Pemetrexed Combined with Oxaliplatin Or Carboplatin As First-Line Treatment in Advanced Non–Small Cell Lung Cancer: a Multicenter, Randomized, Phase II Trial

690 Vol. 11, 690–696, January 15, 2005 Clinical Cancer Research

Pemetrexed Combined with Oxaliplatin or Carboplatin as First-Line Treatment in Advanced Non–Small Cell Lung Cancer: A Multicenter, Randomized, Phase II Trial

Giorgio V. Scagliotti,1 Cornelius Kortsik,2 was 49.9% for PemOx patients and 43.9% for PemCb Graham G. Dark,3 Allan Price,4 patients. Common toxicity criteria grade 3 or 4 hematologic toxicities among PemOx patients were grade 3 or 4 Christian Manegold,5 Rafael Rosell,6 Mary O’Brien,7 8 9 neutropenia (7.3%), grade 3 thrombocytopenia (2.4%), and Patrick M. Peterson, Daniel Castellano, grade 3 anemia (2.4%). PemCb patients experienced grade 3 1 1 Giovanni Selvaggi, Silvia Novello, or 4 neutropenia (25.6%), grade 3 or 4 thrombocytopenia Johannes Blatter,10 Louis Kayitalire,8 Lucio Crino,11 (17.9%), and grade 3 anemia (7.7%). Grade 3 vomiting and Luis Paz-Ares9 occurred in three PemOx patients and grade 3 fatigue 1Department of Clinical and Biological Sciences, S. Luigi Gonzaga occurred in three PemCb patients. One grade 3 neu- Hospital, University of Torino, Turin, Italy; 2St. Hildegardis rosensory toxicity occurred in the PemOx group. Three Krankenhaus, Mainz, Germany; 3Newcastle General Hospital, University patients (PemOx 1 and PemCb 2) experienced febrile of Newcastle upon Tyne, United Kingdom; 4Western General Hospital, 5 neutropenia. University of Edinburgh, Edinburgh, Scotland; Thoraxklinik, Conclusions: Efficacy measures for both regimens seem Heidelberg, Germany; 6Institut Catala d’Oncologia, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; 7Royal Marsden Hospital, similar to the most effective chemotherapies for advanced Surrey, United Kingdom; 8Eli Lilly and Company, Indianapolis, Indiana; non–small cell lung cancer (platinum combinations) with 9Hospital ’12 de Octubize, Madrid, Spain; 10Eli Lilly and Company, Bad less hematologic and nonhematologic toxicity. Comparing 11 Homburg, Germany; and Ospedale Bellaria, Bologna, Italy either of these two regimens to platinum-based therapies in a large randomized trial is warranted. ABSTRACT Purpose: To determine efficacy and toxicity of two INTRODUCTION pemetrexed-based regimens in chemonaive patients with Seventy-five percent of primary lung malignancies are locally advanced or metastatic non–small cell lung cancer. designated as non–small cell lung cancer (NSCLC) and most of Experimental Design: Patients were randomly assigned 2 2 these patients have unresectable, locally advanced (stage IIIB) or to receive pemetrexed 500 mg/m plus oxaliplatin 120 mg/m metastatic (stage IV) disease with 5-year survival rates that range (PemOx) or pemetrexed plus carboplatin AUC6 (PemCb). from 3% to 7% (1). Over the last 10 years, a number of large All drugs were given on day 1 of a 21-day cycle for up to six randomized trials have been conducted in patients with NSCLC. cycles. Folic acid and vitamin B12 were given to all patients to These trials compared platinum-based combinations (either minimize pemetrexed-related toxicities. cisplatin or carboplatin) that also include a taxane (paclitaxel Results: Forty-one patients received PemOx and 39 or docetaxel), a Vinca alkaloid (vinorelbine), or an antimetab- received PemCb. Objective tumor response rates were olite (gemcitabine; refs. 2–5). Studies indicate that no single 26.8% for PemOx patients (95% confidence interval, 14.2- regimen was clearly superior with overall response rates of 17% 42.9) and 31.6% for PemCb patients (95% confidence to 32% and median survival times (MST) of 7 to 10 months. interval, 17.5-48.7). Median time to progression was 5.5 and Although a modest survival benefit was established for cisplatin- 5.7 months, respectively, for PemOx and PemCb. Median based chemotherapy (6), in many of these cases, chemotherapy overall survival times were 10.5 months for both treatment is merely palliative; in addition, cisplatin administration requires groups (range, <1 to >20 months). The 1-year survival rate hydration therapy and is often associated with substantial side effects including nausea, vomiting, and renal and neurologic toxicities. Active therapies with improved toxicity profiles are clearly needed in this setting. Received 6/11/04; revised 9/21/04; accepted 9/28/04. Grant support: Sponsored and funded by Eli Lilly and Company, Pemetrexed (ALIMTA, Eli Lilly and Company, Indianapolis, Indianapolis, IN. IN) is a novel antimetabolite that targets multiple enzymes in the The costs of publication of this article were defrayed in part by the folate pathway (7–10). This agent has shown definitive antitumor payment of page charges. This article must therefore be hereby marked activity in phase III studies of malignant pleural mesothelioma advertisement in accordance with 18 U.S.C. Section 1734 solely to (11, 12). The high incidence of severe toxicities observed in early indicate this fact. Note: Presented in part at the American Society of Clinical Oncology, phase pemetrexed studies (9) was later linked to elevated serum Chicago, IL, May 31–June 3, 2003. homocysteine levels (folate and B12 dietary status marker; ref. 13). Requests for reprints: Giorgio Vittorio Scagliotti, Department of Thus, all pemetrexed-treated patients now receive folic acid and Clinical and Biological Sciences, University of Torino, S. Luigi vitamin B supplements and results suggest that this approach Hospital-Thoracic Oncology Unit, Regione Gonzole 10-10043 12 Orbassano, Turin, Italy. Phone: 011-9026-414; Fax: 011-9038-616; significantly improves the safety profile of pemetrexed (14, 15). E-mail: [email protected]. Single-agent pemetrexed and pemetrexed-based combina- D2005 American Association for Cancer Research. tions have shown activity in NSCLC in both first-line and

second-line settings. Four trials, two single-agent trials (16, 17) since using nonsteroidal anti-inflammatory drugs with other and two combinations trials of pemetrexed and cisplatin (18, 19), antifolates (e.g., methotrexate) can result in delayed renal were conducted before the routine use of folic acid and vitamin excretion and prolonged drug exposure. B12 in previously untreated patients. The single-agent trials The study protocol was approved by institutional ethic showed overall response rates of 16% and 23%, whereas the review boards and conducted according to guidelines for good combination trials yielded overall response rates of 39% and clinical practice and the Helsinki Declaration. All patients 45%, with respective MSTs of 11 and 9 months. In the second- provided written informed consent before treatment. line setting, a large randomized phase III trial compared pemetrexed with vitamin supplementation to docetaxel (20). Study Design Efficacy measures for the two regimens were highly comparable The primary objective was to estimate the objective but clinically relevant toxicities favored pemetrexed therapy. response rates for pemetrexed plus oxaliplatin (PemOx) and These studies support further evaluation of pemetrexed- pemetrexed plus carboplatin (PemCb) in patients with locally based combinations as first-line treatment for locally advanced or advanced (stage IIIB) or metastatic (stage IV) NSCLC not metastatic NSCLC. Oxaliplatin, a diaminocyclohexane platinum, previously exposed to cytotoxic chemotherapy. A two-stage has a different cytotoxicity profile from cisplatin and can be Simon design (28), based on response rate (a = 0.03, b = 0.16), safely given in the outpatient setting without hydration therapy governed enrollment size for each treatment group. To (21–23). Likewise, carboplatin-based combinations seem to offer simultaneously estimate response rate for two regimens and similar, or slightly inferior, efficacy but a better nonhematologic minimize patient selection bias, we randomly assigned patients toxicity profile when compared with cisplatin-based combina- to PemOx or PemCb. Baseline stratification factors included tions (2, 24, 25). Phase I studies evaluated pemetrexed plus serum homocysteine, Eastern Cooperative Oncology Group oxaliplatin in patients with solid tumors (26) and pemetrexed plus performance status, disease stage, and investigational center. carboplatin (27) in patients with malignant pleural mesothelioma. The Pocock and Simon algorithm (29), using a probability Both regimens were efficacious and well tolerated. In the present factor of 0.75, was applied to balance the treatment arms for trial, we used a randomized phase II design in chemonaive these factors. The trial was not powered to make statistical patients with locally advanced or metastatic NSCLC to comparisons between arms. Secondary outcomes included time- simultaneously evaluate the activity of two regimens and to-progressive disease (TTP), overall survival time, and quality minimize inherent patient selection and other sources of bias of life as determined by the lung cancer symptom scale. that can invalidate comparisons between two single-arm trials. Statistical Considerations For analysis purposes, this randomized trial was treated as MATERIALS AND METHODS two simultaneous phase II studies. The exact binomial method Patient Selection was used to determine the 95% confidence intervals (95% CI) Patients had histologic or cytologic confirmation of locally for tumor response rate estimates. Time-to-event efficacy advanced or metastatic NSCLC (stage IIIB or IV) that was not variables were estimated using the Kaplan-Meier Method (30), amenable to curative therapy. Evidence of bidimensionally 95% CIs for the medians were calculated as described by measurable disease, as determined by computerized tomography, Brookmeyer and Crowley (31). magnetic resonance imaging, X-ray with lesion diameter of z0.5 cm, or palpation with both diameters z2 cm was also required. Treatment Plan Other inclusion criteria included Eastern Cooperative Oncology In the PemOx arm, patients received pemetrexed 500 mg/m2 Group performance status of 0 or 1, life expectancy of z12 (i.v. infusion over 10 minutes) then oxaliplatin 120 mg/m2 weeks, age z 18 years, adequate bone marrow reserve (absolute (i.v. infusion over 120 minutes) on day 1 of a 21-day cycle. This neutrophil count, z2.0 109/L; platelets, z100 109/L; and dose and schedule were recommended by Misset et al. (26) in hemoglobin, z9 g/dL), adequate hepatic function (bilirubin, their report of a phase I study with this combination. In the V1.5 times the upper limit of normal; alkaline phosphatase and PemCb arm, patients received pemetrexed 500 mg/m2 (i.v. transaminase levels, V3.0 times the upper limit of normal or V5 infusion over 10 minutes) then carboplatin target area under the for liver involvement; calculated creatinine clearance, z45 mL/ concentration curve (AUC) 6 (i.v. infusion over 30 minutes) on min), and adequate birth control measures. Radiotherapy was day 1 of a 21-day cycle. Carboplatin dosing was based on the allowed if completed z4 weeks before study entry; however, Calvert formula (32) with glomerular filtration rate estimated prior systemic chemotherapy, chemotherapy for pleurodesis, using calculated creatinine clearance (Modified Cockroft and immunotherapy, or biological therapy was not allowed. Other Gault lean body weight formula; ref. 33). When pemetrexed 500 exclusion criteria included active infection, pregnancy, other mg/m2 and carboplatin AUC5 was evaluated in a phase I study, primary malignancy (except in situ carcinoma of the cervix or Hughes et al. (27) used the 51CrEDTA glomerular filtration rate adequately treated nonmelanomatous carcinoma of the skin or determination. In clinical practice, it is generally accepted that the other malignancy treated with no evidence of recurrence within 5 carboplatin dose of AUC6 obtained from the Calvert formula years prior to study entry), documented brain metastases (brain using glomerular filtration rate estimated with the Modified imaging not required in asymptomatic patients), uncontrolled Cockroft and Gault lean body weight formula is clinically pleural effusions, significant weight loss (z10% body weight in equivalent to carboplatin AUC5 obtained using 51CrEDTA the preceding 6 weeks), and an inability to interrupt nonsteroidal glomerular filtration rate estimation. All patients received up to anti-inflammatory drugs. The latter criteria was precautionary 6 cycles of therapy. Greater than six cycles were allowed if the

treating physician and sponsor agreed that additional treatment Overall survival time was defined as the interval between would be beneficial to the individual patient. Reasons for early the randomization date and death. Time-to-progressive disease discontinuation included disease progression, unacceptable was defined as the interval between the randomization date and toxicity, or individual patient decision. the first date of documented disease progression. These time-to- All patients were instructed to take oral daily doses of folic event measures were censored at the date of the last follow-up acid (350-1,000 Ag) beginning 1 to 2 weeks before the first dose of visit or death (for TTP only). pemetrexed and for 3 weeks after therapy. Injections of vitamin Quality of life was assessed with the lung cancer symptom B12 (1,000 Ag i.m.) were given 1 to 2 weeks before the first dose of scale (36) at baseline and before every cycle. Patients who had a pemetrexed and at 9-week intervals during treatment. Dexameth- baseline assessment and at least one post-baseline assessment asone (4 mg, oral, twice daily) was given the day before, the day were evaluated for changes in both individual symptom scales of, and the day after each dose of pemetrexed therapy to prevent (appetite, fatigue, cough, dyspnea, hemoptysis, and pain) and the skin rash. The use of prophylactic antiemetic therapy that included average symptom burden index (ASBI; the mean of the six lung a 5-HT3 antagonist was recommended. Erythropoietin adminis- cancer symptom scales). The SD of baseline ASBIs was tration was allowed as supportive care. Granulocyte colony calculated. A patient was categorized as having an improved stimulating factors were allowed for treatment of serious ASBI if the mean of any two consecutive post-baseline ASBIs neutropenic events but supportive treatment was discontinued at for that patient was at least 0.5 SD below the patient’s baseline least 24 hours before the start of the next therapy cycle. ASBI, a worsened ASBI if the mean was at least 0.5 SD above Drug doses were modified in the event of unacceptable the baseline value, or a stable ASBI if the mean was within 0.5 hematologic (absolute neutrophil count of <1.5 109/L or SD of the baseline value. platelets <100 109/L) or nonhematologic toxicity (common All patients who received at least one dose of PemOx or toxicity criteria grade 3 or 4 diarrhea, grade 3 or 4 mucositis, PemCb were evaluated for safety. Body weight and body surface grade z2 neuropathy, or other selected toxicities, excluding area measurements were evaluated before each cycle. grade 3 transaminase elevation, nausea, or vomiting). Study Hematology, blood chemistry, and calculated creatinine clearance therapy was delayed for up to 42 days in patients who developed were determined within 4 days before study drug administration renal impairment (calculated creatinine clearance, <45 mL/min). for each cycle. Toxicity was assessed before each cycle using Patients requiring >42 days recovery time discontinued study version 2.0 of the National Cancer Institute common toxicity therapy. All patients who required a dose reduction (25% criteria scale (37). When possible, follow-up safety evaluations f reduction for most designated toxicities and 50% for grade 3 or 4 were completed 30 days after the last therapy dose. mucositis) received a reduced dose for the remainder of the study. Patients discontinued treatment if more than two incre- RESULTS ments of dose reductions were required. Ninety-one patients were entered into the study at 13 investigative sites in Germany, Spain, United Kingdom, Italy, Efficacy and Safety Evaluations and Portugal between July 2001 and September 2002. Two Baseline tumor measurements (using computerized tomog- patients withdrew informed consent and six others failed to meet raphy, magnetic resonance imaging, and/or X-ray) were initial entry criteria. Although 83 patients were randomized to completed no more than 4 weeks before treatment. Within 2 either PemOx (42 patients) or PemCb (41 patients), 3 (PemOx 1 weeks before treatment and throughout the study, patients were and PemCb 2) were assigned inadvertently because they did not evaluated by complete medical and neurologic exams and meet eligibility criteria. Eighty patients (PemOx 41, PemCb 39) Eastern Cooperative Oncology Group performance status were treated and Table 1 summarizes the baseline patient assessment. Vitamin deficiency markers (homocysteine, cysta- characteristics for this group. thionine, methylmalonic acid, and methylcitrate) were deter- Treatment Administration mined 1 to 2 weeks before enrollment. All measurable and A total of 382 chemotherapy cycles, 191 per treatment evaluable lesions were assessed throughout the study using the group, were delivered. The median number of cycles delivered same techniques that were used at baseline. was 6 for both PemOx (range, 1-8 cycles) and PemCb (range, 1-7 Enrolled patients who met all of the following criteria cycles). Dose reductions occurred in five (2.6%) PemOx cycles qualified for efficacy analysis: (a) histologic or cytologic and seven (3.7%) PemCb cycles. The majority of PemOx dose confirmation of locally advanced or metastatic NSCLC that reductions (occurring in 3 of 5 cycles) were related to fatigue. In was not amenable to curative therapy, (b) presence of bidimen- four PemCb cycles, dose reductions were due to thrombocyto- sionally measurable disease, (c) no prior or concurrent penia. There were 15 clinically relevant cycle delays (PemOx, 8; chemotherapy, and (d) received at least one cycle of study PemCb, 7), but these interruptions were not linked to a single type therapy. Tumor assessments were repeated every other cycle of toxicity for either treatment group. throughout the study using the Southwest Oncology Group Patients treated with PemCb received 93.7% of the intended standard response criteria (34). The now widely used response weekly mean dose of pemetrexed (166.7 mg/m2) and 103.3% of evaluation criteria in solid tumors method (35) was not widely the planned weekly dose of carboplatin (AUC2). The latter implemented in clinical investigations at the time of trial elevation was due to errors associated with calculation of AUC initiation. Documented tumor responses required confirmation or creatinine clearance. Patients treated with PemOx received with a second assessment 3 to 4 weeks (minimum of 21 days) 95.3% and 100% of the planned weekly mean doses of after the first documentation of response. pemetrexed and oxaliplatin (40 mg/m2), respectively.

Table 1 Baseline patient demographics and disease characteristics was 5.5 months for PemOx (95% CI, 4.5-6.7 months) and 5.7 PemOx arm PemCb arm All months for PemCb (95% CI, 4.2-8.3 months; Fig. 2). The mean No. patients treated 41 39 80 days elapsed between randomization and treatment was 3.3 for Median age (range), y 60 (36-75) 60 (39-79) 60 (36-79) PemOx (range, 1-14) and 3.6 for PemCb (range, 1-22). Median Gender, follow-up times were 9.3 months for PemOx patients and 10.3 Male 28 (68.3) 32 (82.1) 60 (75.0) months for PemCb patients. Female 13 (31.7) 7 (17.9) 20 (25.0) ECOG PS* Quality of Life Analysis 0 14 (34.1) 11 (28.2) 25 (31.3) 1 26 (63.4) 28 (71.8) 54 (67.5) Patient compliance for completion of the lung cancer 2y 1 (2.4) 0 1 (1.3) symptom scale was high for both treatment groups with Histological subtype* 96.9% (185 of 191 expected questionnaires) in PemOx and Adenocarcinoma 24 (58.5) 16 (41.0) 40 (50.0) 92.1% (176 of 191 expected questionnaires) in PemCb. Sixty Squamous cell 11 (26.8) 12 (30.8) 23 (28.8) percent of PemOx patients and 59.4% of PemCb patients had Other 6 (14.6) 10 (25.6)y 16 (20.0)yy Stage* either improved or stable ASBI (Table 3). Changes in the IIIb, no pleural effusion 12 (29.3) 12 (30.8) 24 (30.0) ASBI were not conclusive for 12 patients (PemOx 8 and IIIb, pleural effusion 2 (4.9) 3 (7.7) 5 (10.0) PemCb 4) because these individuals showed inconsistent IV 27 (65.9) 24 (61.5) 51 (63.8) changes (either in magnitude or direction) in ASBI. Most Baseline homocysteine* V12 Amol/L 30 (73.2) 28 (71.8) 58 (72.5) patients who showed improvement in ASBI also had z12 Amol/L 11 (26.8) 11 (28.2) 22 (27.5) improvement in two or more symptoms (26 of 28 total patients), with dyspnea and anorexia improving more Abbreviation: ECOG PS, Eastern Cooperative Oncology Group performance status. frequently than other symptoms. *Values expressed as n (%). yOne patient with ECOG PS 2 was enrolled and treated in error. Toxicity yyHistology not done for one patient in the PemCb arm. The majority of common toxicity criteria grade 3 or 4 toxicities were hematologic (Table 4). Neutropenia was the most prevalent toxicity, occurring in 7.3% of PemOx patients and 25.6% of PemCb patients. Three patients (PemOx, 2.4%; Response PemCb, 5.1%) experienced febrile neutropenia. Thrombocyto- One patient in the PemCb arm did not qualify for efficacy penia was reported among 2.4% of PemOx patients and 17.9% evaluation because histology was not determined. Of the 79 of PemCb patients. The most common grade 3 or 4 patients evaluable for tumor response, 60 (75.9%) achieved either nonhematologic toxicities were vomiting among PemOx complete response, partial response, or stable disease (Table 2). patients (7.3%) and fatigue among PemCb patients (7.7%). Objective tumor response rates were similar for PemOx and One patient treated with PemOx experienced a grade 4 PemCb. Eleven patients (26.8%; 95% CI, 14.2-42.9) responded infection (without neutropenia). Seventy-three percent of (1 complete response, 10 partial responses) in the PemOx arm PemOx patients and 15% of PemCb patients experienced some and 12 patients (31.6%; 95% CI, 17.5-48.7) responded (all form of neurotoxicity (grade 1 to 3). Severe neurosensory partial responses) in the PemCb arm. The best overall response toxicity occurred only in PemOx patients, with one patient assessment was classified as unknown for 10 patients (Table 2). experiencing a grade 3 event and seven patients (17.1%) Seven of these patients (PemOx, 2; PemCb, 5) discontinued experiencing grade 2 events. One patient experienced acute treatment after one or two cycles, due to patient decision, adverse oxaliplatin-induced dysesthesia (grade 1) 3 hours after event or death, therefore, the best overall response could not be receiving the oxaliplatin injection, associated with sweating, determined. Three patients (PemOx, 1; PemCb, 2) completed shortness of breath, muscle spasm, and facial reddening. Seven therapy but Southwest Oncology Group best response could not patients (PemOx 3 and PemCb 4) died during the treatment be determined because some evaluable lesions assessed at phase of the study. One of these deaths (PemOx arm) was baseline were not assessed in later visits. Measurable lesions associated with grade 4 febrile neutropenia and was possibly were assessed appropriately for all three patients. Evaluation of related to study drug. measurable lesion data only, suggests that two of these patients (1 PemOx and 1 PemCb) likely responded to chemotherapy (>50% decrease in the sum of the products of the diameters of Table 2 Best overall response measurable lesions) and one patient had stable disease (PemCb). PemOx arm (N = 41), PemCb arm (N = 38*), Time-to-Event Measures Tumor response no. patients (%) no. patients (%) At the time of analysis, 15 of 41 patients (36.6%) in the Objective response 11 (26.8) 12 (31.6) PemOx arm and 12 of 38 patients (31.6%) in the PemCb arm (95% CI, 14.2-42.9) (95% CI, 17.5-48.7) were alive. The censoring rate for TTP was 7.3% for PemOx (3 Complete response 1 (2.4) 0 (0) Partial response 10 (24.4) 12 (31.6) of 41) and 7.9% for PemCb (3 of 38). Median overall survival Stable disease 20 (48.8) 17 (44.7) times were 10.5 months (Fig. 1) for both treatment groups Progressive disease 7 (17.1) 2 (5.3) (PemOx 95% CI, 7.7-15.3 months; PemCb 95% CI, 7.6-12.8 Unknown 3 (7.3) 7 (18.4) months), with a range of <1 to >20 months. The 1-year survival *One patient in the PemCb arm did not have histology performed at rate was 49.9% for PemOx and 43.9% for PemCb. Median TTP baseline and was excluded from efficacy analyses.

DISCUSSION In advanced or metastatic NSCLC, cytotoxic chemotherapy seems to have reached an efficacy plateau and third- generation platinum-based doublets represent the standard of care with response rates of 17% to 32% and 1-year survival rates of 30% to 45% (2–5). Although platinum-based therapies modestly improve survival and palliate some tumor-related symptoms in patients with locally advanced or metastatic NSCLC, at times the chemotherapy-related toxic side effects outweigh the benefits. Consequently, a practical short-term goal is to identify new regimens that maintain the same level of efficacy as cisplatin-based combinations but offer a better toxicity profile. This multicenter noncomparative randomized phase II trial showed encouraging results for both pemetrexed-based regi- Fig. 2 Kaplan-Meier distribution of time to progressive disease by mens (pemetrexed 500 mg/m2 plus either oxaliplatin 120 mg/ treatment group. m2 or carboplatin AUC6). Objective response rates were 26.8% for PemOx patients and 31.6% for PemCb patients. These comprehensive clinical investigations, objective response rates results are comparable to the preliminary results reported by range from 17% to 32%, MSTs ranged from 7.4 to 11.3 months Zinner et al. (38) who showed an objective response rate of and median TTPs (or median progression-free survival) ranged 29% for stage IIIb/IV NSCLC patients receiving pemetrexed from 3.1 to 5.5 months. and carboplatin. The MST (10.5 months for both arms) and The incidence of serious hematologic and nonhemato- median time to progressive disease reported in this study logic toxicities reported in the present study was very low (5.5.months for PemOx and 5.7 months for PemCb) compare compared with other platinum-based combinations (2–5). favorably with results of recent phase II trials of new drug Grade 3 or 4 neutropenia, the most common toxicity, occurred combinations (39, 40). Gemcitabine in combination with in only 7.3% of PemOx patients and 25.6% of PemCb docetaxel, irinotecan (39), or paclitaxel (40) has produced patients. In Eastern Cooperative Oncology Group 1594, 63% overall response rates ranging from 12.8% to 33.9% and MSTs to 75% of patients treated with a platinum-based regimen ranging from 8 to 12.8 months. Rocha Lima et al. (39) reported experienced grade 3or 4 neutropenia (2). In studies conducted median failure-free survival times of 3.5 months for gemcita- by the Italian Lung Cancer Project (4) and the TAX 326 study bine/irinotecan and 4.5 months for gemcitabine/docetaxel. A group (5) the incidence of severe neutropenia (grade 3 or 4) phase I evaluation of oxaliplatin plus vinorelbine in 28 ranged from 38% to 79% in patients receiving platinum-based chemonaive NSCLC patients showed an objective response combinations. In the present study, nonhematologic toxicities rate of 35%, a MST of 9.8 months, and median progression- were generally rare, with the most common events being free survival time of 5 months (41). grade 3 vomiting (7.3% of PemOx patients) and grade 3 Although it is difficult to compare efficacy results between fatigue (7.7% of PemCb patients). Neurosensory toxicity was phase II and phase III studies, it is notable that the objective prevalent among PemOx patients but generally mild or response rates, MST, and median TTP for both PemOx and moderate (grade V2). PemCb were comparable with the values reported in four large, In conclusion, combining pemetrexed with either oxaliplatin randomized phase III studies evaluating platinum-based doublets or carboplatin is safe and effective for the first-line treatment of (paclitaxel and cisplatin, gemcitabine and cisplatin, docetaxel locally advanced or metastatic NSCLC. Both regimens seem to and cisplatin, paclitaxel and carboplatin, vinorelbine and provide a favorable risk-benefit profile and may represent a cisplatin, and docetaxel and carboplatin; refs. 2–5). In these promising alternative for treating advanced or metastatic NSCLC. Comparing either of these two regimens, or perhaps pemetrexed plus cisplatin, to standard platinum-based therapies in a large randomized trial, is warranted.

Table 3 Change in average symptom burden index of patient LCSS PemOx arm (N = 35), PemCb arm (N = 32), no. patients (%) no. patients (%) Improved 14 (40.0) 14 (43.8) Worsened 6 (17.1) 9 (28.1) Stable 7 (20.0) 5 (15.6) NC* 8 (22.9) 4 (12.5) Abbreviations: LCSS, lung cancer symptom scale; NC, not conclusive. Fig. 1 Kaplan-Meier distribution of overall survival by treatment *Magnitude of change and/or direction of change was not group. consistent.

Table 4 Selected NCI-CTC grade 3 and 4 toxicities 9. Hanauske A-R, Chen V,Paoletti P, Niyikiza C. Pemetrexed disodium: a novel anti-folate clinically active against multiple solid tumors. Oncologist Toxicity Pemetrexed + Pemetrexed + 2001;6:363–73. Oxaliplatin (N = 41) Carboplatin (N = 39) 10. Goldman DI, Zhao R. Molecular, biochemical, and cellular Grade 3 Grade 4 Grade 3 Grade 4 pharmacology of pemetrexed. Semin Oncol 2002;29:3–17. Hematologic, n (%) 11. Scagliotti GV, Shin DM, Kindler HL, et al. Phase II study of Neutropenia 2 (4.9) 1 (2.4) 6 (15.4) 4 (10.3) pemetrexed with and without folic acid and vitamin B12 as front-line Thrombocytopenia 1 (2.4) 0 6 (15.4) 1 (2.6) therapy in malignant pleural mesothelioma. J Clin Oncol 2003;21: Anemia 1 (2.4) 0 3 (7.7) 0 1556–61. Nonhematologic, n (%) 12. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of Fatigue 0 0 3 (7.7) 0 pemetrexed in combination with cisplatin versus cisplatin alone in Stomatitis 0 0 1 (2.6) 0 patients with malignant pleural mesothelioma. J Clin Oncol 2003;21: Vomiting 3 (7.3) 0 0 0 2636–44. Neuropathy 1 (2.4) 0 0 0 13. Niyikiza C, Baker SD, Seitz DE, et al. Homocysteine and (sensory) methylmalonic acid: markers to predict and avoid toxicity from Diarrhea 1 (2.4) 0 0 0 pemetrexed therapy. Mol Cancer Ther 2002;1:545–52. Dizziness 1 (2.4) 0 0 0 14. Bunn P, Paoletti P, Niyikiza C, et al. Vitamin B12 and folate reduce Infection without 0 0 0 1 (2.6) toxicity of ALIMTA (pemetrexed disodium, LY231514, MTA) a novel neutropenia antifolate/antimetabolite [abstract 300]. Proc Amer Soc Clin Oncol Febrile neutropenia 0 1 (2.4) 1 (2.6) 1 (2.6) 2001;20:76a. NOTE. Worst toxicity by patient and numbers of patients in 15. Vogelzang NJ, Emri S, Boyer MJ, et al. Effect of folic acid and designated treatment groups. vitamin B12 supplementation on risk-benefit ratio from phase III study of Abbreviation: NCI-CTC, National Cancer Institute Common pemetrexed + cisplatin versus cisplatin in malignant pleural Toxicity Criteria, version 2. mesothelioma [abstract 2644]. Proc Amer Soc Clin Oncol 2003;22:657. 16. Rusthoven J, Eisenhauer E, Butts C, et al. Multitargeted antifolate, LY231514, as first-line chemotherapy for patients with advanced non- small-cell lung cancer: a phase II study. J Clin Oncol 1999;17: 1194–9. ACKNOWLEDGMENTS 17. Clarke SJ, Abratt R, Goedhals L, Boyer MJ, Millward MJ, We thank David Readett, MD for critical review of study design and Ackland SP. Phase II trial of pemetrexed disodium (ALIMTA, study guidance; the physicians Barbara Parente, Maria-Eulalia Semedo, LY231514) in chemotherapy-naive patients with advanced non-small- Ana C. Duarte, and Jose Miguel Sanchez for assistance with patient care; cell lung cancer. Ann Oncol 2002;13:737–41. and Shafali Pillay, Bernard Tchoula, MS, Takashi Nakamura, Astra 18. Manegold C, VonPawel J, Pirker R, Malayeri R, Blatter J, Liepa, PhrmD, Linda Pfeiffer, Sheila Swain, Sue Sutton, PhD, Noelle Krejcy K. Front-line treatment of advanced non-small cell lung cancer Gasco, Donna L. Miller, and Dr. Teresa Moran who contributed by way with MTA and cisplatin: a multicenter phase II trial. Ann Oncol 2000; of study coordination, data management, statistical analysis, scientific 11:435–40. writing collaboration, and article preparation. 19. Shepherd FA, Dancey J, Arnold A, et al. Phase II study of pemetrexed disodium, a multitargeted antifolate, and cisplatin as first-line therapy in patients with advanced non-small cell lung carcinoma. Cancer REFERENCES 2001;92:595–600. 1. Van Houtte P, McDonald S, Yuang-Chi Chang A, Salazar OM. Lung 20. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III cancer. 8th ed. In: Rubin P, Williams JP, editors. Clinical oncology: a trial of pemetrexed versus docetaxel in patients with non-small cell lung multidisciplinary approach for physicians and students. Philadelphia, PA: cancer previously treated with chemotherapy. J Clin Oncol 2004; WB Saunders Company; 2001. p. 823–43. 22:1589–97. 2. Schiller JH, Harrington D, Belani CP, et al. Comparison of four 21. Becouarn Y, Ychou M, Ducreux M, et al. Phase II trial of oxaliplatin chemotherapy regimens for advanced non-small-cell lung cancer. N Engl as first-line chemotherapy in metastatic colorectal cancer patients. J Med 2002;346:92–8. Digestive Group of French Federation of Cancer Centers. J Clin Oncol 1998;16:2739–44. 3. Kelly K, Crowley J, Bunn PA Jr, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the 22. Diaz-Rubio B, Sastre J, Zaniboni A, et al. Oxaliplatin as single agent treatment of patients with advanced non-small-cell lung cancer: a in previously untreated colorectal carcinoma patients: a phase II Southwest Oncology Group trial. J Clin Oncol 2001;19:3210–8. multicentre study. Ann Oncol 1998;9:105–8. 4. Scagliotti G, De Marinis F, Rinaldi M, et al. Phase III randomized trial 23. Raymond E, Chaney S, Taamma A, Cvitkovic E. Oxaliplatin: a comparing three platinum-based doublets in advanced non-small-cell review of preclinical and clinical studies. Ann Oncol 1998;9:1053–71. lung cancer. J Clin Oncol 2002;20:4285–91. 24. Zatloukal P, Petruzelka L, Zemanova M, et al. Gemcitabine plus 5. Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV non-small phase III study of docetaxel plus platinum combinations versus cell lung cancer: a phase III randomized trial. Lung Cancer vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the 2003;41:321–31. TAX 326 study group. J Clin Oncol 2003;21:3016–24. 25. Rosell R, Gatzemeier U, Betticher DC, et al. Phase III randomized 6. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients non-small cell lung cancer: a meta-analysis using updated data on with advanced non-small-cell lung cancer: a cooperative multinational individual patients from 52 randomized clinical trials. Br Med J trial. Ann Oncol 2002;13:1539–49. 1995;311:899–909. 26. Misset JL, Gamelin E, Campone M, et al. Phase I and 7. Taylor EC, Patel HH. Synthesis of pyrazolo(3,4,-d)pyrimidine pharmacokinetic study of the multitargeted antifolate pemetrexed in analogues of the potent antitumor agent n-{4-(2-(2-amino-4(3h)- combination with oxaliplatin in patients with advanced solid tumors. Ann oxo-7h-pyrrolo(2,3-d)pyrimidin-5-yl)ethyl)benzoyl}-l-glutamic acid Oncol 2004;15:1123–9. (LY231514). Tetrahedron Letters 1992;48:8089–100. 27. Hughes AW, Calvert P, Azzabi A, et al. A phase I clinical and 8. Adjei AA. Pemetrexed (ALIMTA): a novel multitargeted antifolate pharmacokinetic study of pemetrexed and carboplatin in patients with agent. Expert Rev Anticancer Ther 2003;3:145–56. malignant pleural mesothelioma. J Clin Oncol 2002;20:3533–44.

28. Simon R. Optimal two-stage designs for phase II clinical trials. Institute of the United States, National Cancer Institute of Canada. Control Clin Trials 1989;10:1–10. J Natl Cancer Inst 2000;92:205–16. 29. Pocock SJ, Simon R. Sequential treatment assignment with 36. Hollen PJ, Gralla RJ, Kris MG, et al. Measurement of quality of life balancing for prognostic factors in the controlled clinical trial. Biometrics in patients with lung cancer in multicenter trials of new therapies, 1975;31:103–15. psychometric assessment of the lung cancer symptom scale. Cancer 30. Kaplan EL, Meier P. Nonparametric estimation of incomplete 1994;73:2087–98. observations. JASA 1958;53:457–81. 37. National Cancer Institute. Investigator’s handbook: a manual for 31. Brookmeyer R, Crowley J. A confidence interval for the median participants in clinical trials of investigational agents sponsored by the survival time. Biometrics 1982;38:29–41. Division of Cancer Treatment National Cancer Institute. [accessed 32. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: February 13, 2004]. Available from: http://ctep.info.nih. gov/handbook. prospective evaluation of a simple formula based on renal function. J Clin 38. Zinner RG, Obasaju CK, Fossella FV, et al. A phase II trial of Oncol 1989;11:1748–56. ALIMTA plus carboplatin (AC) in patients (pts) with advanced non-small- 33. Shargel L, Yu ABC. Dosage adjustment in renal disease. 2nd ed. cell lung cancer (NSCLC) [abstract P-522]. Lung Cancer 2003;41:S223. In: Shargel L, Yu ABC, editors. Applied biopharmaceutics and 39. Rocha Lima CM, Rizvi NA, Zhang C, et al. Randomized phase II pharmacokinetics. Norwalk (CT): Appleton-Century-Crofts; 1985. trial of gemcitabine plus irinotecan or docetaxel in stage IIIB or stage IV p. 305–30. NSCLC. Ann Oncol 2004;15:410–8. 34. Green S, Weiss GR. Southwest oncology group standard response 40. Isla D, Rosell R, Sa´nchez JJ, et al. Phase II trial of paclitaxel plus criteria, endpoint definitions and toxicity criteria. Invest New Drugs gemcitabine in patients with locally advanced metastatic non-small-cell 1992;10:239–53. lung cancer. J Clin Oncol 2001;19:1071–7. 35. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to 41. Monnet I, de Cremoux H, Soulie´ P, et al. Oxaliplatin plus evaluate the response to treatment in solid tumors. European vinorelbine in advanced non-small-cell lung cancer: final results of a Organization for Research and Treatment of Cancer, National Cancer multicenter phase II study. Ann Oncol 2002;13:103–7.

Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2005 American Association for Cancer Research. Pemetrexed Combined with Oxaliplatin or Carboplatin as First-Line Treatment in Advanced Non−Small Cell Lung Cancer: A Multicenter, Randomized, Phase II Trial

Giorgio V. Scagliotti, Cornelius Kortsik, Graham G. Dark, et al.

Clin Cancer Res 2005;11:690-696.

Updated version Access the most recent version of this article at: http://clincancerres.aacrjournals.org/content/11/2/690

Cited articles This article cites 38 articles, 13 of which you can access for free at: http://clincancerres.aacrjournals.org/content/11/2/690.full#ref-list-1

Citing articles This article has been cited by 11 HighWire-hosted articles. Access the articles at: http://clincancerres.aacrjournals.org/content/11/2/690.full#related-urls

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/11/2/690. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.