Activity of pemetrexed in thoracic malignancies Results of phase III clinical studies of pemetrexed in malignant pleural mesothelioma and non-small cell lung cancer show benefit P emetrexed (Alimta) is an antifolate agent with activity in many tumor types. Its mechanism of action involves inhibition of several enzymes involved in nucleotide synthesis principally thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase thereby inhibiting the replication of tumor cells. Initial experience with the agent showed that it produced rates of hematologic and non-hematologic toxicities similar to those of other antifolate compounds and antimetabolites. Subsequently, it was shown that these toxicities could be markedly reduced through routine folic acid and vitamin B 12 supplementation without adversely affecting the efficacy of the agent. 1 Pemetrexed has recently been evaluated in phase III trials in the settings of malignant pleural mesothelioma and non-small cell lung cancer (NSCLC). lowed 2 hours later by cisplatin (75 mg/m² via a 2-hour infusion) or cisplatin alone on day 1 every 21 days. Folic acid and vitamin B 12 supplementation was not instituted until after 117 patients had been enrolled. Thereafter, patients randomized to receive pemetrexed therapy received folic acid (350 1,000 µg orally) each day, beginning 1 3 weeks before the first dose of pemetrexed and continuing throughout the study therapy, and vitamin B 12 (1,000 µg intramuscularly) 1 3 weeks before starting treatment with pemetrexed and every 9 weeks during treatment. To prevent skin rash, patients treated with pemetrexed were also given dexamethasone on the day before, the day of, and the day after treatment. Patients in the cisplatin-alone group received a saline infusion, vitamin supplementation, and dexamethasone to maintain patient blinding. Baseline characteristics The pemetrexed/cisplatin and cisplatin-alone treatment groups were well matched with regard to baseline characteristics: Median age was Pemetrexed/cisplatin versus cisplatin alone in mesothelioma In the mesothelioma trial, 2 the combination of pemetrexed and cisplatin was compared with cisplatin alone in 456 patients with malignant pleural mesothelioma who were chemotherapy naïve and ineligible for curative surgery. Patients were randomized to receive pemetrexed (500 mg/m² via a 10-minute infusion) fol- Summary by Matt Stenger, MS; reviewed by Ben Solomon, MBBS, PhD, and Paul A. Bunn, Jr., MD, University of Colorado Cancer Center, Denver, CO. FIGURE 1 Kaplan-Meier estimates of overall survival among patients with malignant pleural mesothelioma treated with pemetrexed and cisplatin versus cisplatin alone. Reproduced from Vogelzang et al 2 with permission from the American Society of Clinical Oncology. 2005 Elsevier Inc. All rights reserved. January/February 2005 COMMUNITY ONCOLOGY 21
Setting a new mesothelioma treatment standard Ben Solomon, MBBS, PhD, and Paul A. Bunn, Jr., MD University of Colorado Cancer Center, Denver NTIL RECENTLY, no proven systemic treatments existed for U patients with unresectable malignant pleural mesothelioma. The study by Vogelzang and colleagues described in this summary led in February 2004 to US Food and Drug Administration (FDA) approval of pemetrexed (Alimta) in combination with cisplatin for use in the treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are otherwise not candidates for curative surgery. This large, well-designed, randomized study represents the largest phase III study in mesothelioma reported to date. Patients randomized to the investigational pemetrexed/cisplatin treatment arm demonstrated a statistically significant improvement in clinical outcome, compared with those assigned to the cisplatin control arm, in terms of survival, time to disease progression, and response rate. Importantly, treatment with the pemetrexed/cisplatin combination was also found to result in improved pulmonary function and in improved patient-reported symptom scores and quality of life, compared with cisplatin-only treatment. Thus, this combination is the standard and only FDA-approved therapy for unresectable mesothelioma. Vitamin supplementation important The importance of folic acid and vitamin B 12 supplementation in patients treated with pemetrexed is highlighted in Vogelzang s study. Major toxicity, with three drug-related deaths, was seen in the first 43 patients (7%) recruited to the combination pemetrexed/cisplatin arm. Multivariate analyses of the outcomes of phase I and II studies in patients receiving pemetrexed demonstrated that deficiencies of folic acid and vitamin B 12 predicted an increased risk of various toxicities, including drugrelated death. 1 Elevated total plasma homocysteine (a marker of folic acid and also vitamin B 12 deficiency) levels were found to significantly predict severe thrombocytopenia, neutropenia, diarrhea, mucositis, and infection. Elevated methylmalonic levels (a specific marker of vitamin B 12 deficiency) predicted an increased risk of diarrhea and mucositis. These observations led to the recommendation that all patients treated with pemetrexed receive supplementation with a daily low oral dose of folic acid plus intramuscular injections of vitamin B 12 every 3 months. Folic acid and vitamin B 12 supplementation provided in this way not only reduces pemetrexed toxicity but also allows for the delivery of more cycles of pemetrexed chemotherapy and is associated with preserved or possibly increased efficacy. Reference 1. Niyikiza C, Hanauske AR, Rusthoven JJ, et al. Pemetrexed safety and dosing strategy. Semin Oncol 2002;29(suppl 18):24 29. Dr. Bunn (paul.bunn@uchsc.edu) is Grohne/ Stapp Professor and Director at the University of Colorado Cancer Center, Denver. Dr. Solomon (ben.solomon@uchsc.edu) is a fellow at the same institution. 61 years versus 60 years, respectively; 81.4% of the pemetrexed/cisplatin group were male versus 81.5% of the cisplatin-only group; 51.8% versus 56.3%, respectively, had a Karnofsky performance status of 90 100; 68.1% versus 68.5% had an epithelial histology; and 7.1%, 15.6%, 32.4%, and 45.1% of patients receiving combination therapy versus 6.3%, 15.0%, 30.9%, and 48.2% of those receiving cisplatin alone had stage I, II, III, and IV disease, respectively. In all, 226 patients in the pemetrexed/cisplatin treatment group versus 222 in the cisplatin-alone group constituted the intent-to-treat population. Of this population, 168 versus 163 received full vitamin supplementation, 26 versus 21 received partial supplementation, and 32 versus 38 received no supplementation. Baseline characteristics among these subgroups were also similar. Efficacy Median survival was 12.1 months in the pemetrexed/cisplatin treatment group, significantly greater than the median survival of 9.3 months in the group that received cisplatin only (P = 0.020; Figure 1). The hazard ratio for death in the pemetrexed/cisplatin arm, compared with that in the cisplatin-only arm, was 0.77. The difference in median survival did not quite reach significance among the patients receiving full vitamin supplementation (P = 0.051) but did so among all patients who received full or partial supplementation (P = 0.022). No difference between the subgroups who received no vitamin supplementation was observed, probably reflecting the small patient numbers in these two subgroups. Median time to disease progression was significantly longer (P < 0.01) in the pemetrexed/cisplatin treatment group among all patients, among those who received full vitamin supplementation, and among those with full or partial supplementation. The tumor response rate, assessed by se- 22 COMMUNITY ONCOLOGY January/February 2005 www.communityoncology.net
rial computed tomographic scanning, was significantly greater (P < 0.001) in the pemetrexed/cisplatin treatment group, that is the group receiving cisplatin only, among all patients, among patients who had full vitamin supplementation, and among those with full or partial supplementation. All responses to chemotherapy were partial responses. Safety Compared with cisplatin therapy alone, pemetrexed/cisplatin treatment was associated with a significantly higher incidence of grade 3 or 4 hematologic and non-hematologic toxicities among all patients, including significantly more grade 3 or 4 nausea, vomiting, diarrhea, dehydration, and stomatitis (Table 1). Vitamin supplementation, however, reduced the frequency of adverse events. Patients who received pemetrexed/cisplatin therapy with full vitamin supplementation had significantly fewer occurrences of neutropenia or neutropenia with infection, as well as other grade 3/4 toxicities, compared with similarly treated patients who had partial or no vitamin supplementation (Table 2). Patients with full or partial vitamin supplementation had significantly reduced frequencies of leukopenia, nausea, vomiting, and febrile neutropenia, compared with patients receiving no supplementation. Conclusion These findings indicate a clear superiority of pemetrexed/cisplatin therapy over cisplatin alone in terms of survival time, time to disease progression, and objective response rates in patients with malignant pleural mesothelioma, although there is some cost in terms of increased toxicity. The findings also indicate, however, that the addition of folic acid and vitamin B 12 to pemetrexed therapy can markedly reduce toxicity without adversely affecting its efficacy. TABLE 1 Incidence (%) of grade 3/4 toxicities observed in mesothelioma patients receiving pemetrexed/cisplatin versus cisplatin alone Pemetrexed/cisplatin Cisplatin alone Toxicity (n = 226) (n = 222) Neutropenia 27.9 2.3 Febrile neutropenia 1.8 0.0 Neutropenia with infection 1.3 0.5 Leukopenia 17.7 0.9 Anemia 4.8 0.0 Thrombocytopenia 5.8 0.0 Nausea 14.6 6.3 Vomiting 13.3 3.6 Fatigue 10.2 8.6 Diarrhea 4.4 0.0 Dehydration 4.0 0.5 Stomatitis 4.0 0.0 Anorexia 2.2 0.5 Rash 1.3 0.0 Adapted from Vogelzang et al 2 with permission from the American Society of Clinical Oncology. TABLE 2 Incidence (%) of grade 3/4 toxicities observed in mesothelioma patients receiving pemetrexed/cisplatin with full or no vitamin supplementation Full supplementation No supplementation Toxicity (n = 168) (n = 32) Neutropenia 23.2 37.5 Febrile neutropenia 0.6 9.4 Neutropenia with infection 0.0 6.3 Leukopenia 14.9 34.4 Anemia 4.2 9.4 Thrombocytopenia 5.4 9.4 Nausea 11.9 31.3 Vomiting 10.7 31.3 Fatigue 10.1 15.6 Diarrhea 3.6 9.4 Dehydration 4.1 6.3 Stomatitis 3.0 3.1 Anorexia 1.2 6.3 Rash 0.6 0.0 Adapted from Vogelzang et al 2 with permission from the American Society of Clinical Oncology. January/February 2005 COMMUNITY ONCOLOGY 23
Pemetrexed versus docetaxel as secondline therapy for NSCLC In the lung cancer trial, 3 571 patients who had received one prior chemotherapy regimen for advanced NSCLC and who had adequate organ function and an ECOG performance status of 0 2 were randomized to receive pemetrexed (500 mg/m² via a 10-minute infusion) or docetaxel (Taxotere; 75 mg/m² via a 1-hour infusion) on day 1 every 21 days. Patients receiving pemetrexed were instructed to take folic acid (350 1,000 µg orally) each day, beginning 1 2 weeks before the first dose of pemetrexed and continuing until 3 weeks after the last dose; in addition, a 1,000-µg vitamin B 12 injection was given intramuscularly 1 2 weeks before pemetrexed therapy was started and approximately every 9 weeks thereafter until study discontinuation. Dexamethasone (4 mg twice daily in the pemetrexed treatment group and 8 mg twice daily in the docetaxel treatment group) was administered the day before, the day of, and the day after study drug treatment to prevent skin rash. Baseline characteristics Both patient groups were well matched with regard to baseline characteristics: 68.6% of patients randomized to receive pemetrexed therapy versus 75.3% of those assigned to treatment with docetaxel were male; median age was 59 years versus 57 years, respectively; 88.6% versus 87.6% had an ECOG performance status of 0 or 1; 54.4% versus 49.3% had adenocarcinoma; 27.6% versus 32.3% had squamous cell cancer; 25.8% versus 27.8% had previously been treated with paclitaxel; and 44.2% versus 45.5% had received prior radiation therapy. Efficacy Objective response rates were 9.1% in the pemetrexed treatment FIGURE 2 Kaplan-Meier estimates of overall survival of patients given docetaxel versus pemetrexed as second-line therapy for non-small cell lung cancer. Reproduced from Hanna et al 3 with permission from the American Society of Clinical Oncology. arm and 8.8% in the docetaxel therapy arm, with stable disease occurring in 45.8% versus 46.4% of patients in both arms, respectively. Median disease progression-free survival was 2.9 months in each arm. Median survival was 8.3 months in the pemetrexed treatment arm versus 7.9 months in the docetaxel treatment arm, and the 1-year survival rate was 29.7% in each arm (Figure 2). The treatment groups did not differ significantly in any of these efficacy variables; however, a borderline significant improvement in median time to treatment failure was observed in the pemetrexed treatment group (2.3 months vs 2.1 months in the docetaxel group, P = 0.046). Safety Major differences in toxicity were observed between the two treatment arms (Table 3). Significantly more common in the docetaxel therapy arm were grade 3 or 4 neutropenia (40.2% vs 5.3%), febrile neutropenia (12.7% vs 1.9%), neutropenia with infection (3.3% vs 0.0%), hospitalizations for febrile neutropenia (13.4% vs 1.5%), use of colony-stimulating factor support (19.2% vs 2.6%), and alopecia (37.7% vs 6.4%). A grade 3 or 4 increase in serum alanine aminotransferase levels were observed in 1.9% of patients receiving pemetrexed, compared with none of the patients who received docetaxel. Conclusion These findings indicate that pemetrexed treatment is associated with equivalent efficacy and fewer adverse effects, compared with docetaxel, as second-line treatment of advanced NSCLC and suggest that pemetrexed should be considered a standard option in this setting. 24 COMMUNITY ONCOLOGY January/February 2005 www.communityoncology.net
TABLE 3 Incidence (%) of grade 3/4 toxicities observed in patients receiving pemetrexed or docetaxel as second-line treatment of advanced NSCLC Pemetrexed Docetaxel Toxicity/resource utilization (n = 265) (n = 276) P value a Neutropenia 5.3 40.2 < 0.001 Febrile neutropenia 1.9 12.7 < 0.001 Neutropenia with infection 0.0 3.3 0.004 Anemia 4.2 4.3 0.99 Thrombocytopenia 1.9 0.4 0.116 Hospitalizations and supportive care 1 Hospitalizations for 1.5 13.4 < 0.001 neutropenic fever Granulocyte or granulocyte- 2.6 19.2 < 0.001 macrophage colony-stimulating factor support Erythropoietin support 6.8 10.1 0.169 Red blood cell transfusion 16.6 11.6 0.108 Alopecia b 6.4 37.7 < 0.001 Fatigue 5.3 5.4 0.99 Nausea 2.6 1.8 0.57 Elevation in serum ALT level 1.9 0.0 0.028 a Fisher s exact test. b Any grade. ALT = alanine aminotranferase. Adapted from Hanna et al 3 with permission from the American Society of Clinical Oncology. References 1. Niyikiza C, Hanauske AR, Rusthoven JJ, et al. Pemetrexed safety and dosing strategy. Semin Oncol 2002;29(suppl 18):24 29. 2. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636 2644. 3. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non smallcell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589 1597. Pemetrexed: equivalent to docetaxel but less toxic Ben Solomon, MBBS, PhD, and Paul A. Bunn, Jr., MD University of Colorado Cancer Center, Denver HE PLACE OF DOCETAXEL (Taxotere) in the second-line treat- T ment of non-small cell lung cancer (NSCLC) has been firmly established by randomized studies in which docetaxel has been compared with best supportive care 1 or chemotherapy with vinorelbine or ifosfamide (Ifex). 2 The study of Hanna and colleagues described in this report utilized a non-inferiority statistical design to demonstrate the equivalence of pemetrexed (Alimta) with docetaxel in this setting. This multicenter study randomized 571 patients who had received one previous chemotherapy regimen to undergo treatment with either pemetrexed or docetaxel and represents the largest phase III study conducted to date in the second-line treatment of NSCLC. Treatment with pemetrexed resulted in efficacy equivalent to that of docetaxel, as measured by objective response rate, median disease progression-free survival, and median survival. Patientreported symptomatic improvement was largely equivalent in both treatment groups. However, treatment with pemetrexed, administered with concomitant folic acid and vitamin B 12 supplementation, was associated with less toxicity. Most significantly reduced rates of neutropenia and its related complications including febrile neutropenia and hospitalizations for neutropenic fever were seen in patients receiving pemetrexed. In addition, less alopecia was seen with pemetrexed than with docetaxel. This study establishes pemetrexed as a less-toxic alternative to docetaxel for the second-line treatment of patients with NSCLC and led to accelerated FDA approval of its use in this setting in July 2004. References 1. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000 18:2095 2103. 2. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non- Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354 2362. January/February 2005 COMMUNITY ONCOLOGY 25