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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1465-1471 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.7611
Phase II Trial of Pemetrexed and Gemcitabine in Chemotherapy-Naïve Malignant Pleural Mesothelioma
From the Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital; Massachusetts General Hospital, Boston, MA; H. Lee Moffitt Cancer Center, Tampa, FL; Fox Chase Cancer Center, Philadelphia, PA; Columbia University, New York, NY; University of Colorado Health Sciences Center, Denver, CO; Eli Lilly & Co, Indianapolis, IN; and the University of Chicago Medical Center, Chicago, IL Corresponding author: Pasi A. Jänne, MD, PhD, Dana Farber Cancer Institute, Lowe Center for Thoracic Oncology, 44 Binney St, Dana D820A, Boston, MA 02115; e-mail: pjanne{at}partners.org
Purpose Pemetrexed and gemcitabine have single-agent activity in malignant pleural mesothelioma (MPM). The combination of pemetrexed/gemcitabine has not previously been studied in MPM to our knowledge. Patients and Methods Patients with histologic or cytologic diagnosis of MPM were included. Cohort 1 received gemcitabine 1,250 mg/m2 on days 1 and 8, with pemetrexed 500 mg/m2 on day 8, and cohort 2 received gemcitabine 1,250 mg/m2 on days 1 and 8, with pemetrexed 500 mg/m2 on day 1. Cycles were repeated every 21 days; all patients were supplemented with folic acid and vitamin B12 and received dexamethasone. Results One hundred eight patients (cohort 1, n = 56; cohort 2, n = 52) with pleural mesothelioma were enrolled. Among assessable patients, response rate was 26.0% in cohort 1 and 17.1% in cohort 2. Median time to disease progression was 4.34 months for cohort 1 and 7.43 months for cohort 2. Median survival was 8.08 months for cohort 1 (1-year survival = 31.14%) and 10.12 months for cohort 2 (1-year survival = 45.80%). In cohorts 1 and 2, incidence of grade 4 neutropenia was 25.0% and 29.4%, grade 4 thrombocytopenia was 14.3% and 3.9%, grade 3 or 4 anemia was 5.4% and 5.9%, and grade 3 or 4 fatigue was 23.2% and 15.7%, respectively. Conclusion The combination of pemetrexed and gemcitabine resulted in moderate clinical activity in MPM. However, the median survival times are similar to those with single-agent pemetrexed and inferior to outcomes observed with cisplatin in combination with an antifolate.
Malignant pleural mesothelioma (MPM) is a rare, locally aggressive disease of poor prognosis with increasing incidence worldwide, especially in industrialized nations.1-4 Mesothelioma of the pleura accounts for up to 80% of mesothelioma cases by site,5 and as a result of diffuse thoracic involvement, MPM is not amenable to independent treatment modalities. Surgical resection with curative intent is rarely feasible,6 and radiotherapy alone cannot target sufficient disease volumes without undue toxicity.7,8 For most patients with MPM, systemic chemotherapy remains the standard of care. However, most chemotherapeutic agents have demonstrated only modest activity in MPM.9 Platinum-based combination chemotherapy is the standard of care for patients with MPM. Two randomized clinical trials have demonstrated a survival benefit for cisplatin combined with an antifolate (pemetrexed or raltitrexed) compared with cisplatin alone.10,11 Combinations using alternative platinum agents with antifolates (including carboplatin-pemetrexed12 and oxaliplatin/raltitrexed13) have also demonstrated activity in phase II clinical trials. Combinations of gemcitabine with either cisplatin,14 oxaliplatin,15 or carboplatin16 have resulted in response rates between 20% and 40%. Chemotherapy treatments employing a platinum agent tend to be associated with a greater degree of toxicity compared with non–platinum-based treatments.17 This is a particular concern especially in the treatment of mesothelioma, where the median age of disease onset is 74 years.18 Analogous to investigations in non–small-cell lung cancer (NSCLC), there has been an interest in examining the utility of nonplatinum-based treatment combinations in MPM. To date, the available data on the use of such an approach is limited in mesothelioma.19 Phase II studies have explored the use of gemcitabine and irinotecan20 and gemcitabine and epirubicin.19 Gemcitabine and pemetrexed are chemotherapy agents that have both previously demonstrated modest single-agent activity (response rates of 0% to 31% with gemcitabine21-23 and 16% with pemetrexed24) in patients with MPM. The combination of pemetrexed and gemcitabine has been studied in preclinical and clinical models, and these studies suggest that the two agents might have synergistic antitumor activity in several tumor types.25-27 In prior studies, gemcitabine and pemetrexed have been administered in combination using different dosing schedules for pemetrexed.26,28 An initial phase I study suggested that this combination was better tolerated when gemcitabine was administered on days 1 and 8, and pemetrexed on day 8 of a 21-day cycle.26 However, in a subsequent randomized phase II trial, the schedule associated with the highest response rate was one in which pemetrexed was administered on day 1 and gemcitabine on days 1 and 8 of a 21-day cycle.28Because the combination of gemcitabine and pemetrexed had not previously been examined in MPM to our knowledge, we explored two different schedules (in separate cohorts) of gemcitabine and pemetrexed in a phase II study in chemotherapy-naïve patients with MPM.
Patient Eligibility Patients were required to have a histopathologic or cytologic diagnosis of MPM not amenable to curative treatment with surgery, measurable disease, age of at least18 years, life expectancy of at least 12 weeks, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. All pleural effusions were required to be controlled by drainage or other procedures before study entry. Patients were required to have adequate organ and bone marrow function including an estimated creatinine clearance of at leas 45 mL/min (using the modified Cockcroft and Gault formula29). Patients were staged using clinical and radiographic examinations and according to the International Mesothelioma Interest Group (IMIG) staging system.30 Exclusion criteria included prior systemic chemotherapy, known or suspected brain metastases, and prior radiation therapy to the target lesion. Pregnant women were not eligible, and all patients of reproductive potential were required to use an approved method of birth control. The institutional review board of each site of this trial approved the protocol before study initiation. This study was performed in compliance with the principles of good clinical practice (GCP), the Helsinki Declaration, and federal and institutional guidelines.
Study Design Treatment was repeated every 21 days for a total of six cycles or until progressive disease. Additional cycles of therapy were administered at the discretion of the investigator. Folic acid supplementation, vitamin B12, and dexamethasone were administered as described in Vogelzang et al.11
Dose Reductions
Study End Points
Statistical Considerations Survival and TTP were analyzed using Kaplan-Meier techniques.35 Two-sided 95% CIs for tumor response were calculated using exact binomial probabilities. Toxicity was summarized using descriptive statistics as coded using the modified Medical Dictionary for Regulatory Activities (MedDRA) version 7.0. All calculations were performed using SAS version 8.2 software (SAS Institute, Cary, NC).
Patient Characteristics Between December 2002 and March 2005, 108 patients with MPM were enrolled at 14 centers in the United States. All 56 patients who enrolled before the study amendment were assigned to cohort 1, and the 52 patients who enrolled subsequently were assigned to cohort 2. One patient who was assigned to cohort 2 withdrew before receiving any study drug and was excluded from the intent-to-treat (ITT) population. Because no random assignment occurred in this trial, baseline characteristics were not stratified between the two cohorts. Nonetheless, the characteristics of the two cohort populations were similar (Table 1). The majority of patients in both cohorts were male and white and had epithelial MPM, and a similar percentage of patients in both cohorts received prior radiotherapy. Notably, patients in both cohorts were older, with median ages of 69.0 and 71.0 years, respectively, for cohorts 1 and 2.
Study Drug Administration and Toxicity Treatment administration is summarized in Table 2. Patients in cohort 1 received more treatment cycles (median, 4.0 cycles; 37.5% received at least six cycles of treatment) than patients in cohort 2 (median, 3.0; 25.5% received at least six cycles of treatment). More patients in cohort 2 (60.8%) required dose reductions, with 17 (33%) of 51 patients requiring two or more dose reductions. The delivered dose-intensity of both treatments was greater in cohort 1 than in cohort 2, and the delivered dose-intensity of pemetrexed was greater for pemetrexed than gemcitabine in both cohorts.
Hematologic and nonhematologic toxicities are summarized in Table 3. The most common grade 3 or 4 hematologic toxicity in both treatment groups was neutropenia, which had a rate of 42.9% in cohort 1 (grade 3, 17.9%; grade 4, 25.0%) and 52.9% in cohort 2 (grade 3, 23.5%; grade 4, 29.4%). Although rates were not statistically compared, grade 3 febrile neutropenia was greater in cohort 2 (13.7%) than in cohort 1 (3.6%), but grade 3 thrombocytopenia was greater in cohort 1 (10.7%) than in cohort 2 (3.9%). The most common grade 3 or 4 nonhematologic toxicities in both cohorts were fatigue, dyspnea, hyperglycemia, and pneumonia. These were similar in the two cohorts (Table 3). No treatment-related deaths occurred during this study.
Efficacy Sixteen patients did not undergo response assessment (and were not considered efficacy assessable for tumor response) because of either progressive disease (n = 5), adverse event leading to removal from study (n = 4), patient/physician decision to end therapy (n = 6) or not receiving any study therapy (n = 1). Ninety-two patients completed at least two cycles of therapy and were eligible for response assessments. Response was measured in 81 patients (46 patients in cohort 1 and 35 in cohort 2). Of the 11 patients with a measurement that was unknown or unavailable, five were a result of a patient's decision to discontinue the study, four because protocol entry criteria were not met, and two were early discontinuation for an unspecified reason. Response is summarized in Table 4.
Of the patients who were assessed for response, response rates were 26.0% in cohort 1 and 17.1% in cohort 2. All observed responses were PRs. Of the 18 patients in the two cohorts who had a response, 14 had epithelial histology (77.8%) and four had an ECOG PS of 0 (22.2%). As a percentage of the ITT population, response rates were 21.4% for cohort 1 and 11.8% for cohort 2. Median duration of response was 6.0 months (95% CI, 3.25 to 8.15) in cohort 1 and 6.5 months (95% CI, 2.86 to not assessable [NA]) in cohort 2. In cohort 1, 50.0% of patients had SD, whereas in cohort 2, 68.6% of patients had SD. The median duration of SD was 4.7 months in cohort 1 and 7.4 months in cohort 2. TTP and survival for the ITT (n = 108) populations of both cohorts are shown in Figures 1 and 2, respectively. The median follow-up times were 6.0 and 7.2 months in cohort 1 and 2, respectively. Median TTP was 4.34 months for cohort 1 (95% CI, 3.19 to 6.01; 21.43% censored) and 7.43 months for cohort 2 (95% CI, 3.52 to 10.84; 48.08% censored). At 1 year, the percentage of patients without PD was 9.22% (95% CI, 0.00 to 18.90) in cohort 1 and 27.38% (95% CI, 9.08 to 45.67) in cohort 2. Median survival was 8.08 months for cohort 1 (95% CI, 5.52 to 10.18; 19.64% censored) and 10.12 months for cohort 2 (95% CI, 7.92 to 15.51; 38.46% censored). One-year survival was 31.14% (95% CI, 18.52 to 43.77) in cohort 1 and 45.80% (95% CI, 30.16 to 61.34) in cohort 2.
Each cohort was further stratified by age ± the cohort median age for efficacy parameters. In cohort 1, patients younger than the median age had a median TTP of 4.34 months (95% CI, 3.19 to 10.61) compared with 4.17 months (95% CI, 2.00 to 6.01) among patients older than the median. In cohort 2, patients younger than the median age had a median TTP of 4.40 months (95% CI, 3.25 to 10.84) compared with 10.61 months (95% CI, 3.48 to NA) among patients older than the median. With respect to survival, in cohort 1, patients younger than the median had a median survival of 9.07 months (95% CI, 6.57 to 25.72) compared with 5.82 months (95% CI, 4.57 to 10.09) among patients older than the median. In cohort 2, patients younger than the median age had a median survival of 14.52 months (95% CI, 9.86 to 25.56) compared with 7.29 months (95% CI, 3.35 to 12.52) among patients older than the median age.
Combination chemotherapy with cisplatin and an antifolate agent (pemetrexed or raltitrexed) is the standard of care for patients with MPM. Phase III trials of both combinations have demonstrated a survival advantage compared with single-agent cisplatin.10,11 However, as the population of mesothelioma patients ages, less toxic therapies should be considered given the adverse effects (nausea/vomiting, neurologic and renal impairment) associated with cisplatin. One approach would be to substitute cisplatin with carboplatin. A phase II trial of carboplatin/pemetrexed demonstrated a response rate of 18.6%, a median TTP of 6.5 months, and survival of 12.7 months.12 This combination was also associated with a low incidence of grade 3 or 4 nonhematologic toxicity. An alternative approach would be to substitute a nonplatinum partner agent for cisplatin in combination with an antifolate, as was done in the current trial. Our trial is the largest to our knowledge to date to examine a non–platinum-based chemotherapy combination in MPM. We evaluated two different dosing schedules on the basis of preclinical and clinical studies that tested both sequences in several tumor types, including NSCLC.25-27 Among assessable patients, cohort 1 and cohort 2 produced response rates of 26.0% and 17.1%, respectively. These are lower than the 41.3% response rate reported in the phase III study of cisplatin/pemetrexed11 and are not much greater than the 14.5% response rate reported in a previous phase II study of single-agent pemetrexed.24 Furthermore, the median survivals (8.1 and 10.1 months in cohorts 1 and 2, respectively) are numerically inferior to those previously observed with single-agent pemetrexed (10.7 months)24 or the combination of carboplatin/pemetrexed (12.7 months).12 In addition, the combination of gemcitabine and pemetrexed was associated with significant hematologic toxicity, including development of grade 3 or 4 neutropenia in more than 50% of patients in cohort 2 and development of grade 3 or 4 febrile neutropenia in 15.7% (Table 3). Previous studies in MPM suggest that epithelial subtype, younger age, and earlier stage of disease may be important prognostic factors for improved outcome.36-39 In this respect, there are some differences in this study compared with prior combination chemotherapy trials. Most notably, the median age of patients in this trial was almost a decade greater (69.0 and 71.0 years in cohorts 1 and 2, respectively) compared with the phase III cisplatin/pemetrexed (61.0 years) and cisplatin/raltitrexed (59.0 years) trials.10,11 This could account for some of the toxicity findings in the current study. Although not intended or specified that this study was intended for elderly patients, it is possible that investigators preferentially enrolled older patients onto this study because the treatment regimen did not contain a platinum agent. In addition, in both treatment arms of the phase III trial by Vogelzang et al,11 a majority of patients had stage I to III disease. In comparison, most patients in the current study had stage IV disease (including 71.4% in cohort 1 and 57.7% in cohort 2). Differences in the results observed between treatment cohorts in this study may be explained by differences in the way the drugs were sequenced, in baseline characteristics at study entry, and in the challenges of accurate response assessment in mesothelioma. A randomized phase II trial by Ma et al indicated that, of three sequences, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8 was preferred in NSCLC.28 Although that study employed a 90-minute delay between drugs (not used in the current study), the preferred sequence was followed in cohort 2 of the current study. In the current study, cohort 1 had higher dose-intensity than cohort 2, which might explain the higher toxicity seen in cohort 1. Cohort 2 had a higher disease control rate (PR + SD) despite the higher dose-intensity in cohort 1. Also, cohort 1 included a greater proportion of patients with epithelial diagnosis compared with cohort 2; however, a greater percentage of patients in cohort 1 had stage IV disease. The mixed results when comparing specific outcomes between the two cohorts may be a result of the imbalances in certain characteristics at baseline. Non–platinum-based combination chemotherapy regimes for MPM have previously been evaluated only in small phase II trials. Portalone et al19 examined the combination of epirubicin and gemcitabine followed by interleukin-2 maintenance in 28 chemotherapy-naïve patients. They observed a response rate of 14.3%, a median TTP of 30 weeks, and a median survival of 55 weeks. Given this and findings from the current study, unlike in NSCLC, non–platinum-based chemotherapy combinations appear to be inferior to platinum-based chemotherapy combinations in MPM. Although direct comparisons between the current and prior studies is difficult because of differences in patient populations and response assessments, the median survivals in the two cohorts of the current phase II study (8.1 and 10.1 months in cohorts 1 and 2, respectively) are not compelling enough to pursue this combination further in MPM.10-12 For appropriate patients, combination platinum-based chemotherapy remains the standard of care. For those unable to tolerate a platinum-based chemotherapy combination, single-agent pemetrexed should be considered as an alternative therapy.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Matthew Monberg, Eli Lilly & Co (C); Coleman Obasaju, Eli Lilly & Co (C) Consultant or Advisory Role: Pasi A. Jänne, Eli Lilly & Co (C); George R. Simon, Eli Lilly & Co (C); Corey J. Langer, Eli Lilly & Co (C) Stock Ownership: Matthew Monberg, Eli Lilly & Co; Coleman Obasaju, Eli Lilly & Co Honoraria: George R. Simon, Eli Lilly & Co; Panos Fidias, Eli Lilly & Co Research Funding: George R. Simon, Eli Lilly & Co; Corey J. Langer, Eli Lilly & Co; Hedy Kindler, Eli Lilly & Co Expert Testimony: None Other Remuneration: None
Conception and design: Coleman Obasaju Financial support: Matthew Monberg, Coleman Obasaju Administrative support: Matthew Monberg Provision of study materials or patients: Pasi A. Jänne, George R. Simon, Corey J. Langer, Robert N. Taub, Afshin Dowlati, Panos Fidias, Hedy Kindler Collection and assembly of data: Pasi A. Jänne, George R. Simon, Corey J. Langer, Robert N. Taub, Afshin Dowlati, Panos Fidias, Hedy Kindler Data analysis and interpretation: Pasi A. Jänne, Matthew Monberg, Coleman Obasaju Manuscript writing: Pasi A. Jänne, George R. Simon, Corey J. Langer, Robert N. Taub, Afshin Dowlati, Panos Fidias, Matthew Monberg, Coleman Obasaju, Hedy Kindler Final approval of manuscript: Pasi A. Jänne, George R. Simon, Corey J. Langer, Robert N. Taub, Afshin Dowlati, Panos Fidias, Matthew Monberg, Coleman Obasaju, Hedy Kindler
We thank the following investigators for their contribution to this study: Shirish Gadgeel, MD, Karmanos Institute, Wayne State University; Chandra Belani, MD, University of Pittsburgh Cancer Institute; Petr Hausner, MD, Greenebaum Cancer Center; Claire F. Verschraegen, MD, University of New Mexico Cancer Center; Gregory Kalemkerian, MD, University of Michigan Medical Center; and Anne Traynor, MD, University of Wisconsin Cancer Center.
Sponsored by Eli Lilly & Co. Part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA; and the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
level of .05, the probability of stopping early after stage one was at least 48.0% if the true response rate was no more than 15% (H0), and no greater than 2.4% if the true response rate was as high as 35% (HA). The overall probabilities of type I and type II errors were .021 and .105, respectively. Because this study was not randomized, we avoided direct statistical comparisons of treatment cohorts. 
