reflecting overall less grade 3 4 hematological toxicity (see Table 4). Analysis according to histology Histology was one of the baseline characteristics recorded in the study and a pre-specified subset analysis for it was established. Patient histological characteristics are described in Table 5. When analyzing the efficacy according to the different histological subtypes in both adenocarcinoma and large cell, the pemetrexed/cisplatin combination showed statistically significant improvement in OS compared to gemcitabine/cisplatin doublet (12.6 versus 10.9) for adenocarcinoma (HR, 0.84; 95% CI, ) and 10.4 versus 6.7 in large cell (HR, 0.67; 95% CI, ) (p = 0.03, for both cases). For squamous cell carcinoma, the doublet gemcitabine/cisplatin showed a marginally superior OS (10.8 versus 9.4, HR, 1.23; 95% CI, , p = 0.05) (see Fig. 3). According to statistical methods, 42 a prospective study in the NSCLC other than predominantly squamous population, assuming a hazard ratio of 0.84 and 1252 patients with 906 events (deaths), would have approximately 75% power to demonstrate superior survival for pemetrexed/cisplatin over gemcitabine/cisplatin. A recent multicenter, double-blind Phase III trial 43 that compares the efficacy and safety of pemetrexed versus placebo in patients with Stage IIIB/IV NSCLC who had not progressed on four cycles of platinum-based induction chemotherapy also analyzed the influence of histology in the outcomes of the patients as a secondary end-point. Patients were randomized (2:1 ratio; balanced for stage, ECOG PS, gender, response to induction therapy, non-platinum component of induction therapy, and brain metastases) to receive pemetrexed (500 mg/m 2, day 1) plus best supportive care (BSC) or placebo plus BSC in 21-day cycles until disease progression. All patients received vitamin B 12, folic acid and dexamethasone. A total of 663 patients were ed (pemetrexed = 441; placebo = 222). Pemetrexed had better efficacy than placebo with respect to progression-free survival (4.3 versus 2.6

6 E. Esteban et al. / Cancer Treatment Reviews 35 (2009) Table 5 Histologic type of patients included in Phase III pemetrexed/cisplatin versus gemcitabine/cisplatin in the first-line setting for NSCLC. 40,41 Pem/cis Gem/cis N = 862 N = 863 Adenocarcinoma 436 (50.6%) 411 (47.6%) Squamous cell carcinoma 244 (28.3%) 229 (26.5%) Large cells 76 (8.8%) 77 (8.9%) NSCLC, NOS 106 (12.3%) 146 (16.9%) Abbreviations: NSCLC, non-small cell lung cancer; NOS, not otherwise specified. months [HR, 0.502; p < ]) and tumor response (CR + PR + SD) (51.7% versus 33.3%, p < 0.001). When analyzing efficacy data according to histology, results in non-squamous patients were even better (pemetrexed versus placebo: PFS 4.5 versus 2.6 months (HR 0.444, p < ) and tumor response (CR + PR + SD) (57.7% versus 32.7%, p < 0.001). In squamous patients, there was no clinically meaningful improvement in PFS or tumor response for pemetrexed compared to placebo. Authors concluded that postinduction maintenance therapy with pemetrexed is well tolerated and offers superior PFS compared with placebo in patients with advanced NSCLC. These results are aligned with a retrospective analysis 44 of data from the registry Phase III study of pemetrexed versus docetaxel in second-line treatment 29 in order to assess whether the efficacy is different according to histology. This analysis showed an advantage in PFS for pemetrexed versus docetaxel in non-squamous NSCLC (3.4 versus 3 months, HR, 0.78; 95% CI, ) and for docetaxel versus pemetrexed in squamous NSCLC (2.7 versus 2.3 months, HR 1.40; 95% CI, ). Comparative results from these three trials are shown in Table 6. In the retrospective analysis performed by Peterson, 44 authors assessed not only the differences between treatment arms according to histology but analyzed the differences of the efficacy of pemetrexed between non-squamous and squamous patients. Results showed that median OS and PFS in patients with adenocarcinoma or large cell lung cancer treated with pemetrexed was higher than those with squamous histology (OS 9.2 months versus 6.2 months, HR 0.48, p = 0.001; PFS 3.4 versus 2.3, HR 0.56, p = 0.004, respectively). Results of the treatment-by-histology interaction test also showed that patients with non-squamous histology treated with pemetrexed had higher survival compared to all others on trial, including patients treated with docetaxel (p = 0.001). The results of the Phase III trials and sub-analysis described above showed a higher efficacy in terms of survival in patients with NSCLC other than predominantly squamous cell histology versus those with squamous cell carcinoma, so this specification has been included in the Summary of Product Characteristics. 27 Fig. 3. Kaplan-Meier overall survival (OS) and progression-free survival (PFS) curves for the entire population, patients with nonsquamous histology (adenocarcinoma plus large cell), and patients with squamous histology.

7 370 E. Esteban et al. / Cancer Treatment Reviews 35 (2009) Table 6 Comparative Efficacy Data According to Histologic Type of Patients Included in 3 Phase III Pemetrexed Trials for NSCLC. Efficacy data Hystologic Type Pem/Cis Gem/Cis Adjusted, HR (95% CI) Scagliotti 40,41 PFS Adenocarcinoma or large cell ( ) Median mo Squamous ( ) OS Adenocarcinoma or large cell ( ) Median mo Squamous ( ) Pem Placebo Ciuleanu 43 PFS Median mo Non-squamous (p-value < 0.001) Squamous (p-value = 0.04) Tumor response (%) Non-squamous p-value<0.001 (CR+PR+SD) Squamous p-value = 1 Pem Docetaxel Peterson 44 PFS Median mo Adenocarcinoma or large cell ( ) Squamous ( ) OS Median mo Adenocarcinoma or large cell ( ) Squamous ( ) Abbreviations: CI = confidence interval, CR = complete response,, HR = hazard ratio, mo = months, NSCLC = non-small cell lung cancer, OS = Overall Survival, PFS = progression free survival, PR = partial response,, SD = stable disease. Combined with other agents Pemetrexed has been evaluated in combination with gemcitabine. There have been inconsistencies about the optimal sequencing and timing in combining these two agents in preclinical studies with various cell-lines, translating into poor guidance on the design of clinical trials. Most reports suggest synergy between the two agents, but this may be clearly schedule- and cell-line dependent. 45 Phase II studies of this combination are detailed in Table 7. Ina recent meta-analysis of pemetrexed plus gemcitabine in first-line 46 treatment of patients with advanced NSCLC, authors concluded that, based on four trials (entries 3, 4, 5 and 6 in Table 6), the combination pemetrexed/gemcitabine was efficacious and well tolerated. A low occurrence of alopecia and grade 4 thrombocytopenia were noted. Pemetrexed has also been studied in combination with vinorelbine, in a Phase I/II study performed by Clarke et al. 53 With the recommended dose obtained from the Phase I, 37 patients received pemetrexed 500 mg/m 2 and vinorelbine 30 mg/m 2. Results showed a median OS of 7.9 months with an estimated 12-month survival probability of 15%. The median PFS was 4.2 months and the median TTP was 4.4 months. On an intention-to-treat base, the response rate was 38% (1 CR and 13 PR). Main toxicities reported (grade 3/ 4 over 5%) were neutropenia (65%), febrile neutropenia (11%), fatigue (27%), and nausea (8%). Discussion Pemetrexed has demonstrated clear activity in NSCLC, both in monotherapy (in first- and second-line treatment) and in combination with other agents (especially with platinums). Primary toxicities of pemetrexed treatment are bone marrow depression and skin and gastrointestinal disorders, but the use of concomitant administration of folate, vitamin B 12 and steroids has notably decreased the frequency and severity of these effects. After the recognized results of pemetrexed in monotherapy in the second-line treatment of NSCLC, and the encouraging results of the Phase II trials in combination with other agents, recent results of the Phase III study have shown that for first-line treatment of advanced NSCLC, the pemetrexed/cisplatin doublet provides similar efficacy with better tolerability and more convenient administration than the standard gemcitabine/cisplatin. The efficacy obtained from these studies is comparable to any of the accepted third-generation platinum doublet regimens currently in use. Furthermore, its toxicity profile may offer advantages over other standard regimens like platinum doublets with taxanes and vinorelbine. The efficacy plateau of the most common cytotoxic chemotherapy used in NSCLC in terms of OS has been described in different analyses and studies of doublets used for the treatment of NSCLC, ranging from 7.4 to 11.3 months, 10,54 57 with a rate of around 31 46%. 54,56 In the overall NSCLC population (all histologies), pemetrexed/cisplatin has shown to be equivalent to gemcit- Table 7 Pemetrexed in combination with gemcitabine for NSCLC (Phases II). Author/ references Pemetrexed dose Gemcitabine dose # Pts ORR Progression (TTP) Survival (OS) Ma et al mg/m 2 before G; day mg/m 2 ; days 1, % 4.7 months 11.4 months VS 500 mg/m 2 after G; day mg/m 2 ; days 1, % 4.1 months 10.3 months VS 500 mg/m 2 before G; day mg/m 2 ; days 1, 8; every % 4.4 months 11.8 months 21 days Peacock et al mg/m 2 ; days 1; every 14 days 1500 mg/m 2 ; days 1; every 14 days 35 20% 6-month PFS 51% 6-month overall survival 67% Treat et al mg/m 2 immediately after G; 1250 mg/m 2 ; days 1 and % 3.3 months 10.3 months day 1 Monnerat et al mg/m 2 90 min after G; day mg/m 2 days 1 and % Median PFS 10.1 months 5.0 months West et al mg/m 2 ; before G; day mg/m 2 ; days 1 and % 4.4 months 10.6 months Dudek et al mg/m 2 ; days 1; every 14 days 1500 mg/m 2 ; days 1; every 14 days % 4.6 months 10.1 months Abbreviations: NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; pts, patients; TTP, time to progression.

8 E. Esteban et al. / Cancer Treatment Reviews 35 (2009) abine/cisplatin, a standard regimen for this setting, with a median survival of 10.3 months. A Phase III trial that improved this efficacy plateau was developed by the Eastern Cooperative Oncology Group (ECOG). 58 They conducted a randomized study in which 878 patients were assigned to chemotherapy with paclitaxel and carboplatin alone (444 patients) or paclitaxel and carboplatin plus bevacizumab (a dose of 15 mg/kg given intravenously on day 1) (434 patients), a monoclonal antibody against vascular endothelial growth factor. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG PS > 1) were excluded. Results showed a median OS of 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; p = 0.003). The median PFS in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; p < 0.001), with corresponding ORR of 35% and 15% (p < 0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (p < 0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group (3.45%), including five from pulmonary hemorrhage. Authors concluded that the addition of bevacizumab to a standard doublet platinum-based regimen conferred a significant improvement in OS, PFS and ORR in patients with non-squamous cell carcinoma and a good performance status. Risks related to toxic effects and pulmonary hemorrhage must be considered within the context of the survival benefit conferred by the addition of bevacizumab to standard treatment for non-squamous NSCLC. When analyzing results of the Phase III trial of pemetrexed/cisplatin according to tumor histology, results found in terms of OS in adenocarcinoma (12.6 versus 10.9 months, p = 0.03) to our knowledge, the highest OS rate obtained in adenocarcinoma NSCLC with a chemotherapy doublet, with a favorable toxicity profile. These results, reinforced with those from the other two trials demonstrating differential treatment effects for pemetrexed by NSCLC histology, 43,44 warrant further research in this direction. What seems clear is that histologic diagnosis should be taken into account when choosing the best treatment option for patients. Historically, histologic subtype has not reliably played a prognostic or predictive role in NSCLC. 8 Nevertheless, there is a clear epidemiological shift in the NSCLC with a rise of adenocarcinoma type rates in virtually all areas Some recent chemotherapy studies have suggested a prognostic or predictive role for NSCLC histologic type. 62,63 A recent review from Hirsch et al., 64 pointed out the prognostic and predictive role of histology in advanced NSCLC. Thymidylate synthetase (TS) is a well established genetic marker. 65 According Ceppi et al. 66 squamous cell and high-grade carcinomas are related with higher TS expression levels, which should be considered when treating patients with TS-inhibiting agents. Preclinical data have suggested that over-expression of TS correlates with reduced sensitivity to pemetrexed and antifolateresistant cell-lines. 67 The results of the three Phase III trials and sub-analysis described in this document, that had shown a higher efficacy in terms of survival in patients with histology of adenocarcinoma and large cell NSCLC versus those with squamous cells, could be explained with this hypothesis of TS different expression levels according to histology. The idea of having a genetic marker that can be a predictive factor of the response and sensitive to a specific antitumor agent or an indicator of the clinical outcome is not new. 65,68 Clinical evidence in different tumor types has shown defective DNA-repair capacities, in which the nucleotide excision repair system (NER) is involved, play an important role as predictors of response and outcome. In this context, the BRCA1 gene is a modulator of differential chemosensitivity. 69 Low BRCA1 expression confers high sensitivity to cisplatin, but resistance to paclitaxel and docetaxel. Conversely, high BRCA1 mrna expression causes cisplatin resistance and sensitivity to paclitaxel and docetaxel. 70,71 The excision repair cross-complementing (ERCC1), which is the lead enzyme in the nucleotide excision repair process, is a marker for resistance to cisplatin. 72 These data suggest that pharmacogenomic markers, and now histological diagnosis, may be used for developing customized chemotherapy in prospective studies. Other recent studies adding targeted agents to well-known doublets have also generated promising results. A randomized, double-blind Phase III trial of two different doses of bevacizumab in combination with cisplatin and gemcitabine in chemotherapynaïve patients with advanced or recurrent non-squamous NSCLC reached a median PFS (the primary end-point) of 6.7 months (for the 7.5 mg/kg bevacizumab dose), 6.5 months (for the 15 mg/kg dose) and 6.1 months on the doublet group, (p-value and 0.0, 3 respectively and compared to doublet arm). 73 Nevertheless PFS benefit did not translate into a significant OS benefit. Median OS was 13.1 months for gemcitabine/cisplatin alone, 13.6 months for bevacizumab 7.5 mg/kg plus gemcitabine/cisplatin (HR versus placebo 0.92, 95% CI ) and 13.4 months for bevacizumab 15 mg/kg plus gemcitabine/cisplatin (HR versus placebo 1.02, 95% CI ). Authors pointed out that administration of heterogeneous subsequent therapy may have hampered the detection of a significant difference in OS. 74 The FLEX study, a randomized, multicenter, Phase III trial of cetuximab in combination with cisplatin/ vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced EGFR-expressing NSCLC reached an OS of 11.3 months versus the doublet (10.1 months) (HR, 0.871, 95% CI, to 0.996; p = ). 75 In this sense, the combination pemetrexed/cisplatin, which as a doublet has given one of the highest OS in non-squamous patients, seems to be the ideal platform to test the addition of new targeted agents that can further improve patient outcomes. In a recent Phase II trial, 51 chemonaive patients, with non-squamous NSCLC and ECOG PS 0-1 received pemetrexed/carboplatin plus bevacizumab with very promising results: ORR of 49% (95% CI, 35 61%), median TTP and OS of 7.2 and 14.0 months, respectively. 76 Further research is also very likely in combination with different targeted agents. In conclusion, pemetrexed is a very important drug in the treatment of patients with NSCLC other than predominantly squamous cell histology, both in combination with cisplatin for the front-line treatment and in monotherapy for the second-line setting, with promising activity in maintenance treatment as well. Accordingly, the efficacy differences that were found related to different histology type may achieve the goal of personalizing drug treatments. Conflict of interest Marta Casillas and Alejo Cassinello are full-time Lilly employees. Emilio Esteban has an advisor role for Lilly SA. Acknowledgments Authors wish to thank Katherine P. 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