Overview. Author Summary: Abstract and Brief Discussion

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1 Overview First Published Online March 2, 2015 DOI: /theoncologist Title: Pemetrexed and Gemcitabine Versus Carboplatin and Gemcitabine in Non-Small Cell Lung Cancer: A Randomized Noninferiority Phase II Study in One Center Authors: Eva Branden, Gunnar Hillerdal, Karl Kolbeck, Hirsh Koyi Karolinska Hospital, Stockholm, Sweden ClinicalTrials.gov Identifier: Stockholm EU-nr Sponsor(s): Eli Lilly Sweden Principal Investigator: Gunnar Hillerdal IRB Approved: Yes Disclosures The authors indicated no financial relationships. Author Summary: Abstract and Brief Discussion Background The standard treatment for non-small cell lung cancer (NSCLC) stages IIIb and IV is a platinum compound combined with a third-generation cytotoxic agent.we decided to conduct a phase II study to assess whether the platinum compound could be replaced with pemetrexed with similar results and without an increase in side effects. Methods Consecutive eligible patients were randomized to either the standard arm of gemcitabine plus carboplatin (GC) or the experimental arm of gemcitabine plus pemetrexed (GP). Results Fifty evaluable patients were enrolled in the GC arm, and 44 received GP.There were 10 partial responses in the GC arm and 16 in the GP arm.with GC, mean survival was 9 months compared with 15 months with GP.The side effects were similar in both groups. Conclusion Pemetrexed can replace platinum compounds in the first-line treatment of stage IIIb and IV NSCLC without increasing the side effects. A trend toward better survival was observed in the patients receiving pemetrexed instead of a platinum compound, and this should be studied further. Discussion This study was planned to determine whether, in the first-line setting, a platinum compound could be replaced with another cytotoxic agent for the treatment of stage IIIb and IV NSCLC without an increase in toxicity. Encouraging results were obtained, with the combination of gemcitabine and pemetrexed appearing to improve outcome, with more partial responses and longer survival with better tolerability (Fig. 1). Although the schedule of administration was different, doses

2 werechosen to providesimilardose intensityofgemcitabine.the gemcitabinedoseintensitywas 833 mg/m 2 per week in GC and 750 mg/m 2 per week in GP. This minor dose difference is unlikely to explain any difference between the two groups. In conclusion, this study found encouraging results when pemetrexed was substituted for a platinum compound in the firstline treatment of NSCLC without increasing the side effects. A trend toward better survival was observed with the GP combination, but the study was not powered to show this. Further studies with this combination seem warranted. Trial Information Disease Stage of disease / treatment Prior Therapy Type of study - 1 Type of study - 2 Primary Endpoint Additional Details of Endpoints or Study Design Lung cancer NSCLC Metastatic / Advanced None Phase II Randomized Overall Survival After written informed consent, consecutive patients with newly diagnosed stage IIIB or IV NSCLC not suitable for curative treatment (according to TNM classification 6) and performance status (PS) 0 2 were randomized to either gemcitabine plus carboplatin (GC) or pemetrexed plus gemcitabine (PG). All cases had to be cytologically or pathologically confirmed. In the GC arm, treatment was gemcitabine, 1,250 mg/m 2 and carboplatin AUC 5, onday1,and gemcitabine 1,250 mg/m 2 alone on day 8. Cycles were given on a three-week basis and a total of 4 cycles were given. Thus, treatment lasted 84 days, and the total dose of gemcitabine was planned to be 10,000 mg/m 2, provided there was no dose reductions. In the GP arm, treatment consisted of pemetrexed and gemcitabine 1,500 mg/m 2 every 14th day for 6 cycles.thus,treatmentalso lasted 84 days, and the planned total dose ofgemcitabine was 9,000 mg/m 2.The goalwastoadministerasimilartotaldoseofgemcitabine(whichalmost succeeded) over the same time period. All patients in both groups received supplementation treatment with folic acid and vitamin B12. adjustments: With hematologic toxicity, dose reduction was required. If WBC were per liter or platelets perliteratthestartofnextthenextcycle, 75% ofbothdrugsweregiven, and the reduced doses were then continued throughout the rest of the treatment. If WBC at this the start of the next cycle was, per literor platelets, per liter, treatment was withheld one week to allow for further recovery; if this did not happen within 3 weeks, the patientwasexcludedfromthestudy. reductionswerealsomadeif there was leukopenic fever or hemorrhage due to low thrombocytes necessitating hospitalization, and for grade 3 4 nonhematological toxicity except grade 3 alopecia, nausea, and vomiting. Investigations: Evaluation of tumor status was performed using RECIST criteria [1]. Chest x-ray was performed at baseline (less than 4 weeks before start of treatment), halfway through namely, before fourth cycle in the GP and before the third cycle in the GC arm, 2 4 weeks after the last dose of chemotherapy, and then at every follow-up. Follow-up was done every two months until progressive disease occurred. CT scan of the thorax including upper part of the abdomen was performed at baseline, 2 4 weeks after last dose of chemotherapy, and whenever progression was suspected from chest x-ray. St Georges Questionnaire on Qualityof Life was administered at baseline, halfway through, and 2 4 weeks after the last dose of chemotherapy. Hematology investigations were followed weekly as long as the patient received treatment. Statistical considerations: This was a randomized, open label, phase-ii study with the main purpose to investigate the objective response (OR) rate intwo groups of patientswith stage III/IVnon-small cell lung cancer(nsclc). Study patientswere allocatedrandomlytotreatment with gemcitabine plus carboplatin (GC group) or treatment with gemcitabine plus pemetrexed (GP group). The purpose of the design was to compare the obtained OR-rate in each treatment arm with a predetermined rejection level. The study was not powered for a comparison between the two randomization groups.

3 Investigator s Analysis The Simon optimal two-stage design was used to define the number of patients necessary to complete the study. The Simon two-stage design was conducted separately for each randomized arm. The specifications of the design depended on the lowest OR-rates of clinical interest, a target OR-rate and the type I and II error rates. A treatment would be considered to be of no further clinical interest, if the OR-rate was less than or equal to 20% (Ho: OR rate 2%). A treatment would be of definite clinical interest, if the OR-rate was at least 40% (Ha: OR rate 40%).The type I error rate was 5%, which isthe probability ofconcluding that a treatment is active (i.e., rejecting Ho), whereas in reality it is not so.the type II error rate was 20%, which is the probability of concluding that a treatment is inactive (i.e., rejecting Ha), whereas in reality the treatment is active. The number of evaluable patients required in each treatment arm was 13 in the first stage and possibly an additional 30 in the second stage.thetotalnumberofevaluablepatients, ineachgroup, wastobe either 13 or 43. If there were less than 3 patients whose tumor responded to treatment in the first 13 patients, then that treatment armwastobe closedtofurtheraccrualanditwould be concluded that the treatment is not effective (i.e., rejecting Ha). If there were 3 or more responding patients in the first 13 patients, then 30 additional patients would be enrolled in the second stage. At the end of the second stage more than 12 patients with a response of their tumor in 43 were required to reject Ho and conclude that the treatment is of clinical interest in terms of response rate. Otherwise, Ha is rejected, and the treatment will be considered of no further interest. In order to obtain 86 (43 3 2) evaluable patients a minimum number of 96 were planned to be randomized. The patient accrual time was estimated to be 2 years. All randomized patients who received study treatment were included in the safety analysis. Median duration of response, median time to progression and median survivaltimewasestimatedusingthekaplan-meierproductlimitmethod. Ethics committee. The ethics committee of the Karolinska Institute approved the study. Active and should be pursued further Drug Information Drug 1 Pemetrexed Trade name Alimta Company name Eli Lilly 500 mg/m 2 per Schedule of Administration Every 14th day for maximum 6 cycles Drug 2 Carboplatin per Schedule of Administration AUC 5, on a 3-week basis, 4 cycles Drug 3 Gemcitabine per Schedule of Administration 1,250 mg/m 2 on days 1 and 8, 3-week cycles Drug 4 Gemcitabine per Schedule of Administration 1,500 mg/m 2 every 14 days for a total of 9,000 mg/m 2

4 Patient Characteristics Number of patients, male 43 Number of patients, female 57 Stage IIIb and IV Age Median (range): 67 (47 84) Number of prior systemic therapies Median (range): None Performance Status ECOG Unknown Primary Assessment Method Experimental Arm: Total Patient Population Number of patients enrolled 45 Number of patients evaluable for toxicity 44 Number of patients evaluated for efficacy 44 Evaluation method Clinical Response assessment PR 16% Response assessment SD 13% Response assessment PD 15% (Median) duration assessments OS 15 months Control Arm: Total Patient Population Number of patients enrolled 50 Number of patients evaluable for toxicity 49 Number of patients evaluated for efficacy 49 Evaluation method Clinical Response assessment PR 10% Response assessment SD 19% Response assessment PD 20% (Median) duration assessments OS 9 months Assessment, Analysis, and Discussion Completion Pharmacokinetics / Pharmacodynamics Investigator s Assessment Study completed Not Collected Active and should be pursued further Discussion The standard treatment for non-small cell lung cell cancer (NSCLC) stages IIb and IV is a platinum compound combined with a third-generation cytotoxic agent [2 6]. This study was planned to determine whether, in the first line setting, a platinum compound could be replaced with another cytotoxic agent in the treatment of stage IIIb and IV NSCLC without any increased toxicity.the combination of gemcitabine and pemetrexed (GP) appeared to retain activity, possibly improving the outcome, with more partial responses and longer survival. Tolerability was also better (Fig. 1). The schedule of administration was different, but the doses were chosen so that the dose intensity of gemcitabine should be as similar as possible. The gemcitabine dose intensity was 833 mg/m 2 per week in the gemcitabine and carboplatin (GC) group and 750 mg/m 2 per week in the GP group. This minor dose difference is unlikely to explain any difference between the two arms.

5 The combination of gemcitabine and pemetrexed had shown synergistic effects in cultured cell lines [7, 8] and one phase II study for NSCLC was available at the time of planning this study, showing the feasibility of this treatment[9]. Since then, more studies have been published [10 13]. A combination of pemetrexed 500 mg and gemcitabine 1,500 mg in a biweekly cycle was well tolerated in an escalating study [15] but later proved too toxic for patients aged.70 years [13]. It was better tolerated in anotherstudy in which survival was not as good as in the present study [14].The main difference between that study and ours seems to be a higher incidence of adenocarcinoma in our study. In Sweden today, adenocarcinoma is the most common type of lung cancer, and women have overtaken men in incidence, as found in this study. These tendencies occur today all over the Western world. When this study was planned, the importance of histology for the effect of pemetrexed was not known. It is now generally accepted that its effects are best for nonsquamous NSCLC [15], and the fact that adenocarcinomas were the most common tumor type in our study might be reflected in the better performance of GP. TheresultsintheGCarmarecomparabletotheearlierSwedishstudies[16,17]withoverallsurvivalof8 9months;however, GP has survival that seems superior to earlier published studies with pemetrexed and carboplatin with overall survival of months [10 13] or with pemetrexed and cisplatin with overall survival of 10 months [12]. This indicates that the combination of pemetrexed and gemcitabine should be investigated further. In conclusion, this study shows that pemetrexed can be substituted for a platinum compound in the first-line treatment of NSCLC without increasing the side effects. A trend toward better survival was observed with the GP combination, but the study was not powered to show this. Further studies with this combination seem warranted. References 1. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: Chemotherapy in non-small cell lung cancer: A meta-analysis fron 52 randomized clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995;311: Pfister DG, Johnson DH, Azzoli CG et al. American Society of Clinical Oncology treatment of unresectable non-small cell lung cancer guideline: Update J Clin Oncol 2004;22: Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346: Le Chevalier T, Scagliotti G, Natale R et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: A meta-analysis of survival outcomes. Lung Cancer 2005;47: Zatlukal P, Novakova L, Peyruzelka L et al. Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: A phase III randomized trial. Lung Cancer 2003;41: Tesei A, Ricotti L, De Paola F et al. In vitro schedule dependent interactions between the multitargeted antifolate LY and gemcitabine in human colon adenocarcinoma cells. Clin Cancer Res 2002;8: Giovannetti E, Mey V, Danesi R et al. Synergistic cytotoxicity and pharmacogenetics of gemcitabine and pemetrexed combination in pancreatic cancer cell lines. Clin Cancer Res 2004;10: Adjei AA, Nair S, Reuter N et al. Pemetrexed/gemcitabine as front line therapy for advanced NSCLC: A randomized, phase II trial of three schedules. J Clin Oncol 2004;22(suppl):7070a. 10. Monnerat C, Le Chevalier T, Kelly K et al. Phase II study of pemetrexed-gemcitabine combination in patients with advanced-stage non-small cell lung cancer. Clin Cancer Res 2004;10: Adjei AA. Clinical studies of pemetrexed and gemcitabine combinations. Ann Oncol 2006;17(suppl 5):v29 v Dudek AZ, Larson T, McCleod MJ et al. Phase 1/2 dose escalating study of twice-monthly pemetrexed and gemcitabine in patients with advanced cancer and non-small cell lung cancer. J Thorac Oncol 2008;3: Sequist LV, Fidias P, Heist RS et al. Brief report of biweekly pemetrexed and gemcitabine in elderly patients with non-small cell lung cancer. J Thorac Oncol 2009;4: Spigel DR, Hainsworth JD, Barton JH et al. Phase II study of biweekly pemetrexed and gemcitabine in patients with previously untreated advanced non-small cell lung cancer. J Thorac Oncol 2010;5: Scagliotti G, Brodowicz T, Shepherd FA et al. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol 2011;6: Sederholm C, Hillerdal G, Lamberg K et al. 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6 17. Hillerdal G, Sederholm C, Andersson K. Randomized phase II study of gemcitabine and carboplatin 1/- sequential docetaxel in non-small cell lung cancer. Lung Cancer 2011;71: Figures and Tables Figure 1. Actual survival in the two arms. Abbreviations: GC, gemcitabine and carboplatin; GP, gemcitabine and pemetrexed. Table 1. Basic findings Characteristic GC GP n Age, years, median (range) 66.7 (54 84) 67.4 (47 84) Female/male, % 57/43 54/46 Pack years Never smokers, % Adenocarcinoma, % Low differentiated/large cell, % 10 7 Squamous cell, % Abbreviations: GC, gemcitabine and carboplatin; GP, gemcitabine and pemetrexed. Table 2. Side effects Event GC GP Side effects grade 3 (mainly lecopenia),% Lowered doses (mainly lecopenia), % Stopped treatment (mainly progressive disease), % Abbreviations: GC, gemcitabine and carboplatin; GP, gemcitabine and pemetrexed.

7 Table 3. Nonhematological toxicity Toxicity GC GP Fatigue grade Total Nausea grade Total Rash grade Total 4 19 GI grade Total 9 13 Abbreviations: GC, gemcitabine and carboplatin; GI, gastrointestinal; GP, gemcitabine and pemetrexed. Click here to access other published clinical trials.