A randomised phase II study of pemetrexed versus pemetrexed+erlotinib as second-line treatment for locally advanced or metastatic non-squamous non-small cell lung cancer.

INTRODUCTION: Pemetrexed and erlotinib have been approved as second-line monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). This multicentre, randomised, open-label, parallel phase II study assessed efficacy and safety of pemetrexed versus pemetrexed+erlotinib in patients with advanced non-squamous NSCLC. METHODS: NSCLC stage III-IV patients who failed one prior platinum-based chemotherapy regimen, ≥ 1 measurable lesion by Response Evaluation Criteria in Solid Tumors, and Eastern Cooperative Oncology Group performance status ≤ 2 were eligible. Patients received pemetrexed 500 mg/m(2) with vitamin B12 and folic acid q3w alone or combined with erlotinib 150 mg daily. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), time-to-treatment failure (TTTF), response and toxicity. RESULTS: Of 165 randomised non-squamous patients, 159 were treated (pemetrexed: 83; pemetrexed+erlotinib: 76). The median PFS (months; 95% CI) was 2.89 (1.94, 3.38) for pemetrexed versus 3.19 (2.86, 4.70) for pemetrexed+erlotinib (hazard ratio [HR] 0.63; 95% CI: (0.44, 0.90); P = 0.0047). The median OS (months; 95% CI) was 7.75 (5.29, 10.41) for pemetrexed versus 11.83 (8.18, 16.66) for pemetrexed+erlotinib (HR: 0.68; 95% CI: 0.46, 0.98; P = 0.019). The median TTTF (months: 95% CI) was 2.4 (1.74, 2.99) for pemetrexed versus 3.0 (2.23, 4.07) for pemetrexed+erlotinib (HR 0.64; 95% CI: 0.46, 0.89; P = 0.0034). One patient died in pemetrexed+erlotinib arm due to febrile neutropenia. Grades 3/4 drug-related toxicities (in ≥ 5% of patients) in pemetrexed/pemetrexed+erlotinib were febrile neutropenia (2.4%/10.5%), diarrhoea (1.2%/5.3%), rash (1.2%/9.2%); anaemia (6%/11.8%), leukopenia (9.6%/23.7%), neutropenia (9.6%/25.0%), and thrombocytopenia (4.8%/14.5%). CONCLUSIONS: Pemetrexed+erlotinib treatment significantly improved PFS, OS and TTTF in 2nd line non-squamous NSCLC and was associated with an increase in grade 3/4 toxicities compared with pemetrexed alone.

A randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as first-line therapy for patients with locally advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Pemetrexed plus cisplatin was approved for first-line treatment of non-small-cell lung cancer (NSCLC) in patients with nonsquamous histology after initiation of this study. This phase II study evaluated pemetrexed plus cisplatin and pemetrexed plus carboplatin as first-line treatments for stage IIIB/IV NSCLC. PATIENTS AND METHODS: The patients were randomized (1:1) to 2 parallel arms: pemetrexed (500 mg/m(2)) plus cisplatin (75 mg/m(2)) or pemetrexed (500 mg/m(2)) plus carboplatin (area under the curve 6) day 1 every 3 weeks (maximum, 6 cycles). Progression-free survival (PFS) was the primary objective; secondary objectives included overall survival (OS), 1-year survival, and safety. RESULTS: Sixty-five patients were randomized to each treatment arm. The patients treated with pemetrexed plus cisplatin had a median age of 64 years and were predominantly men (42 [64.6%]) with nonsquamous histology (53 [81.5%]), stage IV (61 [92.4%]) disease, and a performance status of 0 (40 [61.5%]). Median PFS was 6.0 months, 6-month PFS rate was 50.5%, median OS was 11.7 months, and 1-year survival rate was 47.5%. Drug-related grade 3/4 toxicities included neutropenia (11 [16.9%]), anemia (5 [7.7%]), thrombocytopenia (2 [3.1%]), and nausea (3 [4.6%]). Patients treated with pemetrexed plus carboplatin had a median age of 63 years, were predominantly men (46 [70.8%]) with nonsquamous histology (52 [80.0%]), stage IV (58 [86.6%]) disease, and a performance status of 0 (45 [69.2%]). The median PFS was 4.7 months, the 6-month PFS rate was 34.9%, median OS was 8.9 months, and 1-year survival rate was 39.2%. Drug-related grade 3/4 toxicities included neutropenia (17 [26.2%]), thrombocytopenia (11 [16.9%]), anemia (7 [10.8%]), and nausea (5 [7.7%]). CONCLUSIONS: Both the pemetrexed plus cisplatin and pemetrexed plus carboplatin arms met their primary endpoints and demonstrated efficacy and tolerability as first-line therapy in patients with advanced NSCLC. http://ClinicalTrials.gov: NCT00402051.

Observation of the treatment and outcomes of patients receiving chemotherapy for advanced NSCLC in Europe (ACTION study).

OBJECTIVE: The ACTION (Assessment of Cost and ouTcomes of chemotherapy In an Observational setting) study investigated associations between chemotherapy, patient/disease characteristics and outcomes in advanced non-small cell lung cancer (NSCLC) patients in clinical practice. RESEARCH DESIGN AND METHODS: Chemonaïve NSCLC patients from five European countries were observed for 18 months from initiation of first-line chemotherapy; care was at the physician's discretion. MAIN OUTCOME MEASURES: Survival and associated prognostic factors were estimated using Kaplan-Meier methods and a Cox proportional hazards model, respectively. Cluster analyses of baseline patient characteristics were also performed. Toxicity data were not considered in these analyses. RESULTS: A total of 975 eligible patients with NSCLC (Stage IIIb/IV) were enrolled and provided baseline and response data; cluster analysis was performed on 829 patients and survival data were available from 906 patients. In first-line treatment, a 39.8% response rate, a 39.5% 1-year survival rate and unadjusted median survival of 9.3 months were observed. Prognostic factors for survival included performance status (PS), number of metastatic organs, gender and age. Five patient clusters were identified, highlighting patient heterogeneity in terms of baseline condition and age. PS was maintained or improved throughout first-line and second-line chemotherapy in half the patients receiving these treatments. CONCLUSIONS: ACTION provides valuable information about patient population, disease characteristics, treatment choices, prescribing patterns and outcomes in routine clinical practice in advanced NSCLC in Europe. Our findings suggest that maintenance of PS after first and subsequent lines of chemotherapy, and survival rates may both be higher than previously anticipated. Our results also showed an association between age and survival, which suggests that age should not exclude patients from receiving chemotherapy if they meet all other eligibility criteria.

Pemetrexed in the treatment of malignant mesothelioma: results from an expanded access program in Germany.

An international expanded access program was initiated to provide access to treatment with pemetrexed prior registration and reimbursement for malignant mesothelioma (MM). Chemonaïve and pretreated patients with inoperable MM of the pleura or peritoneum were eligible. This report describes the results obtained in German centers. Investigators could choose between three treatments: Pemetrexed 500 mg/m(2) alone (P) or in combination with cisplatin 75 mg/m(2) (PC) or carboplatin AUC 5 (PCb). From November 2002 to June 2004, a total of 567 patients (554 with pleural MM; 41% pretreated) were included. Of 548 evaluable patients with pleural MM, 191 received P, 137 PC and 220 PCb. Patients in the P group were more often pretreated (70%) and had worse performance status compared with the other groups. In the P, PC, and PCb groups overall response rate (ORR) was 16%, 24% and 18%, median time to progression (TTP) was 5.5, 8.2, and 6.9 months, and median overall survival (OS) was 8.7, 11.3 and 9.7 months respectively. Efficacy outcomes were better for chemonaïve than for pretreated patients, and P was less hematotoxic than PC or PCb. Treatment of pleural MM with pemetrexed alone or in combination with platinum was safe and active as first and second-line therapy.

[Gemcitabine in the first line therapy of advanced and metastatic non-small-cell lung carcinoma (NSCLC): review of the results of phase III studies]. / Gemcitabin in der First-line-Therapie des lokal fortgeschrittenen und metastasierten nicht-kleinzelligen Bronchialkarzinoms (NSCLC): Ergebnisübersicht randomisierter Phase-III-Studien.

Modern platinum-based combination therapies containing gemcitabine, vinorelbine or taxanes produce response rates of 30-40%, median survival times of 8-10 months and 1-year survival rates of approximately 35% in patients with advanced non-small-cell lung cancer (NSCLC). Of the new drugs available, gemcitabine (Gemzar, Lilly, Bad Homburg, Germany) has been the most extensively researched in clinical trials and exhibits a consistent database. A total of 37 randomized phase III trials involving more than 15,000 patients have been published to evaluate gemcitabine as first-line therapy for treating locally advanced and/or metastatic NSCLC. One trial studied gemcitabine exclusively as a single agent and another four trials investigated the drug in monotherapy and combination therapy. Of the 36 combination treatment studies, 21 included gemcitabine plus cisplatin treatment arms, 6 investigated gemcitabine plus carboplatin, and another 12 evaluated platinum-free gemcitabine combinations with other third generation cytostatic agents (multiple nominations possible). In single-agent treatment, gemcitabine was similarly effective to older platinum-based combinations such as vindesine-cisplatin but was less toxic. Thrombocytopenia was the main dose-limiting toxicity but was rarely clinically relevant. A 3-week cycle with gemcitabine on days 1 and 8 was confirmed as being the most convenient of the gemcitabine-based combinations studied. No other modern platinum-based doublet with vinorelbine or taxanes was superior to gemcitabine plus cisplatin in terms of survival or time to progression in any of the eight phase III studies performed. These results are consistent with previous phase II data and with a recent meta-analysis of 11 phase III and 2 randomized phase II studies involving more than 4,500 patients (1,861 in gemcitabine-based treatment arms). This meta-analysis also demonstrated a statistically significant benefit regarding overall and progression-free survival for gemcitabine-platinum- based regimens compared with other platinum combinations. In summary, currently available data indicate that gemcitabine-platinum 2-agent combinations given in 3-week cycles may at present have the best benefit-risk ratio in the treatment of advanced NSCLC. In contrast, platinum based 3-agent schedules do not offer any survival benefit. In elderly patients with poor performance status single agent treatment with a modern cytotoxic agent should be considered. Furthermore, according to the experiences from phase III studies so far, platinum- free combinations open up the possibility of a more feasible and clinically practical, active and well tolerated treatment which is associated with a positive impact on patient quality of life.

Lowering of microalbuminuria in diabetic patients by a sympathicoplegic agent: novel approach to prevent progression of diabetic nephropathy?

There is convincing evidence for a specific BP-independent effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on albuminuria in glomerular disease. Because progression of glomerular disease is not consistently halted by these agents, there is a need to explore potential renoprotective effects of other drugs. Recent animal work documented that nonhypotensive doses of moxonidine, a sympathicoplegic agent, reduce albuminuria and development of glomerulosclerosis in a BP-independent manner. A randomized, crossover design was used to assess the human relevance of the experimental data in 15 normotensive, nonsmoking type 1 diabetic mellitus patients with good glycemic control (age, 37.3 +/- 6.6 yr; 9 men/6 women; duration of diabetes, 23.6 +/- 5.1 yr) with baseline urinary albumin excretion rates (AER) >20 microg/min in the run-in phase. AER was assessed in overnight timed urine collections. The patients were assigned to a 3-wk placebo and a 3-wk moxonidine (0.2 mg twice a day) period, respectively, in random order. This dose causes modest BP lowering in hypertensive individuals but does not affect BP in normotensive individuals. There was no significant effect on ambulatory BP (mean arterial pressure, 91.8 +/- 7.1 mmHg in the third week of placebo and 91.1 +/- 8.7 mm Hg on moxonidine). There was a significant (P< 0.006) difference of the treatment effects between placebo and moxonidine, respectively, on AER; median AER at the end of the placebo period was 39.8 microg/min (range, 15.9 to 117 microg/min) versus 29.0 (range, 9.03 to 85.8 microg/min) at the end of the moxonidine period. The data document an antialbuminuric effect of nonhypotensive doses of moxonidine. Diminished sympathetic traffic to the kidney is the most plausible explanation for the finding.